Targeting cAMP/PKA pathway for glycemic control and type 2 diabetes therapy

in Journal of Molecular Endocrinology
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  • 1 Division of Endocrinology, Zhengzhou Children’s Hospital, Zhengzhou, Henan, China
  • 2 Department of Pharmacology, University of Washington, Seattle, Washington, USA

In mammals, cyclic adenosine monophosphate (cAMP) is an intracellular second messenger that is usually elicited by binding of hormones and neurotransmitters to G protein-coupled receptors (GPCRs). cAMP exerts many of its physiological effects by activating cAMP-dependent protein kinase (PKA), which in turn phosphorylates and regulates the functions of downstream protein targets including ion channels, enzymes, and transcription factors. cAMP/PKA signaling pathway regulates glucose homeostasis at multiple levels including insulin and glucagon secretion, glucose uptake, glycogen synthesis and breakdown, gluconeogenesis, and neural control of glucose homeostasis. This review summarizes recent genetic and pharmacological studies concerning the regulation of glucose homeostasis by cAMP/PKA in pancreas, liver, skeletal muscle, adipose tissues, and brain. We also discuss the strategies for targeting cAMP/PKA pathway for research and potential therapeutic treatment of type 2 diabetes mellitus (T2D).

Abstract

In mammals, cyclic adenosine monophosphate (cAMP) is an intracellular second messenger that is usually elicited by binding of hormones and neurotransmitters to G protein-coupled receptors (GPCRs). cAMP exerts many of its physiological effects by activating cAMP-dependent protein kinase (PKA), which in turn phosphorylates and regulates the functions of downstream protein targets including ion channels, enzymes, and transcription factors. cAMP/PKA signaling pathway regulates glucose homeostasis at multiple levels including insulin and glucagon secretion, glucose uptake, glycogen synthesis and breakdown, gluconeogenesis, and neural control of glucose homeostasis. This review summarizes recent genetic and pharmacological studies concerning the regulation of glucose homeostasis by cAMP/PKA in pancreas, liver, skeletal muscle, adipose tissues, and brain. We also discuss the strategies for targeting cAMP/PKA pathway for research and potential therapeutic treatment of type 2 diabetes mellitus (T2D).

cAMP/PKA pathway

cAMP was initially discovered as an intracellular mediator of the glycogenolytic effect of glucagon and epinephrine in the liver (Berthet et al. 1957). It was later revealed in skeletal muscle that the glycogenolytic effect of cAMP depends on a cascade of protein phosphorylation: cAMP/PKA-phosphorylase kinase-glycogen phosphorylase-glycogen degradation, which was a breakthrough discovery in biochemistry showing that protein phosphorylation is a regulatory mechanism for enzyme activity. The 1992 Nobel Prize in Physiology or Medicine was awarded to Edwin Krebs and Edmond Fischer for their discovery of this phosphorylation cascade. The major receptors for cAMP in mammals are PKA regulatory (R) subunits and exchange proteins directly activated by cAMP (Epac). The role of Epac in the regulation of metabolism has been recently reviewed (Almahariq et al. 2014). The physiological role of PKA in glucose metabolism is increasingly appreciated with the availability of genetically modified mice and pharmacological evidence.

In cells, cAMP is synthesized from adenosine triphosphate (ATP) catalyzed by adenylyl cyclase (AC), which is activated by stimulatory Gα protein (Gsα) following the activation of Gs protein-coupled receptors (Fig. 1). The termination of cAMP signaling is mediated by the conversion of cAMP to AMP by phosphodiesterases (PDEs) (Furman et al. 2010). PKA is a serine/threonine kinase and the holoenzyme is inactive and formed by a dimer of two regulatory (R) subunits that each binds a catalytic (C) subunit (Krebs & Beavo 1979). Each R subunit contains two cAMP binding sites, and cAMP binding leads to conformational changes in the R subunits and release of the active C subunits. Four types of R subunits (RIα, RIβ, RIIα, and RIIβ) and two types of C subunits (Cα and Cβ) have been identified in mice to be encoded by different genes. In human, a third C subunit (Cγ) gene has been identified specifically in testes and postulated to be a retroposon of the Cα gene (Beebe et al. 1990, Reinton et al. 1998). In general, the α isoforms of RI, RII, and C subunits are expressed in all tissues, whereas β isoforms show more restricted expression. Type I PKA holoenzymes contain homodimers of RIα or RIβ subunits and are activated at a lower cAMP level compared with type II holoenzymes containing homodimers of RIIα or RIIβ subunits. The subcellular localization of PKA is dependent on the binding of R subunits to A kinase anchoring proteins (AKAPs), which generally show higher affinity for type II holoenzymes (Tasken & Aandahl 2004). Binding to AKAPs is essential for the spatial and temporal regulation of cAMP/PKA signaling (Fig. 1) (Smith et al. 2006, Pidoux & Tasken 2010). Mice with global or conditional mutants of R subunits, C subunits, or AKAPs have been generated (Kirschner et al. 2009) and greatly enhanced our understanding of the role of cAMP/PKA in different physiological and pathological processes, such as neural synaptic plasticity (Rosenmund et al. 1994), cardiac hypertrophy (Antos et al. 2001, Enns et al. 2010), tumor progression (Kirschner et al. 2000), and glucose homeostasis (Niswender et al. 2005, Willis et al. 2011).

Figure 1
Figure 1

cAMP/PKA signaling pathway in mammalian cells. The activation of cAMP/PKA signaling starts from ligand-dependent activation of the G protein-coupled receptors (GPCRs) and is followed by Gsα activation, adenylyl cyclase (AC) activation, and cAMP generation. cAMP activates PKA by binding to PKA regulatory subunits (RIs or RIIs). The PKA catalytic subunits (C) are then released from the PKA tetramer to phosphorylate targets in the cytoplasm, in the plasma membrane (CaV, KATP, etc.), and in the nucleus (CREB). The subcellular localization of PKA is dependent on binding of R subunits to different A-kinase anchoring proteins (AKAPs). The termination of cAMP signaling is dependent on phosphodiesterases (PDEs)-mediated degradation of cAMP to AMP. A full colour version of this figure is available at http://dx.doi.org/10.1530/JME-15-0316.

Citation: Journal of Molecular Endocrinology 57, 2; 10.1530/JME-15-0316

Blood glucose is regulated by coordinated actions of different tissues, especially the pancreatic islet, liver, skeletal muscle, fat, and the brain (Fig. 2). This review discusses how cAMP/PKA signaling in each of these tissues affects glucose homeostasis and potential strategies targeting this pathway for glycemic control.

Figure 2
Figure 2

Glucose homeostasis is regulated by the coordinated actions of various organs. Glucose inputs from food absorption and hepatic release can be either inhibited or increased by neural signals from the brain. Hepatic glucose production (HGP) is increased by glucagon during fasting and inhibited by insulin after food absorption. Insulin also lowers blood glucose by stimulating its uptake into various tissues, mainly muscle and fat tissue. Glucose uptake by liver and brain does not require insulin (not shown). The secretions of glucagon and insulin by pancreatic α and β cells, respectively, are regulated by glucose and hormones.

Citation: Journal of Molecular Endocrinology 57, 2; 10.1530/JME-15-0316

cAMP/PKA in pancreatic islets

β cell

A hallmark of T2D is an early defect in glucose-stimulated insulin secretion from pancreatic β cells (Nolan et al. 2011). Following a meal, glucose levels in the circulation increase, leading to increased uptake of glucose into β cells via the glucose transporter GLUT2. Increased intracellular glucose then leads to production of ATP and inactivation of the ATP-sensitive potassium channel (KATP) and depolarization of the cell. Cell depolarization activates voltage-gated calcium channel (Cav) on the plasma membrane and calcium influx into β cells. Accumulation of Ca2+ in the cell then promotes insulin secretion via exocytosis. Subsequently, insulin circulates and acts on a variety of tissues, mainly fat, muscle, and liver, to increase glucose uptake and inhibit glucose production. This process is essential for postprandial glycemic control.

Although glucose is the primary regulator for insulin secretion, many hormones and neurotransmitters such as glucagon, glucagon-like peptide 1 (GLP1), epinephrine, and norepinephrine can either enhance or suppress insulin secretion through GPCRs on β cells (Ahren 2009). cAMP/PKA pathway acts downstream of the GPCRs and regulates the activities of key molecules involved in insulin secretion, including GLUT2, KATP, and Cav (Fig. 3A). It has been shown that GLUT2 is phosphorylated at multiple sites in the carboxyl-terminal domain by PKA following either forskolin or GLP1 stimulation of β cells (Thorens et al. 1996). PKA-dependent phosphorylation suppresses the catalytic activity of GLUT2 and reduces glucose uptake into β cells (Thorens et al. 1996). However, because activation of PKA potentiates glucose-induced insulin release, these results suggest that phosphorylation of GLUT2 may regulate insulin secretion independent of its transporter activity (Hughes et al. 1993).

Figure 3
Figure 3

Schematic illustration of the regulation of glucose homeostasis by cAMP/PKA pathway in pancreatic β cell, hepatocyte, and adipocyte. (A) Regulation of insulin production by cAMP/PKA signaling in pancreatic β cell. Upon stimulation by incretins such as glucagon-like peptide 1 (GLP1), PKA is activated to promote insulin transcription and secretion by phosphorylating the transcription factor CREB, ATP-sensitive potassium channel (KATP), glucose transporter GLUT2, L-type voltage-gated calcium channels (LTCC), and secretory vesicle-associated protein snapin. Activated CREB promotes the expression of MAFA, a transcription factor that stimulates the expression of insulin. In conditions of long-term hyperglycemia, insulin secretion is impaired at least partially due to the induction of the intrinsic PKA inhibitor B (PKIB). The effect of PKA on insulin release is also dependent on its subcellular localization that is determined by binding to A-kinase anchoring proteins (AKAPs). (B) Regulation of hepatic glucose production by cAMP/PKA. During a fasting, cAMP/PKA is activated in hepatocytes by glucagon and epinephrine binding to GPCRs. PKA inhibits glycogen synthesis and increases glycogenolysis and gluconeogenesis by phosphorylating glycogen synthase, glycogen phosphorylase kinase (PhK), and phosphofructokinase-2/fructose-2,6-bisphosphatase (PFK2/F-2,6-BPase), respectively (see text for detail). At the transcription level, PKA promotes the expression of gluconeogenic genes such as phosphoenolpyruvate carboxykinase (PEPCK), glucose-6-phosphatase (G6Pase), and PPARγ coactivator-1α (PGC1α) by CREB phosphorylation. PKA also promotes the nuclear import of cAMP-regulated transcriptional coactivator 2 (CRTC2) by stimulating its dephosphorylation (through IP3 receptor (IP3R)-calcium-calcineurin (CaN) pathway) and inhibiting its phosphorylation (through phosphorylation and inhibition of salt-inducible kinase SIK2). Insulin and metformin suppress hepatic glucose production at least partially by stimulating the activation of phosphodiesterase (PDE) and downregulation of cAMP signaling. Metformin also increases cellular AMP to inhibit adenylyl cyclase (AC) and thus suppresses cAMP synthesis. (C) Regulation of lipolysis in adipocyte. Glucagon and epinephrine increase lipolysis in adipocytes by stimulating PKA-dependent phosphorylation of lipid droplet-associated protein perilipin A, hormone-sensitive lipase (HSL), and adipose triglyceride lipase (ATGL). Insulin promotes glucose uptake and de novo lipogenesis, and inhibits lipolysis by activating PDE3B to suppress cAMP/PKA signaling. Metformin inhibits lipolysis by downregulation of the cAMP/PKA pathway in adipocytes, probably also via AMP and PDE activation. TAG, triacylglycerol; DAG, diacylglycerol; MAG, monoacylglycerol; FFA, free fatty acid.

Citation: Journal of Molecular Endocrinology 57, 2; 10.1530/JME-15-0316

KATP channels serve to couple cellular metabolism to electrical excitability in pancreatic β cells and are the targets for sulfonylureas, a group of antidiabetic drugs. KATP channels are regulated by receptor-mediated signals that modulate insulin release, including the cAMP/PKA pathway (Beguin et al. 1999, Chen et al. 2013). PKA-dependent phosphorylation of KATP channels at S1448 in the SUR1 subunit inactivates the channels in an ADP-dependent manner and is required for GLP1 stimulation of insulin secretion (Light et al. 2002). In another scenario, however, leptin-induced PKA activation in β cells promotes KATP trafficking to the plasma membrane, increases potassium current, and inhibits insulin release (Chen et al. 2013). Thus, under different conditions, cAMP/PKA activation may have either positive or negative effect on insulin release through KATP regulation, although it remains unknown if leptin treatment also leads to increased phosphorylation of KATP channels by PKA. This discrepancy can be due to that GLP1 and leptin activate distinct PKA pools that have different subcellular localizations and downstream targets within β cells.

Multiple types of Cav channels have been identified in pancreatic β cells and play essential roles in insulin secretion as well as β cell development, survival, and growth (Yang & Berggren 2006). L-type Cav1.2 and Cav1.3 are the major mediators of Cav current in β cell from many species tested (Sinnegger-Brauns et al. 2004, Yang & Berggren 2006). In human patients with Timothy syndrome, a G406R point mutation in Cav1.2 increases the channel activity and can lead to excessive insulin secretion and life-threatening hypoglycemia (Splawski et al. 2004). PKA-dependent phosphorylation of Cav1.2 increases channel activity although the exact PKA site responsible for the regulation remains elusive (Weiss et al. 2013). The potentiation of insulin secretion by cAMP is at least partially through PKA-mediated phosphorylation of Cav channels and increased Ca2+ influx (Ammala et al. 1993). More important, PKA can directly enhance insulin exocytosis through phosphorylating secretory granule-associated proteins such as snapin and synaptotagmin (Fig. 3A) (Seino & Shibasaki 2005, Song et al. 2011, Wu et al. 2015) to increase Ca2+ responsiveness, and this mechanism may account for the majority of PKA’s effect on insulin release (Ammala et al. 1993).

RIα-PKA is the most abundant subtype of PKA in mouse pancreatic islets (Petyuk et al. 2008). Selective ablation of RIα in β cells leads to disinhibition of PKA and increased phosphorylation of the transcription factor cAMP-response element-binding protein (CREB) (Song et al. 2011). Mice with RIα ablation in β cells show greatly enhanced glucose-stimulated insulin secretion and increased glucose tolerance (Song et al. 2011, Hussain et al. 2012). More importantly, human patients with heterozygous RIα-inactivating mutation (Carney’s complex) also showed increased insulin release during oral glucose tolerance test (Song et al. 2011). Another strategy to increase β cell PKA activity is the selective expression of a constitutively active PKA Cα subunit in β cells. It has been shown that this enhances both acute and sustained glucose-stimulated insulin release (Kaihara et al. 2013) and improves glucose control in mouse models with diet-induced insulin resistance or streptozotocin-mediated glucose intolerance (Kaihara et al. 2015). Importantly, the enhanced insulin release by either RIα ablation or constitutively active mutant Cα expression in β cells is not associated with hypoglycemia, suggesting that pancreatic PKA can be a safe target for potential T2D drug development.

By contrast, β cell-selective deletion of Gsα in mice leads to severely impaired β cell proliferation and reduced insulin expression, accompanied by hyperglycemia and glucose intolerance (Xie et al. 2007), suggesting that cAMP signaling is indispensable for β cell physiology. A recent study has shown that cAMP/PKA/CREB signaling promotes insulin transcription by stimulating the expression of transcription factor MAFA (Fig. 3A) (Blanchet et al. 2015). Under conditions of chronic hyperglycemia, PKA signaling is disrupted and insulin expression is suppressed due to the induction of PKA inhibitor B (PKIB) in β cells. Mice overexpressing PKIB in pancreatic islets are relatively glucose intolerant and have lower circulating concentrations of insulin during oral glucose tolerance test, whereas Pkib-knockout mice are protected from high-fat diet-induced glucose intolerance and impairment in insulin release (Blanchet et al. 2015). These results suggested that dysfunctional PKA was involved in the deterioration of β cell function during transition from insulin resistance to T2D. Indeed, in patients with T2D, PKIs appear to be upregulated in pancreatic islets (Gunton et al. 2005), suggesting that reducing the expression of PKI can be therapeutically beneficial.

The subcellular localization of PKA in pancreatic β cells is also essential for its regulation of insulin secretion and several AKAPs have been identified in β cells (Tasken & Aandahl 2004). Disruption of PKA anchoring to AKAPs with inhibitory peptides suppresses GLP1- and cAMP-induced insulin secretion in pancreatic β cells concurrent with decreased Ca2+ accumulation in the cytoplasm (Lester et al. 1997), suggesting that PKA anchoring is required for the regulation of Cav channel activity, Ca2+ influx, or Ca2+ release from internal stores. Selective ablation of AKAP150 in β cells leads to reduced L-type Ca2+ influx, suppressed glucose-induced insulin secretion, and impaired glucose tolerance in mice (Hinke et al. 2012), indicating that AKAP150 is required for proper PKA localization in β cells. It should be noted that AKAP150 binds type II-PKA (RIIα and RIIβ) with much higher affinity than RIα (Herberg et al. 2000), suggesting that, in addition to RIα-PKA (Hussain et al. 2012), type II PKA may also be involved in the process of insulin secretion. Although RIα is usually considered soluble, dual-specific AKAPs (Jarnaess et al. 2008) that bind both RI and RII subunits and RI-specific AKAPs (Means et al. 2011, Burgers et al. 2012) have been identified. It remains unknown if such an AKAP exists in pancreatic β cells to mediate the regulation of insulin secretion by RIα-PKA.

α cell

The whole-body glucose homeostasis is largely dependent on the coordinated secretion of insulin and glucagon by β cells and α cells, respectively, in pancreatic islets (Fig. 2). As opposed to insulin, glucagon secretion is increased during fasting to increase blood glucose. The hyperglycemia in diabetic patients has been associated with excessive glucagon levels in the circulation that lead to increased hepatic glucose production (Dunning & Gerich 2007). Glucagon expression and secretion are regulated by multiple factors including glucose, fatty acids, amino acids, hormones, and neurotransmitters (Quesada et al. 2008). At the transcription level, glucagon expression is promoted by cAMP/PKA/CREB pathway (Knepel et al. 1990, Miller et al. 1993). Somatostatin inhibits the transcription of glucagon potentially by suppressing the cAMP/PKA pathway in a pancreatic cell line (Kendall et al. 1995). Through a positive autocrine feedback mechanism, glucagon increases its own transcription (Leibiger et al. 2012) and secretion (Ma et al. 2005) by stimulating the glucagon receptor/cAMP/PKA/CREB pathway in mouse and human pancreatic islets.

In contrast to its inhibitory effects on β cell proliferation and insulin production (Xie et al. 2007), Gsα deficiency promotes the proliferation of α cells without effect on the transcription and serum level of glucagon in mice with pancreas-selective deletion of Gsα (Xie et al. 2010). Normal glucagon expression in the presence of increased α cell numbers suggests that the expression of glucagon per cell is decreased due to Gsα deficiency, indicating that cAMP signaling may have opposite effects on α cell proliferation and glucagon expression.

Similar to insulin, glucagon secretion via exocytosis is also dependent on Ca2+. At basal conditions, low glucose-induced glucagon secretion requires Ca2+ influx via N-type Ca2+ channels (Gromada et al. 1997). In isolated rat α cells, GLP1 stimulates glucagon secretion by activating cAMP/PKA (Ding et al. 1997). However, in whole animal and perfused islets, GLP1 inhibits glucagon secretion also in a PKA-dependent manner (Dunning et al. 2005), suggesting that the stimulation of glucagon secretion from isolated α cells is not a physiological effect of GLP1. Further study revealed that the inhibitory effect of GLP1 on glucagon secretion is dependent on PKA-induced phosphorylation and inactivation of N-type Ca2+ channels on α cells (De Marinis et al. 2010). Under conditions with higher cAMP production in the cell, such as during fasting or with adrenaline stimulation, both PKA and Epac are activated and L-type Ca2+ channels are activated and become the major Ca2+ conduit. As a result, glucagon secretion is enhanced (Gromada et al. 1997, De Marinis et al. 2010). This binary regulation of glucagon secretion by GLP1 and adrenaline-elicited cAMP signaling is likely related to the activation of PKA with distinct subcellular localizations within α cells.

cAMP/PKA in the liver

One essential function of liver is to store and produce glucose to meet the body’s needs. Liver is one of the two major sites (another one is skeletal muscle) for glycogen storage and is the main site for glucose release into the circulation during a fasting (Fig. 2). Two main processes contribute to hepatic glucose production (HGP): glycogenolysis and gluconeogenesis. cAMP/PKA signaling in hepatocytes regulates both processes and the synthesis of glycogen as well (Fig. 3B). As stated above, when blood glucose levels drop during an energy deficit, PKA is activated by the binding of glucagon and epinephrine to their Gs-coupled receptors on hepatocytes and acts as the upstream kinase for glycogen phosphorylase kinase (PhK) to promote glycogenolysis in the liver (Berthet et al. 1957). Meanwhile, PKA can phosphorylate glycogen synthase to inhibit its activity and thus suppress the synthesis of glycogen (Proud et al. 1977). When the state of energy deficiency continues, glycogen is depleted and gluconeogenesis is increased to meet the body’s glucose demand. The master hormone that promotes gluconeogenesis is glucagon. In hepatocytes, glucagon-induced cAMP/PKA activation promotes gluconeogenesis at multiple levels. A rate-limiting enzyme for gluconeogenesis is fructose-1,6-bisphosphatase (F-1,6-BPase) whose activity is suppressed by the powerful negative allosteric effector fructose-2,6-bisphosphate (F-2,6-BP). The level of F-2,6-BP in hepatocytes is determined by the bifunctional enzyme phosphofructokinase-2/fructose-2,6-bisphosphatase (PFK2/F-2,6-BPase). PKA phosphorylation of the enzyme turns on the F-2,6-BPase activity leading to dephosphorylation of F-2,6-BP and concomitant increases in F-1,6-BPase activity and gluconeogenesis (Rider et al. 2004). At the level of gene expression, activation of the cAMP/PKA/CREB pathway promotes the expression of several key enzymes and factors to increase gluconeogenesis, including phosphoenolpyruvate carboxykinase (PEPCK) (Quinn 1994, Leahy et al. 1999, Yang et al. 2009), glucose-6-phosphatase (G6Pase) (Streeper et al. 2001), and PPARγ coactivator-1α (PGC-1α) (Herzig et al. 2001, Fernandez-Marcos & Auwerx 2011). PEPCK and G6Pase are two rate-limiting enzymes for gluconeogenesis. Overexpression of PEPCK in mice leads to increased hepatic glucose production and impaired insulin sensitivity in the liver (Sun et al. 2002). Increased Pepck mRNA levels have been observed in several animal models of T2D and also in human T2D patients (Hanson & Reshef 1997), although probably not in all T2D patients (Samuel et al. 2009). Increased expression of G6Pase in the liver is also associated with diabetes (Haber et al. 1995, van Schaftingen & Gerin 2002). PGC1α is a transcriptional coactivator that plays a central role in the regulation of energy metabolism (Liang & Ward 2006). In hepatocytes, PGC1α interacts with other factors such as FOXO1 (Puigserver et al. 2003) to increase the expression of gluconeogenic genes. On the other hand, insulin inhibits hepatic gluconeogenesis at least partially through suppressing cAMP/PKA/CREB pathway to inhibit the expression of PEPCK, G6Pase, and PGC1α (Fig. 3B) (Park et al. 1972, He et al. 2009).

Another PKA target that is involved in the regulation of hepatic gluconeogenesis is inositol-1,4,5-trisphosphate receptor (IP3R), which forms the main channels for Ca2+ release from endoplasmic reticulum (ER) (Fig. 3B) (Wang et al. 2012). PKA-dependent phosphorylation of IP3Rs increases Ca2+ release and activates the protein phosphatase calcineurin which in turn dephosphorylates cAMP-regulated transcriptional coactivator 2 (CRTC2). Dephosphorylated CRTC2 translocates to the nucleus, where it binds to CREB and stimulates the transcription of gluconeogenic genes. PKA can also promote the activity of CRTC2 by phosphorylation and inactivation of salt-inducible kinase 2 (SIK2) (Altarejos & Montminy 2011), which phosphorylates CRTC2 and promotes its translocation out of the nucleus.

Hyperglucagonemia-induced increase in liver gluconeogenesis is considered as the main cause of fasting hyperglycemia in T2D (Consoli 1992). Recently, it was shown that metformin, the most widely prescribed T2D medicine, suppresses gluconeogenesis by inhibiting hepatic cAMP/PKA pathway, in addition to the activation of AMP-activated protein kinase (AMPK) (Miller et al. 2013). The study showed that metformin increased cellular level of AMP, which directly inhibited the activity of adenylyl cyclase (Fig. 3B) to suppress glucagon-induced cAMP production and PKA activation. The phosphorylation of two key PKA substrates that promote gluconeogenesis, PFK2 and IP3R, were both reduced after metformin treatment (Miller et al. 2013). Moreover, a recent study has shown that hepatic AMPK can phosphorylate and activate PDE4B to suppress glucagon-mediated cAMP/PKA activation (Johanns et al. 2016), suggesting that metformin inhibits hepatic PKA via multiple pathways. Another study showed that selective inactivation of NF-κB in mouse liver enhanced insulin sensitivity and suppressed hepatic gluconeogenesis also via inhibition of the cAMP/PKA/CREB pathway (Ke et al. 2015). These studies suggest that cAMP/PKA is the major positive regulator for hepatic gluconeogenesis.

Mice with selective expression of a constitutively active PKA CαR subunit in hepatic cells exhibit decreased levels of liver glycogen, F-2,6-BP content, and glucokinase expression in the fed state, indicating suppressed glycogen synthesis and increased glycogenolysis and gluconeogenesis (Niswender et al. 2005). These mice exhibit fasting hyperglycemia, impaired glucose tolerance, and defective glucose-induced insulin release (Niswender et al. 2005), suggesting the presence of crosstalk between liver and pancreatic islets. By contrast, mice with selective expression of a dominant-negative PKA RIαB subunit in hepatic cells exhibit enhanced glucose disposal in glucose-tolerance test, suggesting improved insulin sensitivity in the liver (Willis et al. 2011). The expression of PGC1α, PEPCK, and G6Pase is unchanged despite of dramatically reduced PKA activity in the liver (Willis et al. 2011). The normal levels of expression of gluconeogenic genes in the liver with either CαR or RIαB expression suggest the existence of compensatory mechanisms during animal development. Temporally conditional manipulations of PKA activity in the liver would be ideal for studying the role of PKA in hepatic gluconeogenic gene expression at the physiological level. Consistent with the effect of RIαB, liver-specific knockout of Gsα in mice leads to improved glucose tolerance and increased insulin sensitivity in liver and skeletal muscle. These mice also had increased glycogen content and decreased expression of gluconeogenic genes in the liver, accompanied by hypoglycemia and more than 100-fold higher blood glucagon levels compared with controls (Chen et al. 2005b), indicating a condition of glucagon resistance. Recently, it was shown that mice with deficiency of the RIIα subunit of PKA had decreased PKA activity in the liver and showed resistance to diet-induced insulin resistance and diabetes (London et al. 2014). Collectively, these studies indicate that cAMP/PKA inhibition is not only sufficient but also necessary for efficient insulin-induced synthesis of glycogen and suppression of HGP.

cAMP/PKA in skeletal muscle

Signals via cAMP/PKA pathway control the development (Chen et al. 2005a, Knight & Kothary 2011) and metabolism (Berdeaux & Stewart 2012) of skeletal muscle, which plays an essential role in the regulation of glucose homeostasis (Stump et al. 2006). As mentioned above, liver and skeletal muscle are the major sites for glycogen storage. In humans, about 80% of the glycogen is stored in skeletal muscles (Jensen et al. 2011) because of their much greater mass than the liver. Unlike liver, however, skeletal muscles are unable to release glucose into the blood because muscles lack glucose 6-phosphatase and muscle glycogen is mainly a local energy source for exercise. Exercise-induced glycogen depletion is largely induced by activation of the β-adrenergic receptor (βAR)/cAMP/PKA signaling pathway (Goldfarb et al. 1989). Consistently, exercise is able to increase cAMP level and PKA activity in skeletal muscle (Mehrani & Storey 1993). Skeletal muscles mainly express β2-AR and adrenaline promotes glycogen breakdown through PKA-dependent activation of glycogen phosphorylase and inactivation of glycogen synthase (Cohen 2002). Exercise-induced depletion of muscle glycogen can increase skeletal muscle insulin sensitivity and enhance glycemic control (Jensen et al. 2011).

Skeletal muscle is the major site for insulin-mediated glucose uptake in the postprandial state in humans (DeFronzo et al. 1981, Thiebaud et al. 1982). Skeletal muscle insulin resistance has been suggested as the primary defect in T2D and plays an essential role in the pathogenesis of the disease (DeFronzo & Tripathy 2009). Insulin stimulates skeletal muscle glucose uptake by increasing translocation of glucose transporter GLUT4 from intracellular vesicles to the plasma membrane and transverse tubules (Zisman et al. 2000). Insulin also increases the synthesis of muscle glycogen by activating glycogen synthase (Cohen 1993). These effects of insulin are at least partially dependent on suppression of muscle PKA activity, and diabetes has been associated with the failure of insulin to inhibit PKA activity in skeletal muscle (Ortmeyer 1997).

Thus, insulin signaling and βAR/cAMP/PKA signaling appear to reciprocally regulate each other and have opposite effects on glucose metabolism in skeletal muscle. This is supported by studies showing that epinephrine or norepinephrine inhibits insulin-induced glucose uptake in skeletal muscle (Chiasson et al. 1981, Lembo et al. 1994), while blockade of βAR activity increases GLUT4 expression in skeletal muscle and improves insulin sensitivity in diabetic animals (Alves-Wagner et al. 2015). Mice with βAR deficiency exhibit increased peripheral insulin sensitivity despite of systemic glucose intolerance because of defective insulin secretion (Asensio et al. 2005). Genetic deletion of adenylyl cyclase 5 (Ac5) also leads to improved glucose tolerance largely due to increased insulin sensitivity in skeletal muscle (Ho et al. 2015). Similarly, sustained stimulation of β2-AR leads to cardiac insulin resistance by suppressing GLUT4 expression and glucose uptake in cardiomyocytes in a PKA-dependent manner, suggesting that the mechanism is also present in cardiac muscle (Mangmool et al. 2016).

However, other studies have shown that activation of the β2-AR/cAMP/PKA pathway can also increase glucose uptake in skeletal muscle by promoting GLUT4 translocation to the plasma membrane in an insulin-independent manner (Ngala et al. 2013, Sato et al. 2014). The controversial results may be related to different physiological conditions: in the postprandial and rest state, when insulin level is increased, βAR/cAMP/PKA pathway is usually suppressed to facilitate anabolic processes in skeletal muscles; activation of the βAR/cAMP/PKA pathway at this time would antagonize the actions of insulin and lead to insulin resistance. In conditions of exercise or fasting, insulin level is low and βAR/cAMP/PKA system is activated to promote catabolic processes to meet the energy demands of skeletal muscles. The increased muscle glucose uptake by activation of β2-AR/cAMP/PKA pathway could be a mechanism to provide energy substrate for muscle activity in the latter conditions. In T2D patients with insulin resistance, selective activation of PKA in skeletal muscle can serve as an alternative pathway for glucose disposal and glycemic control.

Consistent with the role of cAMP signaling in skeletal muscle development and systemic glucose homeostasis, Gsα deficiency in skeletal muscles leads to reduced skeletal muscle mass and impaired glucose tolerance, although muscle insulin sensitivity is intact (Chen et al. 2009a). PDE4 is a cAMP-selective hydrolase and is the predominant PDE subtype in skeletal muscle. The inhibition of muscle PDE4 at least partially accounts for the beneficial effects of resveratrol on metabolism, including improved glucose tolerance, by activation of cAMP/Epac/Sirt1 pathway (Park et al. 2012). Whether PKA is involved in this process remains unknown, but it should be noted that PKA can directly phosphorylate and activate SIRT1 in skeletal muscles (Gerhart-Hines et al. 2011). Consistently, PDE content in skeletal muscle is positively related to fasting plasma glucose level in diabetic patients (Szendroedi et al. 2011), suggesting a correlation between suppressed cAMP signaling and impaired glucose homeostasis. Generation of mouse models with conditional loss- or gain-of-function of cAMP signaling components such as PDE4, EPAC1, and PKA specifically in skeletal muscle will provide further insights into the physiological role of muscle cAMP signaling in glycemic control.

Insulin resistance are often associated with increased lipid accumulation and impaired lipid oxidation in skeletal muscle (Turcotte & Fisher 2008). Pharmacological or physiological stimulation of β-adrenergic signaling in skeletal muscle leads to PKA-dependent activation of SIRT1 which promotes fatty acid oxidation and energy expenditure (Gerhart-Hines et al. 2011). The monounsaturated fatty acid oleic acid is able to improve skeletal muscle insulin resistance partially through a PKA-dependent mechanism (Coll et al. 2008). Specifically, oleic acid can activate PKA/Sirt1/PGC1α pathway to stimulate fatty acid oxidation in skeletal muscle (Lim et al. 2013). These data suggest that PKA is positively associated with lipid oxidation and insulin sensitivity in skeletal muscle.

Taken together, these genetic and pharmacological studies have shown that appropriately regulated cAMP/PKA activity is essential for skeletal muscle insulin sensitivity and systemic glucose homeostasis.

cAMP/PKA in adipose tissues

Adipose tissues are crucial regulators for energy balance and glucose homeostasis through actions in glucose uptake, lipid metabolism, and hormone secretion (Rosen & Spiegelman 2006). Adipose tissues account for only about 10% of insulin-mediated glucose uptake; however, selective GLUT4 deletion in adipose tissues leads to glucose intolerance and insulin resistance in muscle and liver (Abel et al. 2001). By contrast, adipose-specific overexpression of GLUT4 enhances systemic insulin sensitivity and reverses diabetes in mice with muscle-specific GLUT4 deficiency (Carvalho et al. 2005), suggesting that adipose glucose uptake can compensate for defective muscle glucose uptake. In addition to insulin, norepinephrine can also increase glucose uptake in both white (WAT) and brown adipose tissues (BAT) (Liu et al. 1994), potentially by activation of the β3-AR/cAMP/PKA pathway (Chernogubova et al. 2004).

cAMP/PKA signaling is the major positive regulator of lipolysis in WAT and BAT (Fig. 3C). PKA promotes lipolysis by phosphorylating several proteins including lipid droplet-associated protein perilipin A (Miyoshi et al. 2007), hormone-sensitive lipase (HSL) (Krintel et al. 2008), and adipose triglyceride lipase (ATGL) (Pagnon et al. 2012). In normal fed condition, insulin promotes lipogenesis and suppresses lipolysis partially through inhibition of cAMP/PKA signaling by activation of PDE3B in adipocyte (Eriksson et al. 1995, Kitamura et al. 1999). Obesity is associated with increased basal lipolysis and elevated levels of serum free fatty acids (FFAs) that contribute to insulin resistance (Bergman & Ader 2000). In diabetic patients with obesity, metformin improves insulin sensitivity by decreasing circulating FFAs (Abbasi et al. 1998). Further study showed that metformin inhibits lipolysis by suppressing cAMP production and PKA activation in adipocytes (Zhang et al. 2009). Thus, metformin exerts its antidiabetic effects by inhibiting cAMP/PKA signaling in both adipose tissue and liver to suppress excessive lipolysis and glucose production, respectively.

RIIβ is the major PKA subtype in adipose tissues in mouse (Cummings et al. 1996) and human (Mantovani et al. 2009, Peverelli et al. 2013). In mice, RIIβ deficiency is associated with compensatory increase in RIα PKA and increased basal PKA activity in WAT and BAT. βAR-stimulated lipolysis is impaired but the basal rate of lipolysis is increased in the WAT of Riiβ-knockout mice (Planas et al. 1999). In BAT, RIIβ deficiency leads to increases in mitochondrial content and thermogenesis (Nolan et al. 2004, Newhall et al. 2005). However in human, obesity is associated with reduced RIIβ expression and PKA activity in WAT (Mantovani et al. 2009). βAR-stimulated lipolysis and mitochondrial respiration are also decreased in WAT of obese patients (Yehuda-Shnaidman et al. 2010). In 3T3-L1 adipocytes, it has been shown that the anchoring of PKA to AKAP is required for βAR-stimulated lipolysis (Pidoux et al. 2011). These results suggest that RIIβ-PKA is required for βAR-stimulated lipolysis in the WAT of both mouse and human and impaired adipose RIIβ-PKA signaling may contribute to human obesity.

Deletion of Gsα in mouse adipocytes leads to decreased lipogenesis and lipolysis, increased muscle insulin sensitivity, and improved glucose tolerance (Chen et al. 2010, Li et al. 2016). The increased insulin sensitivity is likely caused by decreased circulating lipids and lower fat contents in muscle and liver, because insulin-mediated glucose uptake in adipose tissues is suppressed by Gsα deficiency (Li et al. 2016). Interestingly, Gsα deletion in mature adipocytes has no overall effect on fat content and body weight despite of impaired BAT and WAT functions (Li et al. 2016). However, deletion of Gsα in preadipocytes from an earlier developmental stage leads to leanness with impaired adipocyte differentiation (Chen et al. 2010). These data suggest that cAMP signaling in mature adipocytes affects glucose homeostasis mainly by regulating lipid metabolism.

Glucose homeostasis is also closely regulated by adipokines produced by adipocytes, such as leptin and adiponectin (Rosen & Spiegelman 2006, Coppari & Bjorbaek 2012). Leptin expression and secretion is enhanced by insulin but suppressed by the activation of cAMP/PKA signaling (Szkudelski et al. 2005, Maeda & Horiuchi 2009). The expression of adiponectin has been shown to be positively regulated by PKA (Otani et al. 2015) and CREB signaling in 3T3-L1 adipocytes (Kim et al. 2010), whereas other studies suggested that βAR/PKA signaling inhibits adiponectin expression in these cells (Fasshauer et al. 2001). Further studies are needed to determine if cAMP/PKA signaling regulates the expression of these adipokines in vivo.

cAMP/PKA in the brain

The brain regulates energy balance and glucose homeostasis through cooperation with peripheral tissues including fat, pancreatic islets, and liver (Morton & Schwartz 2011, Grayson et al. 2013, Schwartz et al. 2013, Rojas & Schwartz 2014, Scarlett & Schwartz 2015). Leptin, a fat-derived hormone, regulates food intake, energy expenditure, and glucose homeostasis mainly by its actions on hypothalamic neurons (Morton & Schwartz 2011). Insulin also acts in the brain to regulate food intake and HGP (Gray et al. 2014, Rojas & Schwartz 2014). In hypothalamic neurons, cAMP signaling is modulated by several hormones including leptin and insulin to affect food intake (Zhao 2005). A recent study found that glucagon acts in the hypothalamus to inhibit HGP by a PKA-dependent mechanism (Mighiu et al. 2013). Inhibition of PKA activity in the mediobasal hypothalamus (MBH) abolishes the suppressive effect of glucagon on HGP and leads to increased i.v. glucagon injection-induced HGP. By contrast, activation of PKA in MBH inhibits HGP and resembles the effects of glucagon injection to the hypothalamus. The glucagon-induced activation of hypothalamic PKA and inhibition of HGP are both attenuated in rats fed a high-fat diet, whereas activation of PKA by Sp-cAMPS infusion to MBH can still efficiently inhibit HGP in these rats (Mighiu et al. 2013). These findings suggest that hypothalamic glucagon resistance contributes to increased HGP and hyperglycemia in diabetes and obesity and that pharmacological activation of PKA in MBH can bypass the glucagon resistance with therapeutic potential for diabetes treatment.

The gene encoding Gsα (GNAS) shows parental-specific imprinting and patients with maternal inactive mutations exhibit obesity and insulin resistance (Weinstein 2014). Animal studies have shown that brain-specific maternal Gsα mutation leads to obesity, severe insulin resistance, and diabetes (Chen et al. 2009b). Especially, these mice developed insulin-resistant diabetes before the development of obesity, indicating that central Gsα signaling directly regulates peripheral glucose metabolism. Specific maternal Gsα deficiency in paraventricular nucleus of the hypothalamus leads to milder obesity and has marginal effects on glucose homeostasis (Chen et al. 2012). By contrast, Gsα deletion selectively in ventromedial hypothalamic neurons leads to improved glucose homeostasis especially when the mice fed a high-fat diet (Berger et al. 2016). Thus, the specific neuronal populations that mediate the negative effects of Gsα mutations on glucose homeostasis remain to be determined. As discussed above, Gsα deficiency in glucagon-responsive neurons in MBH can lead to central glucagon resistance and contribute to the development of hyperglycemia and diabetes.

In mouse hypothalamus, multiple PKA R and C subunits are expressed with RIIβ-PKA as one of the major subtypes (Yang & McKnight 2015). Mice with global knockout of RIIβ subunit exhibit leanness, elevated insulin and leptin sensitivity, and resistance to diet-induced obesity and diabetes (Schreyer et al. 2001, Enns et al. 2009b, Yang & McKnight 2015). The lean phenotype and likely the improved glucose metabolism as well are caused by RIIβ-PKA deficiency in the hypothalamus (Zheng et al. 2013). RIIβ deficiency leads to reduced PKA Cα and Cβ subunits and decreased total PKA activity in multiple brain regions (Brandon et al. 1998, Yang & McKnight 2015) that is accompanied by a compensatory increase in type I PKA. This shift from type II to type I PKA leads to increased sensitivity to activation by cAMP (Brandon et al. 1998) and likely altered the intracellular localization of PKA as well. Leanness and increased insulin sensitivity have also been observed in mice lacking PKA Cβ subunits, which are highly expressed in the hypothalamus (Guthrie et al. 1997, Enns et al. 2009a). Cβ deficiency reduces basal PKA activity, but has no significant effect on total PKA activity in some brain regions due to a compensatory increase in Cα subunits (Howe et al. 2002). It remains unknown to what extent PKA activity is impaired by Cβ deficiency in hypothalamic regions that are essential for the regulation of energy balance. Generation of conditional mutant mice lacking Cβ in specific types of neurons will provide more mechanistic insights. Although the neuronal populations and molecular mechanisms responsible for the improved glucose metabolism in RIIβ KO and Cβ KO mice remain largely unknown, these findings suggest that PKA manipulations in the brain, most likely in hypothalamic neurons, has the potential to improve glycemic control in diabetes.

Strategies for cAMP/PKA pathway targeting

Recent findings have supported the feasibility of cAMP/PKA pathway as a target for treatment of a variety of diseases, such as cancers (Chochung 1993, Tortora & Ciardiello 2003, Sapio et al. 2014), polycystic kidney disease (Torres & Harris 2014), cardiovascular diseases (Lee et al. 2013), and diabetes (Miller et al. 2013). Several strategies have been proposed for cAMP/PKA pathway targeting, including the following: (1) modulation of cAMP levels. As an example, metformin inhibits hepatic gluconeogenesis by suppressing glucagon-induced cAMP production in hepatocytes (Miller et al. 2013). Another class of drugs that have been clinically prescribed or in clinical trials for T2D treatment are GPCR agonists or antagonists (Ahren 2009). For example, the GLP1R agonists exenatide (Byetta) and liraglutide (Victoza) are FDA-approved antidiabetic drugs and are able to enhance insulin secretion by stimulating cAMP production in β cells. Small molecular antagonists for glucagon receptor are under preclinical or clinical investigations for their inhibitory effects on HGP (Sammons & Lee 2015). cAMP-degrading PDEs have been suggested as antidiabetic targets (Furman & Pyne 2006). Inhibitors for PDE4 has been recently shown to be able to improve glucose homeostasis in diabetic mice (Vollert et al. 2012) and human patients (Wouters et al. 2012), potentially by enhancing cAMP-mediated GLP1 secretion (Vollert et al. 2012); (2) inhibition of PKA. Small molecular inhibitors for PKA such as H89 and KT 5720 have exhibited beneficial effects in animal models of cardiac diseases (Oddis et al. 1996, Makaula et al. 2005). The specificity of these inhibitors, however, is questioned (Murray 2008). A more specific approach for PKA manipulation, antisense oligonucleotide-based knockdown of PKA R subunit, has shown anticancer effects in preclinical (Tortora et al. 1997) and clinical studies (Goel et al. 2006). It remains unknown if these strategies have any effect on glucose control in animal models or human patients with T2D; and (3) disruption of AKAP signaling complexes. AKAPs interact with PKA, PDEs, and protein phosphatases to ensure their appropriate intracellular localization and facilitate signal transduction, specificity, and termination. The signaling complexes have been suggested as potential drug targets for cancers, chronic heart failure, diabetes, etc. (Alto et al. 2002, Troger et al. 2012, Esseltine & Scott 2013). Although peptide disruptors for AKAP-PKA interaction have been extensively studied in research, validated small molecule disruptors suitable for therapeutic purposes are still lacking and under investigation (Troger et al. 2012). Another approach to suppress AKAP-mediated signaling is small interference RNA (siRNA)-mediated knockdown of AKAP expression (Josefsen et al. 2010).

Concluding remarks

In summary, cAMP/PKA signaling in different tissues has pleiotropic effects on whole-body glucose homeostasis and regulates glucose metabolism at multiple levels. Genetic and pharmacological studies in animal models suggest that selective activation of cAMP/PKA pathway in pancreatic β cells or selective inhibition of cAMP/PKA pathway in liver can be safe and effective in improving glycemic control in T2D. Activation of βAR/cAMP/PKA pathway in skeletal muscle is coupled to glycogen breakdown and lipolysis and positively regulates glucose homeostasis. However, chronic overactivation of the sympathetic nervous system is associated with increased basal lipolysis in adipose tissue and may contribute to insulin resistance in obesity and diabetes. Inhibition of cAMP/PKA in fat tissue has been suggested to contribute to the insulin-sensitizing effect of metformin via suppression of lipolysis and circulating FFAs. In the hypothalamus, cAMP/PKA pathway has profound effects on energy balance and glucose homeostasis that merit further studies. Although it is clinically challenging to yield tissue-specific manipulation of cAMP/PKA pathway, the findings that metformin exerts its antidiabetic effect by inhibiting hepatic cAMP/PKA/CREB pathway (He et al. 2009, Miller et al. 2013, Pernicova & Korbonits 2014) strongly support this signaling cascade as a target for the development of new T2D therapeutics.

Declaration of interest

The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of this review.

Funding

This work was partially supported by US National Institutes of Health (NIH R01 GM32875).

Acknowledgment

The authors thank Ying Lai for help with manuscript editing.

References

  • Abbasi F, Carantoni M, Chen YD & Reaven GM 1998 Further evidence for a central role of adipose tissue in the antihyperglycemic effect of metformin. Diabetes Care 21 13011305. (doi:10.2337/diacare.21.8.1301)

    • Search Google Scholar
    • Export Citation
  • Abel ED, Peroni O, Kim JK, Kim YB, Boss O, Hadro E, Minnemann T, Shulman GI & Kahn BB 2001 Adipose-selective targeting of the GLUT4 gene impairs insulin action in muscle and liver. Nature 409 729733. (doi:10.1038/35055575)

    • Search Google Scholar
    • Export Citation
  • Ahren B 2009 Islet G protein-coupled receptors as potential targets for treatment of type 2 diabetes. Nature Reviews. Drug Discovery 8 369385. (doi:10.1038/nrd2782)

    • Search Google Scholar
    • Export Citation
  • Almahariq M, Mei FC & Cheng X 2014 Cyclic AMP sensor EPAC proteins and energy homeostasis. Trends in Endocrinology and Metabolism 25 6071. (doi:10.1016/j.tem.2013.10.004)

    • Search Google Scholar
    • Export Citation
  • Altarejos JY & Montminy M 2011 CREB and the CRTC co-activators: sensors for hormonal and metabolic signals. Nature Reviews. Molecular Cell Biology 12 141151. (doi:10.1038/nrm3072)

    • Search Google Scholar
    • Export Citation
  • Alto N, Carlisle Michel JJ, Dodge KL, Langeberg LK & Scott JD 2002 Intracellular targeting of protein kinases and phosphatases. Diabetes 51 S385388. (doi:10.2337/diabetes.51.2007.S385)

    • Search Google Scholar
    • Export Citation
  • Alves-Wagner AB, Mori RC, Sabino-Silva R, Fatima LA, Alves Ada S, Britto LR, Schaan BD & Machado UF 2015 Beta-adrenergic blockade increases GLUT4 and improves glycemic control in insulin-treated diabetic Wistar rats. Autonomic Neuroscience 193 108116. (doi:10.1016/j.autneu.2015.10.003)

    • Search Google Scholar
    • Export Citation
  • Ammala C, Ashcroft FM & Rorsman P 1993 Calcium-independent potentiation of insulin release by cyclic AMP in single beta-cells. Nature 363 356358. (doi:10.1038/363356a0)

    • Search Google Scholar
    • Export Citation
  • Antos CL, Frey N, Marx SO, Reiken S, Gaburjakova M, Richardson JA, Marks AR & Olson EN 2001 Dilated cardiomyopathy and sudden death resulting from constitutive activation of protein kinase a. Circulation Research 89 9971004. (doi:10.1161/hh2301.100003)

    • Search Google Scholar
    • Export Citation
  • Asensio C, Jimenez M, Kuhne F, Rohner-Jeanrenaud F & Muzzin P 2005 The lack of beta-adrenoceptors results in enhanced insulin sensitivity in mice exhibiting increased adiposity and glucose intolerance. Diabetes 54 34903495. (doi:10.2337/diabetes.54.12.3490)

    • Search Google Scholar
    • Export Citation
  • Beebe SJ, Oyen O, Sandberg M, Froysa A, Hansson V & Jahnsen T 1990 Molecular cloning of a tissue-specific protein kinase (C gamma) from human testis—representing a third isoform for the catalytic subunit of cAMP-dependent protein kinase. Molecular Endocrinology 4 465475. (doi:10.1210/mend-4-3-465)

    • Search Google Scholar
    • Export Citation
  • Beguin P, Nagashima K, Nishimura M, Gonoi T & Seino S 1999 PKA-mediated phosphorylation of the human K(ATP) channel: separate roles of Kir6.2 and SUR1 subunit phosphorylation. EMBO Journal 18 47224732. (doi:10.1093/emboj/18.17.4722)

    • Search Google Scholar
    • Export Citation
  • Berdeaux R & Stewart R 2012 cAMP signaling in skeletal muscle adaptation: hypertrophy, metabolism, and regeneration. American Journal of Physiology: Endocrinology and Metabolism 303 E1E17. (doi:10.1152/ajpendo.00555.2011)

    • Search Google Scholar
    • Export Citation
  • Berger A, Kablan A, Yao C, Ho T, Podyma B, Weinstein LS & Chen M 2016 Gsalpha deficiency in the ventromedial hypothalamus enhances leptin sensitivity and improves glucose homeostasis in mice on a high-fat diet. Endocrinology 157 600610. (doi:10.1210/en.2015-1700)

    • Search Google Scholar
    • Export Citation
  • Bergman RN & Ader M 2000 Free fatty acids and pathogenesis of type 2 diabetes mellitus. Trends in Endocrinology and Metabolism 11 351356. (doi:10.1016/S1043-2760(00)00323-4)

    • Search Google Scholar
    • Export Citation
  • Berthet J, Rall TW & Sutherland EW 1957 The relationship of epinephrine and glucagon to liver phosphorylase. IV. Effect of epinephrine and glucagon on the reactivation of phosphorylase in liver homogenates. Journal of Biological Chemistry 224 463475.

    • Search Google Scholar
    • Export Citation
  • Blanchet E, Van de Velde S, Matsumura S, Hao E, LeLay J, Kaestner K & Montminy M 2015 Feedback inhibition of CREB signaling promotes beta cell dysfunction in insulin resistance. Cell Reports 10 11491157. (doi:10.1016/j.celrep.2015.01.046)

    • Search Google Scholar
    • Export Citation
  • Brandon EP, Logue SF, Adams MR, Qi M, Sullivan SP, Matsumoto AM, Dorsa DM, Wehner JM, McKnight GS & Idzerda RL 1998 Defective motor behavior and neural gene expression in RIIbeta-protein kinase A mutant mice. Journal of Neuroscience 18 36393649.

    • Search Google Scholar
    • Export Citation
  • Burgers PP, Ma Y, Margarucci L, Mackey M, van der Heyden MA, Ellisman M, Scholten A, Taylor SS & Heck AJ 2012 A small novel A-kinase anchoring protein (AKAP) that localizes specifically protein kinase A-regulatory subunit I (PKA-RI) to the plasma membrane. Journal of Biological Chemistry 287 4378943797. (doi:10.1074/jbc.M112.395970)

    • Search Google Scholar
    • Export Citation
  • Carvalho E, Kotani K, Peroni OD & Kahn BB 2005 Adipose-specific overexpression of GLUT4 reverses insulin resistance and diabetes in mice lacking GLUT4 selectively in muscle. American Journal of Physiology: Endocrinology and Metabolism 289 E551561. (doi:10.1152/ajpendo.00116.2005)

    • Search Google Scholar
    • Export Citation
  • Chen AE, Ginty DD & Fan CM 2005a Protein kinase A signalling via CREB controls myogenesis induced by Wnt proteins. Nature 433 317322. (doi:10.1038/nature03126)

    • Search Google Scholar
    • Export Citation
  • Chen M, Gavrilova O, Zhao WQ, Nguyen A, Lorenzo J, Shen L, Nackers L, Pack S, Jou W & Weinstein LS 2005b Increased glucose tolerance and reduced adiposity in the absence of fasting hypoglycemia in mice with liver-specific Gs alpha deficiency. Journal of Clinical Investigation 115 32173227. (doi:10.1172/JCI24196)

    • Search Google Scholar
    • Export Citation
  • Chen M, Feng HZ, Gupta D, Kelleher J, Dickerson KE, Wang J, Hunt D, Jou W, Gavrilova O & Jin JP 2009a G(s)alpha deficiency in skeletal muscle leads to reduced muscle mass, fiber-type switching, and glucose intolerance without insulin resistance or deficiency. American Journal of Physiology: Cell Physiology 296 C930C940. (doi:10.1152/ajpcell.00443.2008)

    • Search Google Scholar
    • Export Citation
  • Chen M, Wang J, Dickerson KE, Kelleher J, Xie T, Gupta D, Lai EW, Pacak K, Gavrilova O & Weinstein LS 2009b Central nervous system imprinting of the G protein G(s)alpha and its role in metabolic regulation. Cell Metabolism 9 548555. (doi:10.1016/j.cmet.2009.05.004)

    • Search Google Scholar
    • Export Citation
  • Chen M, Chen H, Nguyen A, Gupta D, Wang J, Lai EW, Pacak K, Gavrilova O, Quon MJ & Weinstein LS 2010 G(s)alpha deficiency in adipose tissue leads to a lean phenotype with divergent effects on cold tolerance and diet-induced thermogenesis. Cell Metabolism 11 320330. (doi:10.1016/j.cmet.2010.02.013)

    • Search Google Scholar
    • Export Citation
  • Chen M, Berger A, Kablan A, Zhang J, Gavrilova O & Weinstein LS 2012 Gsalpha deficiency in the paraventricular nucleus of the hypothalamus partially contributes to obesity associated with Gsalpha mutations. Endocrinology 153 42564265. (doi:10.1210/en.2012-1113)

    • Search Google Scholar
    • Export Citation
  • Chen PC, Kryukova YN & Shyng SL 2013 Leptin regulates KATP channel trafficking in pancreatic beta-cells by a signaling mechanism involving AMP-activated protein kinase (AMPK) and cAMP-dependent protein kinase (PKA). Journal of Biological Chemistry 288 3409834109. (doi:10.1074/jbc.M113.516880)

    • Search Google Scholar
    • Export Citation
  • Chernogubova E, Cannon B & Bengtsson T 2004 Norepinephrine increases glucose transport in brown adipocytes via beta3-adrenoceptors through a cAMP, PKA, and PI3-kinase-dependent pathway stimulating conventional and novel PKCs. Endocrinology 145 269280. (doi:10.1210/en.2003-0857)

    • Search Google Scholar
    • Export Citation
  • Chiasson JL, Shikama H, Chu DT & Exton JH 1981 Inhibitory effect of epinephrine on insulin-stimulated glucose uptake by rat skeletal muscle. Journal of Clinical Investigation 68 706713. (doi:10.1172/JCI110306)

    • Search Google Scholar
    • Export Citation
  • Chochung Y 1993 Differentiation therapy of cancer targeting the ri-alpha regulatory subunit of cAMP-dependent protein-kinase (review). International Journal of Oncology 3 141148. (doi:10.3892/ijo.3.2.141)

    • Search Google Scholar
    • Export Citation
  • Cohen P 1993 Dissection of the protein phosphorylation cascades involved in insulin and growth factor action. Biochemical Society Transactions 21 555567. (doi:10.1042/bsbib210555)

    • Search Google Scholar
    • Export Citation
  • Cohen P 2002 The origins of protein phosphorylation. Nature Cell Biology 4 E127E130. (doi:10.1038/ncb0502-e127)

  • Coll T, Eyre E, Rodriguez-Calvo R, Palomer X, Sanchez RM, Merlos M, Laguna JC & Vazquez-Carrera M 2008 Oleate reverses palmitate-induced insulin resistance and inflammation in skeletal muscle cells. Journal of Biological Chemistry 283 1110711116. (doi:10.1074/jbc.M708700200)

    • Search Google Scholar
    • Export Citation
  • Consoli A 1992 Role of liver in pathophysiology of NIDDM. Diabetes Care 15 430441. (doi:10.2337/diacare.15.3.430)

  • Coppari R & Bjorbaek C 2012 Leptin revisited: its mechanism of action and potential for treating diabetes. Nature Reviews. Drug Discovery 11 692708. (doi:10.1038/nrd3757)

    • Search Google Scholar
    • Export Citation
  • Cummings DE, Brandon EP, Planas JV, Motamed K, Idzerda RL & McKnight GS 1996 Genetically lean mice result from targeted disruption of the RII beta subunit of protein kinase A. Nature 382 622626. (doi:10.1038/382622a0)

    • Search Google Scholar
    • Export Citation
  • De Marinis YZ, Salehi A, Ward CE, Zhang Q, Abdulkader F, Bengtsson M, Braha O, Braun M, Ramracheya R & Amisten S 2010 GLP-1 inhibits and adrenaline stimulates glucagon release by differential modulation of N- and L-type Ca2+ channel-dependent exocytosis. Cell Metabolism 11 543553. (doi:10.1016/j.cmet.2010.04.007)

    • Search Google Scholar
    • Export Citation
  • DeFronzo RA, Ferrannini E, Sato Y, Felig P & Wahren J 1981 Synergistic interaction between exercise and insulin on peripheral glucose uptake. Journal of Clinical Investigation 68 14681474. (doi:10.1172/JCI110399)

    • Search Google Scholar
    • Export Citation
  • DeFronzo RA & Tripathy D 2009 Skeletal muscle insulin resistance is the primary defect in type 2 diabetes. Diabetes Care 32 S157S163. (doi:10.2337/dbib9-S302)

    • Search Google Scholar
    • Export Citation
  • Ding WG, Renstrom E, Rorsman P, Buschard K & Gromada J 1997 Glucagon-like peptide I and glucose-dependent insulinotropic polypeptide stimulate Ca2+-induced secretion in rat alpha-cells by a protein kinase A-mediated mechanism. Diabetes 46 792800. (doi:10.2337/diab.46.5.792)

    • Search Google Scholar
    • Export Citation
  • Dunning BE & Gerich JE 2007 The role of alpha-cell dysregulation in fasting and postprandial hyperglycemia in type 2 diabetes and therapeutic implications. Endocrine Reviews 28 253283. (doi:10.1210/er.2006-0026)

    • Search Google Scholar
    • Export Citation
  • Dunning BE, Foley JE & Ahren B 2005 Alpha cell function in health and disease: influence of glucagon-like peptide-1. Diabetologia 48 17001713. (doi:10.1007/s00125-005-1878-0)

    • Search Google Scholar
    • Export Citation
  • Enns LC, Morton JF, Mangalindan RS, McKnight GS, Schwartz MW, Kaeberlein MR, Kennedy BK, Rabinovitch PS & Ladiges WC 2009a Attenuation of age-related metabolic dysfunction in mice with a targeted disruption of the Cbeta subunit of protein kinase A. Journals of Gerontology. Series A, Biological Sciences and Medical Sciences 64 12211231. (doi:10.1093/gerona/glp133)

    • Search Google Scholar
    • Export Citation
  • Enns LC, Morton JF, Treuting PR, Emond MJ, Wolf NS, McKnight GS, Rabinovitch PS & Ladiges WC 2009b Disruption of protein kinase A in mice enhances healthy aging. PLoS ONE 4 e5963. (doi:10.1371/journal.pone.0005963)

    • Search Google Scholar
    • Export Citation
  • Enns LC, Bible KL, Emond MJ & Ladiges WC 2010 Mice lacking the Cbeta subunit of PKA are resistant to angiotensin II-induced cardiac hypertrophy and dysfunction. BMC Research Notes 3 307. (doi:10.1186/1756-0500-3-307)

    • Search Google Scholar
    • Export Citation
  • Eriksson H, Ridderstrale M, Degerman E, Ekholm D, Smith CJ, Manganiello VC, Belfrage P & Tornqvist H 1995 Evidence for the key role of the adipocyte cGMP-inhibited cAMP phosphodiesterase in the antilipolytic action of insulin. Biochimica et Biophysica Acta 1266 101107. (doi:10.1016/0167-4889(94)00237-9)

    • Search Google Scholar
    • Export Citation
  • Esseltine JL & Scott JD 2013 AKAP signaling complexes: pointing towards the next generation of therapeutic targets? Trends in Pharmacological Sciences 34 648655. (doi:10.1016/j.tips.2013.10.005)

    • Search Google Scholar
    • Export Citation
  • Fasshauer M, Klein J, Neumann S, Eszlinger M & Paschke R 2001 Adiponectin gene expression is inhibited by beta-adrenergic stimulation via protein kinase A in 3T3-L1 adipocytes. FEBS Letters 507 142146. (doi:10.1016/S0014-5793(01)02960-X)

    • Search Google Scholar
    • Export Citation
  • Fernandez-Marcos PJ & Auwerx J 2011 Regulation of PGC-1alpha, a nodal regulator of mitochondrial biogenesis. American Journal of Clinical Nutrition 93 884S-890. (doi:10.3945/ajcn.110.001917)

    • Search Google Scholar
    • Export Citation
  • Furman B & Pyne N 2006 Modulation of cyclic nucleotides and cyclic nucleotide phosphodiesterases in pancreatic islet beta-cells and intestinal L-cells as targets for treating diabetes mellitus. Current Opinion in Investigational Drugs 7 898905.

    • Search Google Scholar
    • Export Citation
  • Furman B, Ong WK & Pyne NJ 2010 Cyclic AMP signaling in pancreatic islets. Advances in Experimental Medicine and Biology 654 281304. (doi:10.1007/978-90-481-3271-3)

    • Search Google Scholar
    • Export Citation
  • Gerhart-Hines Z, Dominy JE Jr, Blattler SM, Jedrychowski MP, Banks AS, Lim JH, Chim H, Gygi SP & Puigserver P 2011 The cAMP/PKA pathway rapidly activates SIRT1 to promote fatty acid oxidation independently of changes in NAD(+). Molecular Cell 44 851863. (doi:10.1016/j.molcel.2011.12.005)

    • Search Google Scholar
    • Export Citation
  • Goel S, Desai K, Macapinlac M, Wadler S, Goldberg G, Fields A, Einstein M, Volterra F, Wong B & Martin R 2006 A phase I safety and dose escalation trial of docetaxel combined with GEM231, a second generation antisense oligonucleotide targeting protein kinase A R1alpha in patients with advanced solid cancers. Investigational New Drugs 24 125134. (doi:10.1007/s10637-006-2378-x)

    • Search Google Scholar
    • Export Citation
  • Goldfarb AH, Bruno JF & Buckenmeyer PJ 1989 Intensity and duration of exercise effects on skeletal muscle cAMP, phosphorylase, and glycogen. Journal of Applied Physiology 66 190194.

    • Search Google Scholar
    • Export Citation
  • Gray SM, Meijer RI & Barrett EJ 2014 Insulin regulates brain function, but how does it get there? Diabetes 63 39923997. (doi:10.2337/db14-0340)

  • Grayson BE, Seeley RJ & Sandoval DA 2013 Wired on sugar: the role of the CNS in the regulation of glucose homeostasis. Nature Reviews. Neuroscience 14 2437. (doi:10.1038/nrn3409)

    • Search Google Scholar
    • Export Citation
  • Gromada J, Bokvist K, Ding WG, Barg S, Buschard K, Renstrom E & Rorsman P 1997 Adrenaline stimulates glucagon secretion in pancreatic A-cells by increasing the Ca2+ current and the number of granules close to the L-type Ca2+ channels. Journal of General Physiology 110 217228. (doi:10.1085/jgp.110.3.217)

    • Search Google Scholar
    • Export Citation
  • Gunton JE, Kulkarni RN, Yim S, Okada T, Hawthorne WJ, Tseng YH, Roberson RS, Ricordi C, O’Connell PJ & Gonzalez FJ 2005 Loss of ARNT/HIF1beta mediates altered gene expression and pancreatic-islet dysfunction in human type 2 diabetes. Cell 122 337349. (doi:10.1016/j.cell.2005.05.027)

    • Search Google Scholar
    • Export Citation
  • Guthrie CR, Skalhegg BS & McKnight GS 1997 Two novel brain-specific splice variants of the murine Cbeta gene of cAMP-dependent protein kinase. Journal of Biological Chemistry 272 2956029565. (doi:10.1074/jbc.272.47.29560)

    • Search Google Scholar
    • Export Citation
  • Haber BA, Chin S, Chuang E, Buikhuisen W, Naji A & Taub R 1995 High levels of glucose-6-phosphatase gene and protein expression reflect an adaptive response in proliferating liver and diabetes. Journal of Clinical Investigation 95 832841. (doi:10.1172/JCI117733)

    • Search Google Scholar
    • Export Citation
  • Hanson RW & Reshef L 1997 Regulation of phosphoenolpyruvate carboxykinase (GTP) gene expression. Annual Review of Biochemistry 66 581611. (doi:10.1146/annurev.biochem.66.1.581)

    • Search Google Scholar
    • Export Citation
  • He L, Sabet A, Djedjos S, Miller R, Sun X, Hussain MA, Radovick S & Wondisford FE 2009 Metformin and insulin suppress hepatic gluconeogenesis through phosphorylation of CREB binding protein. Cell 137 635646. (doi:10.1016/j.cell.2009.03.016)

    • Search Google Scholar
    • Export Citation
  • Herberg FW, Maleszka A, Eide T, Vossebein L & Tasken K 2000 Analysis of A-kinase anchoring protein (AKAP) interaction with protein kinase A (PKA) regulatory subunits: PKA isoform specificity in AKAP binding. Journal of Molecular Biology 298 329339. (doi:10.1006/jmbi.2000.3662)

    • Search Google Scholar
    • Export Citation
  • Herzig S, Long F, Jhala US, Hedrick S, Quinn R, Bauer A, Rudolph D, Schutz G, Yoon C & Puigserver P 2001 CREB regulates hepatic gluconeogenesis through the coactivator PGC-1. Nature 413 179183. (doi:10.1038/35093131)

    • Search Google Scholar
    • Export Citation
  • Hinke SA, Navedo MF, Ulman A, Whiting JL, Nygren PJ, Tian G, Jimenez-Caliani AJ, Langeberg LK, Cirulli V & Tengholm A 2012 Anchored phosphatases modulate glucose homeostasis. EMBO Journal 31 39914004. (doi:10.1038/emboj.2012.244)

    • Search Google Scholar
    • Export Citation
  • Ho D, Zhao X, Yan L, Yuan C, Zong H, Vatner DE, Pessin JE & Vatner SF 2015 Adenylyl cyclase type 5 deficiency protects against diet-induced obesity and insulin resistance. Diabetes 64 26362645. (doi:10.2337/db14-0494)

    • Search Google Scholar
    • Export Citation
  • Howe DG, Wiley JC & McKnight GS 2002 Molecular and behavioral effects of a null mutation in all PKA C beta isoforms. Molecular and Cellular Neurosciences 20 515524. (doi:10.1006/mcne.2002.1119)

    • Search Google Scholar
    • Export Citation
  • Hughes SD, Quaade C, Johnson JH, Ferber S & Newgard CB 1993 Transfection of AtT-20ins cells with GLUT-2 but not GLUT-1 confers glucose-stimulated insulin secretion. Relationship to glucose metabolism. Journal of Biological Chemistry 268 1520515212.

    • Search Google Scholar
    • Export Citation
  • Hussain MA, Stratakis C & Kirschner L 2012 Prkar1a in the regulation of insulin secretion. Hormone and Metabolic Research 44 759765. (doi:10.1055/s-00000025)

    • Search Google Scholar
    • Export Citation
  • Jarnaess E, Ruppelt A, Stokka AJ, Lygren B, Scott JD & Tasken K 2008 Dual specificity A-kinase anchoring proteins (AKAPs) contain an additional binding region that enhances targeting of protein kinase A type I. Journal of Biological Chemistry 283 3370833718. (doi:10.1074/jbc.M804807200)

    • Search Google Scholar
    • Export Citation
  • Jensen J, Rustad PI, Kolnes AJ & Lai YC 2011 The role of skeletal muscle glycogen breakdown for regulation of insulin sensitivity by exercise. Frontiers in Physiology 2 112. (doi:10.3389/fphys.2011.00112)

    • Search Google Scholar
    • Export Citation
  • Johanns M, Lai YC, Hsu MF, Jacobs R, Vertommen D, Van Sande J, Dumont JE, Woods A, Carling D & Hue L 2016 AMPK antagonizes hepatic glucagon-stimulated cyclic AMP signalling via phosphorylation-induced activation of cyclic nucleotide phosphodiesterase 4B. Nature Communications 7 10856. (doi:10.1038/ncomms10856)

    • Search Google Scholar
    • Export Citation
  • Josefsen K, Lee YC, Thams P, Efendic S & Nielsen JH 2010 AKAP 18 alpha and gamma have opposing effects on insulin release in INS-1E cells. FEBS Letters 584 8185. (doi:10.1016/j.febslet.2009.10.086)

    • Search Google Scholar
    • Export Citation
  • Kaihara KA, Dickson LM, Jacobson DA, Tamarina N, Roe MW, Philipson LH & Wicksteed B 2013 beta-Cell-specific protein kinase A activation enhances the efficiency of glucose control by increasing acute-phase insulin secretion. Diabetes 62 15271536. (doi:10.2337/db12-1013)

    • Search Google Scholar
    • Export Citation
  • Kaihara KA, Dickson LM, Ellenbroek JH, Orr CM, Layden BT & Wicksteed B 2015 PKA enhances the acute insulin response leading to the restoration of glucose control. Diabetes 64 16881697. (doi:10.2337/db14-1051)

    • Search Google Scholar
    • Export Citation
  • Ke B, Zhao Z, Ye X, Gao Z, Manganiello V, Wu B & Ye J 2015 Inactivation of NF-kappaB p65 (RelA) in liver improved insulin sensitivity and inhibited cAMP/PKA pathway. Diabetes 64 33553362. (doi:10.2337/db15-0242)

    • Search Google Scholar
    • Export Citation
  • Kendall DM, Poitout V, Olson LK, Sorenson RL & Robertson RP 1995 Somatostatin coordinately regulates glucagon gene expression and exocytosis in HIT-T15 cells. Journal of Clinical Investigation 96 24962502. (doi:10.1172/JCI118309)

    • Search Google Scholar
    • Export Citation
  • Kim HB, Kim WH, Han KL, Park JH, Lee J, Yeo J & Jung MH 2010 cAMP-response element binding protein (CREB) positively regulates mouse adiponectin gene expression in 3T3-L1 adipocytes. Biochemical and Biophysical Research Communications 391 634639. (doi:10.1016/j.bbrc.2009.11.111)

    • Search Google Scholar
    • Export Citation
  • Kirschner LS, Carney JA, Pack SD, Taymans SE, Giatzakis C, Cho YS, Cho-Chung YS & Stratakis CA 2000 Mutations of the gene encoding the protein kinase A type I-alpha regulatory subunit in patients with the Carney complex. Nature Genetics 26 8992. (doi:10.1038/79238)

    • Search Google Scholar
    • Export Citation
  • Kirschner LS, Yin Z, Jones GN & Mahoney E 2009 Mouse models of altered protein kinase A signaling. Endocrine-Related Cancer 16 773793. (doi:10.1677/ERC-09-0068)

    • Search Google Scholar
    • Export Citation
  • Kitamura T, Kitamura Y, Kuroda S, Hino Y, Ando M, Kotani K, Konishi H, Matsuzaki H, Kikkawa U & Ogawa W 1999 Insulin-induced phosphorylation and activation of cyclic nucleotide phosphodiesterase 3B by the serine-threonine kinase Akt. Molecular Cell Biology 19 62866296. (doi:10.1128/MCB.19.9.6286)

    • Search Google Scholar
    • Export Citation
  • Knepel W, Chafitz J & Habener JF 1990 Transcriptional activation of the rat glucagon gene by the cyclic AMP-responsive element in pancreatic islet cells. Molecular Cell Biology 10 67996804. (doi:10.1128/MCB.10.12.6799)

    • Search Google Scholar
    • Export Citation
  • Knight JD & Kothary R 2011 The myogenic kinome: protein kinases critical to mammalian skeletal myogenesis. Skeletal Muscle 1 29. (doi:10.1186/2044-5040-1-29)

    • Search Google Scholar
    • Export Citation
  • Krebs EG & Beavo JA 1979 Phosphorylation-dephosphorylation of enzymes. Annual Review of Biochemistry 48 923959. (doi:10.1146/annurev.bi.48.070179.004423)

    • Search Google Scholar
    • Export Citation
  • Krintel C, Osmark P, Larsen MR, Resjo S, Logan DT & Holm C 2008 Ser649 and Ser650 are the major determinants of protein kinase A-mediated activation of human hormone-sensitive lipase against lipid substrates. PLoS ONE 3 e3756. (doi:10.1371/journal.pone.0003756)

    • Search Google Scholar
    • Export Citation
  • Leahy P, Crawford DR, Grossman G, Gronostajski RM & Hanson RW 1999 CREB binding protein coordinates the function of multiple transcription factors including nuclear factor I to regulate phosphoenolpyruvate carboxykinase (GTP) gene transcription. Journal of Biological Chemistry 274 88138822. (doi:10.1074/jbc.274.13.8813)

    • Search Google Scholar
    • Export Citation
  • Lee LC, Maurice DH & Baillie GS 2013 Targeting protein-protein interactions within the cyclic AMP signaling system as a therapeutic strategy for cardiovascular disease. Future Medicinal Chemistry 5 451464. (doi:10.4155/fmc.12.216)

    • Search Google Scholar
    • Export Citation
  • Leibiger B, Moede T, Muhandiramlage TP, Kaiser D, Vaca Sanchez P, Leibiger IB & Berggren PO 2012 Glucagon regulates its own synthesis by autocrine signaling. PNAS 109 2092520930. (doi:10.1073/pnas.1212870110)

    • Search Google Scholar
    • Export Citation
  • Lembo G, Capaldo B, Rendina V, Iaccarino G, Napoli R, Guida R, Trimarco B & Sacca L 1994 Acute noradrenergic activation induces insulin resistance in human skeletal muscle. American Journal of Physiology 266 E242E247.

    • Search Google Scholar
    • Export Citation
  • Lester LB, Langeberg LK & Scott JD 1997 Anchoring of protein kinase A facilitates hormone-mediated insulin secretion. PNAS 94 1494214947. (doi:10.1073/pnas.94.26.14942)

    • Search Google Scholar
    • Export Citation
  • Li YQ, Shrestha YB, Chen M, Chanturiya T, Gavrilova O & Weinstein LS 2016 Gsalpha deficiency in adipose tissue improves glucose metabolism and insulin sensitivity without an effect on body weight. PNAS 113 446451. (doi:10.1073/pnas.1517142113)

    • Search Google Scholar
    • Export Citation
  • Liang H & Ward WF 2006 PGC-1alpha: a key regulator of energy metabolism. American Journal of Physiology: Advances in Physiology Education 30 145151. (doi:10.1152/advan.00052.2006)

    • Search Google Scholar
    • Export Citation
  • Light PE, Manning Fox JE, Riedel MJ & Wheeler MB 2002 Glucagon-like peptide-1 inhibits pancreatic ATP-sensitive potassium channels via a protein kinase A- and ADP-dependent mechanism. Molecular Endocrinology 16 21352144. (doi:10.1210/me.2002-0084)

    • Search Google Scholar
    • Export Citation
  • Lim JH, Gerhart-Hines Z, Dominy JE, Lee Y, Kim S, Tabata M, Xiang YK & Puigserver P 2013 Oleic acid stimulates complete oxidation of fatty acids through protein kinase A-dependent activation of SIRT1-PGC1alpha complex. Journal of Biological Chemistry 288 71177126. (doi:10.1074/jbc.M112.415729)

    • Search Google Scholar
    • Export Citation
  • Liu X, Perusse F & Bukowiecki LJ 1994 Chronic norepinephrine infusion stimulates glucose uptake in white and brown adipose tissues. American Journal of Physiology 266 R914R920.

    • Search Google Scholar
    • Export Citation
  • London E, Nesterova M, Sinaii N, Szarek E, Chanturiya T, Mastroyannis SA, Gavrilova O & Stratakis CA 2014 Differentially regulated protein kinase A (PKA) activity in adipose tissue and liver is associated with resistance to diet-induced obesity and glucose intolerance in mice that lack PKA regulatory subunit type IIalpha. Endocrinology 155 33973408. (doi:10.1210/en.2014-1122)

    • Search Google Scholar
    • Export Citation
  • Ma X, Zhang Y, Gromada J, Sewing S, Berggren PO, Buschard K, Salehi A, Vikman J, Rorsman P & Eliasson L 2005 Glucagon stimulates exocytosis in mouse and rat pancreatic alpha-cells by binding to glucagon receptors. Molecular Endocrinology 19 198212. (doi:10.1210/me.2004-0059)

    • Search Google Scholar
    • Export Citation
  • Maeda T & Horiuchi N 2009 Simvastatin suppresses leptin expression in 3T3-L1 adipocytes via activation of the cyclic AMP-PKA pathway induced by inhibition of protein prenylation. Journal of Biochemistry 145 771781. (doi:10.1093/jb/mvp035)

    • Search Google Scholar
    • Export Citation
  • Makaula S, Lochner A, Genade S, Sack MN, Awan MM & Opie LH 2005 H-89, a non-specific inhibitor of protein kinase A, promotes post-ischemic cardiac contractile recovery and reduces infarct size. Journal of Cardiovascular Pharmacology 45 341347. (doi:10.1097/01.fjc.0000156825.80951.14)

    • Search Google Scholar
    • Export Citation
  • Mangmool S, Denkaew T, Phosri S, Pinthong D, Parichatikanond W, Shimauchi T & Nishida M 2016 Sustained betaAR stimulation mediates cardiac insulin resistance in a PKA-dependent manner. Molecular Endocrinology 30 118132. (doi:10.1210/me.2015-1201)

    • Search Google Scholar
    • Export Citation
  • Mantovani G, Bondioni S, Alberti L, Gilardini L, Invitti C, Corbetta S, Zappa MA, Ferrero S, Lania AG & Bosari S 2009 Protein kinase A regulatory subunits in human adipose tissue: decreased R2B expression and activity in adipocytes from obese subjects. Diabetes 58 620626. (doi:10.2337/db08-0585)

    • Search Google Scholar
    • Export Citation
  • Means CK, Lygren B, Langeberg LK, Jain A, Dixon RE, Vega AL, Gold MG, Petrosyan S, Taylor SS & Murphy AN 2011 An entirely specific type I A-kinase anchoring protein that can sequester two molecules of protein kinase A at mitochondria. PNAS 108 E1227E1235. (doi:10.1073/pnas.1107182108)

    • Search Google Scholar
    • Export Citation
  • Mehrani H & Storey KB 1993 Control of glycogenolysis and effects of exercise on phosphorylase kinase and cAMP-dependent protein kinase in rainbow trout organs. Biochemistry and Cell Biology 71 501506. (doi:10.1139/o93-072)

    • Search Google Scholar
    • Export Citation
  • Mighiu PI, Yue JT, Filippi BM, Abraham MA, Chari M, Lam CK, Yang CS, Christian NR, Charron MJ & Lam TK 2013 Hypothalamic glucagon signaling inhibits hepatic glucose production. Nature Medicine 19 766772. (doi:10.1038/nm.3115)

    • Search Google Scholar
    • Export Citation
  • Miller CP, Lin JC & Habener JF 1993 Transcription of the rat glucagon gene by the cyclic AMP response element-binding protein CREB is modulated by adjacent CREB-associated proteins. Molecular and Cellular Biology 13 70807090. (doi:10.1128/MCB.13.11.7080)

    • Search Google Scholar
    • Export Citation
  • Miller RA, Chu Q, Xie J, Foretz M, Viollet B & Birnbaum MJ 2013 Biguanides suppress hepatic glucagon signalling by decreasing production of cyclic AMP. Nature 494 256260. (doi:10.1038/nature11808)

    • Search Google Scholar
    • Export Citation
  • Miyoshi H, Perfield JW2nd, Souza SC, Shen WJ, Zhang HH, Stancheva ZS, Kraemer FB, Obin MS & Greenberg AS 2007 Control of adipose triglyceride lipase action by serine 517 of perilipin A globally regulates protein kinase A-stimulated lipolysis in adipocytes. Journal of Biological Chemistry 282 9961002. (doi:10.1074/jbc.M605770200)

    • Search Google Scholar
    • Export Citation
  • Morton GJ & Schwartz MW 2011 Leptin and the central nervous system control of glucose metabolism. Physiological Reviews 91 389411. (doi:10.1152/physrev.00007.2010)

    • Search Google Scholar
    • Export Citation
  • Murray AJ 2008 Pharmacological PKA inhibition: all may not be what it seems. Science Signaling 1 re4. (doi:10.1126/scisignal.122re4)

  • Newhall KJ, Cummings DE, Nolan MA & McKnight GS 2005 Deletion of the RIIbeta-subunit of protein kinase A decreases body weight and increases energy expenditure in the obese, leptin-deficient ob/ob mouse. Molecular Endocrinology 19 982991. (doi:10.1210/me.2004-0343)

    • Search Google Scholar
    • Export Citation
  • Ngala RA, O’Dowd JF, Stocker CJ, Cawthorne MA & Arch JR 2013 beta2-adrenoceptor agonists can both stimulate and inhibit glucose uptake in mouse soleus muscle through ligand-directed signalling. Naunyn-Schmiedeberg’s Archives of Pharmacology 386 761773. (doi:10.1007/s00210-013-0860-5)

    • Search Google Scholar
    • Export Citation
  • Niswender CM, Willis BS, Wallen A, Sweet IR, Jetton TL, Thompson BR, Wu C, Lange AJ & McKnight GS 2005 Cre recombinase-dependent expression of a constitutively active mutant allele of the catalytic subunit of protein kinase A. Genesis 43 109119. (doi:10.1002/gene.20159)

    • Search Google Scholar
    • Export Citation
  • Nolan CJ, Damm P & Prentki M 2011 Type 2 diabetes across generations: from pathophysiology to prevention and management. Lancet 378 169181. (doi:10.1016/S0140-6736(11)60614-4)

    • Search Google Scholar
    • Export Citation
  • Nolan MA, Sikorski MA & McKnight GS 2004 The role of uncoupling protein 1 in the metabolism and adiposity of RII beta-protein kinase A-deficient mice. Molecular Endocrinology 18 23022311. (doi:10.1210/me.2004-0194)

    • Search Google Scholar
    • Export Citation
  • Oddis CV, Simmons RL, Hattler BG & Finkel MS 1996 Protein kinase A activation is required for IL-1-induced nitric oxide production by cardiac myocytes. American Journal of Physiology 271 C429C434.

    • Search Google Scholar
    • Export Citation
  • Ortmeyer HK 1997 Insulin decreases skeletal muscle cAMP-dependent protein kinase (PKA) activity in normal monkeys and increases PKA activity in insulin-resistant rhesus monkeys. Journal of Basic and Clinical Physiology and Pharmacology 8 223235. (doi:10.1515/JBCPP.1997.8.4.223)

    • Search Google Scholar
    • Export Citation
  • Otani T, Mizokami A, Hayashi Y, Gao J, Mori Y, Nakamura S, Takeuchi H & Hirata M 2015 Signaling pathway for adiponectin expression in adipocytes by osteocalcin. Cellular Signalling 27 532544. (doi:10.1016/j.cellsig.2014.12.018)

    • Search Google Scholar
    • Export Citation
  • Pagnon J, Matzaris M, Stark R, Meex RC, Macaulay SL, Brown W, O’Brien PE, Tiganis T & Watt MJ 2012 Identification and functional characterization of protein kinase A phosphorylation sites in the major lipolytic protein, adipose triglyceride lipase. Endocrinology 153 42784289. (doi:10.1210/en.2012-1127)

    • Search Google Scholar
    • Export Citation
  • Park CR, Lewis SB & Exton JH 1972 Relationship of some hepatic actions of insulin to the intracellular level of cyclic adenylate. Diabetes 21 439446. (doi:10.2337/diab.21.2.S439)

    • Search Google Scholar
    • Export Citation
  • Park SJ, Ahmad F, Philp A, Baar K, Williams T, Luo H, Ke H, Rehmann H, Taussig R & Brown AL 2012 Resveratrol ameliorates aging-related metabolic phenotypes by inhibiting cAMP phosphodiesterases. Cell 148 421433. (doi:10.1016/j.cell.2012.01.017)

    • Search Google Scholar
    • Export Citation
  • Pernicova I & Korbonits M 2014 Metformin--mode of action and clinical implications for diabetes and cancer. Nature Reviews. Endocrinology 10 143156. (doi:10.1038/nrendo.2013.256)

    • Search Google Scholar
    • Export Citation
  • Petyuk VA, Qian WJ, Hinault C, Gritsenko MA, Singhal M, Monroe ME, Camp DG2nd, Kulkarni RN & Smith RD 2008 Characterization of the mouse pancreatic islet proteome and comparative analysis with other mouse tissues. Journal of Proteome Research 7 31143126. (doi:10.1021/pr800205b)

    • Search Google Scholar
    • Export Citation
  • Peverelli E, Ermetici F, Corbetta S, Gozzini E, Avagliano L, Zappa MA, Bulfamante G, Beck-Peccoz P, Spada A & Mantovani G 2013 PKA regulatory subunit R2B is required for murine and human adipocyte differentiation. Endocrine Connections 2 196207. (doi:10.1530/EC-13-0049)

    • Search Google Scholar
    • Export Citation
  • Pidoux G & Tasken K 2010 Specificity and spatial dynamics of protein kinase A signaling organized by A-kinase-anchoring proteins. Journal of Molecular Endocrinology 44 271284. (doi:10.1677/JME-10-0010)

    • Search Google Scholar
    • Export Citation
  • Pidoux G, Witczak O, Jarnaess E, Myrvold L, Urlaub H, Stokka AJ, Kuntziger T & Tasken K 2011 Optic atrophy 1 is an A-kinase anchoring protein on lipid droplets that mediates adrenergic control of lipolysis. EMBO Journal 30 43714386. (doi:10.1038/emboj.2011.365)

    • Search Google Scholar
    • Export Citation
  • Planas JV, Cummings DE, Idzerda RL & McKnight GS 1999 Mutation of the RIIbeta subunit of protein kinase A differentially affects lipolysis but not gene induction in white adipose tissue. Journal of Biological Chemistry 274 3628136287. (doi:10.1074/jbc.274.51.36281)

    • Search Google Scholar
    • Export Citation
  • Proud CG, Rylatt DB, Yeaman SJ & Cohen P 1977 Amino acid sequences at the two sites on glycogen synthetase phosphorylated by cyclic AMP-dependent protein kinase and their dephosphorylation by protein phosphatase-III. FEBS Letters 80 435442. (doi:10.1016/0014-5793(77)80493-6)

    • Search Google Scholar
    • Export Citation
  • Puigserver P, Rhee J, Donovan J, Walkey CJ, Yoon JC, Oriente F, Kitamura Y, Altomonte J, Dong H & Accili D 2003 Insulin-regulated hepatic gluconeogenesis through FOXO1-PGC-1alpha interaction. Nature 423 550555. (doi:10.1038/nature01667)

    • Search Google Scholar
    • Export Citation
  • Quesada I, Tuduri E, Ripoll C & Nadal A 2008 Physiology of the pancreatic alpha-cell and glucagon secretion: role in glucose homeostasis and diabetes. Journal of Endocrinology 199 519. (doi:10.1677/JOE-08-0290)

    • Search Google Scholar
    • Export Citation
  • Quinn PG 1994 Inhibition by insulin of protein kinase A-induced transcription of the phosphoenolpyruvate carboxykinase gene. Mediation by the activation domain of cAMP response element-binding protein (CREB) and factors bound to the TATA box. Journal of Biological Chemistry 269 1437514378.

    • Search Google Scholar
    • Export Citation
  • Reinton N, Haugen TB, Orstavik S, Skalhegg BS, Hansson V, Jahnsen T & Tasken K 1998 The gene encoding the C gamma catalytic subunit of cAMP-dependent protein kinase is a transcribed retroposon. Genomics 49 290297. (doi:10.1006/geno.1998.5240)

    • Search Google Scholar
    • Export Citation
  • Rider MH, Bertrand L, Vertommen D, Michels PA, Rousseau GG & Hue L 2004 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase: head-to-head with a bifunctional enzyme that controls glycolysis. Biochemical Journal 381 561579. (doi:10.1042/BJ20040752)

    • Search Google Scholar
    • Export Citation
  • Rojas JM & Schwartz MW 2014 Control of hepatic glucose metabolism by islet and brain. Diabetes, Obesity & Metabolism 16 3340. (doi:10.1111/dom.12332)

    • Search Google Scholar
    • Export Citation
  • Rosen ED & Spiegelman BM 2006 Adipocytes as regulators of energy balance and glucose homeostasis. Nature 444 847853. (doi:10.1038/nature05483)

    • Search Google Scholar
    • Export Citation
  • Rosenmund C, Carr DW, Bergeson SE, Nilaver G, Scott JD & Westbrook GL 1994 Anchoring of protein kinase A is required for modulation of AMPA/kainate receptors on hippocampal neurons. Nature 368 853856. (doi:10.1038/368853a0)

    • Search Google Scholar
    • Export Citation
  • Sammons MF & Lee EC 2015 Recent progress in the development of small-molecule glucagon receptor antagonists. Bioorganic & Medicinal Chemistry Letters 25 40574064. (doi:10.1016/j.bmcl.2015.07.092)

    • Search Google Scholar
    • Export Citation
  • Samuel VT, Beddow SA, Iwasaki T, Zhang XM, Chu X, Still CD, Gerhard GS & Shulman GI 2009 Fasting hyperglycemia is not associated with increased expression of PEPCK or G6Pc in patients with Type 2 Diabetes. PNAS 106 1212112126. (doi:10.1073/pnas.0812547106)

    • Search Google Scholar
    • Export Citation
  • Sapio L, Di Maiolo F, Illiano M, Esposito A, Chiosi E, Spina A & Naviglio S 2014 Targeting protein kinase a in cancer therapy: an update. EXCLI Journal 13 843855.

    • Search Google Scholar
    • Export Citation
  • Sato M, Dehvari N, Oberg AI, Dallner OS, Sandstrom AL, Olsen JM, Csikasz RI, Summers RJ, Hutchinson DS & Bengtsson T 2014 Improving type 2 diabetes through a distinct adrenergic signaling pathway involving mTORC2 that mediates glucose uptake in skeletal muscle. Diabetes 63 41154129. (doi:10.2337/db13-1860)

    • Search Google Scholar
    • Export Citation
  • Scarlett JM & Schwartz MW 2015 Gut-brain mechanisms controlling glucose homeostasis. F1000Prime Reports 7 12. (doi:10.12703/P7-12)

  • Schreyer SA, Cummings DE, McKnight GS & LeBoeuf RC 2001 Mutation of the RIIbeta subunit of protein kinase A prevents diet-induced insulin resistance and dyslipidemia in mice. Diabetes 50 25552562. (doi:10.2337/diabetes.50.11.2555)

    • Search Google Scholar
    • Export Citation
  • Schwartz MW, Seeley RJ, Tschop MH, Woods SC, Morton GJ, Myers MG & D’Alessio D 2013 Cooperation between brain and islet in glucose homeostasis and diabetes. Nature 503 5966. (doi:10.1038/nature12709)

    • Search Google Scholar
    • Export Citation
  • Seino S & Shibasaki T 2005 PKA-dependent and PKA-independent pathways for cAMP-regulated exocytosis. Physiological Reviews 85 13031342. (doi:10.1152/physrev.00001.2005)

    • Search Google Scholar
    • Export Citation
  • Sinnegger-Brauns MJ, Hetzenauer A, Huber IG, Renstrom E, Wietzorrek G, Berjukov S, Cavalli M, Walter D, Koschak A & Waldschutz R 2004 Isoform-specific regulation of mood behavior and pancreatic beta cell and cardiovascular function by L-type Ca 2+ channels. Journal of Clinical Investigation 113 14301439. (doi:10.1172/JCI20208)

    • Search Google Scholar
    • Export Citation
  • Smith FD, Langeberg LK & Scott JD 2006 The where’s and when’s of kinase anchoring. Trends in Biochemical Sciences 31 316323. (doi:10.1016/j.tibs.2006.04.009)

    • Search Google Scholar
    • Export Citation
  • Song WJ, Seshadri M, Ashraf U, Mdluli T, Mondal P, Keil M, Azevedo M, Kirschner LS, Stratakis CA & Hussain MA 2011 Snapin mediates incretin action and augments glucose-dependent insulin secretion. Cell Metabolism 13 308319. (doi:10.1016/j.cmet.2011.02.002)

    • Search Google Scholar
    • Export Citation
  • Splawski I, Timothy KW, Sharpe LM, Decher N, Kumar P, Bloise R, Napolitano C, Schwartz PJ, Joseph RM & Condouris K 2004 Ca(V)1.2 calcium channel dysfunction causes a multisystem disorder including arrhythmia and autism. Cell 119 1931. (doi:10.1016/j.cell.2004.09.011)

    • Search Google Scholar
    • Export Citation
  • Streeper RS, Hornbuckle LA, Svitek CA, Goldman JK, Oeser JK & O’Brien RM 2001 Protein kinase A phosphorylates hepatocyte nuclear factor-6 and stimulates glucose-6-phosphatase catalytic subunit gene transcription. Journal of Biological Chemistry 276 1911119118. (doi:10.1074/jbc.M101442200)

    • Search Google Scholar
    • Export Citation
  • Stump CS, Henriksen EJ, Wei Y & Sowers JR 2006 The metabolic syndrome: role of skeletal muscle metabolism. Annals of Medicine 38 389402. (doi:10.1080/07853890600888413)

    • Search Google Scholar
    • Export Citation
  • Sun Y, Liu S, Ferguson S, Wang L, Klepcyk P, Yun JS & Friedman JE 2002 Phosphoenolpyruvate carboxykinase overexpression selectively attenuates insulin signaling and hepatic insulin sensitivity in transgenic mice. Journal of Biological Chemistry 277 2330123307. (doi:10.1074/jbc.M200964200)

    • Search Google Scholar
    • Export Citation
  • Szendroedi J, Schmid AI, Chmelik M, Krssak M, Nowotny P, Prikoszovich T, Kautzky-Willer A, Wolzt M, Waldhausl W & Roden M 2011 Skeletal muscle phosphodiester content relates to body mass and glycemic control. PLoS ONE 6 e21846. (doi:10.1371/journal.pone.0021846)

    • Search Google Scholar
    • Export Citation
  • Szkudelski T, Nowicka E & Szkudelska K 2005 Leptin secretion and protein kinase A activity. Physiological Research 54 7985.

  • Tasken K & Aandahl EM 2004 Localized effects of cAMP mediated by distinct routes of protein kinase A. Physiological Reviews 84 137167. (doi:10.1152/physrev.00021.2003)

    • Search Google Scholar
    • Export Citation
  • Thiebaud D, Jacot E, DeFronzo RA, Maeder E, Jequier E & Felber JP 1982 The effect of graded doses of insulin on total glucose uptake, glucose oxidation, and glucose storage in man. Diabetes 31 957963. (doi:10.2337/diacare.31.11.957)

    • Search Google Scholar
    • Export Citation
  • Thorens B, Deriaz N, Bosco D, DeVos A, Pipeleers D, Schuit F, Meda P & Porret A 1996 Protein kinase A-dependent phosphorylation of GLUT2 in pancreatic beta cells. Journal of Biological Chemistry 271 80758081. (doi:10.1074/jbc.271.14.8075)

    • Search Google Scholar
    • Export Citation
  • Torres VE & Harris PC 2014 Strategies targeting cAMP signaling in the treatment of polycystic kidney disease. Journal of the American Society of Nephrology 25 1832. (doi:10.1681/ASN.2013040398)

    • Search Google Scholar
    • Export Citation
  • Tortora G, Caputo R, Damiano V, Bianco R, Pepe S, Bianco AR, Jiang Z, Agrawal S & Ciardiello F 1997 Synergistic inhibition of human cancer cell growth by cytotoxic drugs and mixed backbone antisense oligonucleotide targeting protein kinase A. PNAS 94 1258612591. (doi:10.1073/pnas.94.23.12586)

    • Search Google Scholar
    • Export Citation
  • Tortora G & Ciardiello F 2003 Antisense targeting protein kinase A type I as a drug for integrated strategies of cancer therapy. Annals of the New York Academy of Sciences 1002 236243. (doi:10.1196/annals.1281.026)

    • Search Google Scholar
    • Export Citation
  • Troger J, Moutty MC, Skroblin P & Klussmann E 2012 A-kinase anchoring proteins as potential drug targets. British Journal of Pharmacology 166 420433. (doi:10.1111/j.1476-5381.2011.01796.x)

    • Search Google Scholar
    • Export Citation
  • Turcotte LP & Fisher JS 2008 Skeletal muscle insulin resistance: roles of fatty acid metabolism and exercise. Physical Therapy 88 12791296. (doi:10.2522/ptj.20080018)

    • Search Google Scholar
    • Export Citation
  • van Schaftingen E & Gerin I 2002 The glucose-6-phosphatase system. Biochemical Journal 362 513532. (doi:10.1042/bj3620513)

  • Vollert S, Kaessner N, Heuser A, Hanauer G, Dieckmann A, Knaack D, Kley HP, Beume R & Weiss-Haljiti C 2012 The glucose-lowering effects of the PDE4 inhibitors roflumilast and roflumilast-N-oxide in db/db mice. Diabetologia 55 27792788. (doi:10.1007/s00125-012-2632-z)

    • Search Google Scholar
    • Export Citation
  • Wang Y, Li G, Goode J, Paz JC, Ouyang K, Screaton R, Fischer WH, Chen J, Tabas I & Montminy M 2012 Inositol-1,4,5-trisphosphate receptor regulates hepatic gluconeogenesis in fasting and diabetes. Nature 485 128132. (doi:10.1038/nature10988)

    • Search Google Scholar
    • Export Citation
  • Weinstein LS 2014 Role of G(s)alpha in central regulation of energy and glucose metabolism. Hormone and Metabolic Research 46 841844. (doi:10.1055/s-00000025)

    • Search Google Scholar
    • Export Citation
  • Weiss S, Oz S, Benmocha A & Dascal N 2013 Regulation of cardiac L-type Ca(2)(+) channel CaV1.2 via the beta-adrenergic-cAMP-protein kinase A pathway: old dogmas, advances, and new uncertainties. Circulation Research 113 617631. (doi:10.1161/CIRCRESAHA.113.301781)

    • Search Google Scholar
    • Export Citation
  • Willis BS, Niswender CM, Su T, Amieux PS & McKnight GS 2011 Cell-type specific expression of a dominant negative PKA mutation in mice. PLoS ONE 6 e18772. (doi:10.1371/journal.pone.0018772)

    • Search Google Scholar
    • Export Citation
  • Wouters EF, Bredenbroker D, Teichmann P, Brose M, Rabe KF, Fabbri LM & Goke B 2012 Effect of the phosphodiesterase 4 inhibitor roflumilast on glucose metabolism in patients with treatment-naive, newly diagnosed type 2 diabetes mellitus. Journal of Clinical Endocrinology and Metabolism 97 E1720E1725. (doi:10.1210/jc.2011-2886)

    • Search Google Scholar
    • Export Citation
  • Wu B, Wei S, Petersen N, Ali Y, Wang X, Bacaj T, Rorsman P, Hong W, Sudhof TC & Han W 2015 Synaptotagmin-7 phosphorylation mediates GLP-1-dependent potentiation of insulin secretion from beta-cells. PNAS 112 999610001. (doi:10.1073/pnas.1513004112)

    • Search Google Scholar
    • Export Citation
  • Xie T, Chen M & Weinstein LS 2010 Pancreas-specific Gsalpha deficiency has divergent effects on pancreatic alpha- and beta-cell proliferation. Journal of Endocrinology 206 261269. (doi:10.1677/JOE-10-0030)

    • Search Google Scholar
    • Export Citation
  • Xie T, Chen M, Zhang QH, Ma Z & Weinstein LS 2007 Beta cell-specific deficiency of the stimulatory G protein alpha-subunit Gsalpha leads to reduced beta cell mass and insulin-deficient diabetes. PNAS 104 1960119606. (doi:10.1073/pnas.0704796104)

    • Search Google Scholar
    • Export Citation
  • Yang SN & Berggren PO 2006 The role of voltage-gated calcium channels in pancreatic beta-cell physiology and pathophysiology. Endocrine Reviews 27 621676. (doi:10.1210/er.2005-0888)

    • Search Google Scholar
    • Export Citation
  • Yang L & McKnight GS 2015 Hypothalamic PKA regulates leptin sensitivity and adiposity. Nature Communations 6 8237. (doi:10.1038/ncomms9237)

  • Yang J, Reshef L, Cassuto H, Aleman G & Hanson RW 2009 Aspects of the control of phosphoenolpyruvate carboxykinase gene transcription. Journal of Biological Chemistry 284 2703127035. (doi:10.1074/jbc.R109.040535)

    • Search Google Scholar
    • Export Citation
  • Yehuda-Shnaidman E, Buehrer B, Pi J, Kumar N & Collins S 2010 Acute stimulation of white adipocyte respiration by PKA-induced lipolysis. Diabetes 59 24742483. (doi:10.2337/db10-0245)

    • Search Google Scholar
    • Export Citation
  • Zhang T, He J, Xu C, Zu L, Jiang H, Pu S, Guo X & Xu G 2009 Mechanisms of metformin inhibiting lipolytic response to isoproterenol in primary rat adipocytes. Journal of Molecular Endocrinology 42 5766. (doi:10.1677/JME-08-0130)

    • Search Google Scholar
    • Export Citation
  • Zhao AZ 2005 Control of food intake through regulation of cAMP. Current Topics in Developmental Biology 67 207224. (doi:10.1016/S0070-2153(05)67006-8)

    • Search Google Scholar
    • Export Citation
  • Zheng R, Yang L, Sikorski MA, Enns LC, Czyzyk TA, Ladiges WC & McKnight GS 2013 Deficiency of the RIIbeta subunit of PKA affects locomotor activity and energy homeostasis in distinct neuronal populations. PNAS 110 E1631E1640. (doi:10.1073/pnas.1219542110)

    • Search Google Scholar
    • Export Citation
  • Zisman A, Peroni OD, Abel ED, Michael MD, Mauvais-Jarvis F, Lowell BB, Wojtaszewski JF, Hirshman MF, Virkamaki A & Goodyear LJ 2000 Targeted disruption of the glucose transporter 4 selectively in muscle causes insulin resistance and glucose intolerance. Nature Medicine 6 924928. (doi:10.1038/78693)

    • Search Google Scholar
    • Export Citation

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    cAMP/PKA signaling pathway in mammalian cells. The activation of cAMP/PKA signaling starts from ligand-dependent activation of the G protein-coupled receptors (GPCRs) and is followed by Gsα activation, adenylyl cyclase (AC) activation, and cAMP generation. cAMP activates PKA by binding to PKA regulatory subunits (RIs or RIIs). The PKA catalytic subunits (C) are then released from the PKA tetramer to phosphorylate targets in the cytoplasm, in the plasma membrane (CaV, KATP, etc.), and in the nucleus (CREB). The subcellular localization of PKA is dependent on binding of R subunits to different A-kinase anchoring proteins (AKAPs). The termination of cAMP signaling is dependent on phosphodiesterases (PDEs)-mediated degradation of cAMP to AMP. A full colour version of this figure is available at http://dx.doi.org/10.1530/JME-15-0316.

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    Glucose homeostasis is regulated by the coordinated actions of various organs. Glucose inputs from food absorption and hepatic release can be either inhibited or increased by neural signals from the brain. Hepatic glucose production (HGP) is increased by glucagon during fasting and inhibited by insulin after food absorption. Insulin also lowers blood glucose by stimulating its uptake into various tissues, mainly muscle and fat tissue. Glucose uptake by liver and brain does not require insulin (not shown). The secretions of glucagon and insulin by pancreatic α and β cells, respectively, are regulated by glucose and hormones.

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    Schematic illustration of the regulation of glucose homeostasis by cAMP/PKA pathway in pancreatic β cell, hepatocyte, and adipocyte. (A) Regulation of insulin production by cAMP/PKA signaling in pancreatic β cell. Upon stimulation by incretins such as glucagon-like peptide 1 (GLP1), PKA is activated to promote insulin transcription and secretion by phosphorylating the transcription factor CREB, ATP-sensitive potassium channel (KATP), glucose transporter GLUT2, L-type voltage-gated calcium channels (LTCC), and secretory vesicle-associated protein snapin. Activated CREB promotes the expression of MAFA, a transcription factor that stimulates the expression of insulin. In conditions of long-term hyperglycemia, insulin secretion is impaired at least partially due to the induction of the intrinsic PKA inhibitor B (PKIB). The effect of PKA on insulin release is also dependent on its subcellular localization that is determined by binding to A-kinase anchoring proteins (AKAPs). (B) Regulation of hepatic glucose production by cAMP/PKA. During a fasting, cAMP/PKA is activated in hepatocytes by glucagon and epinephrine binding to GPCRs. PKA inhibits glycogen synthesis and increases glycogenolysis and gluconeogenesis by phosphorylating glycogen synthase, glycogen phosphorylase kinase (PhK), and phosphofructokinase-2/fructose-2,6-bisphosphatase (PFK2/F-2,6-BPase), respectively (see text for detail). At the transcription level, PKA promotes the expression of gluconeogenic genes such as phosphoenolpyruvate carboxykinase (PEPCK), glucose-6-phosphatase (G6Pase), and PPARγ coactivator-1α (PGC1α) by CREB phosphorylation. PKA also promotes the nuclear import of cAMP-regulated transcriptional coactivator 2 (CRTC2) by stimulating its dephosphorylation (through IP3 receptor (IP3R)-calcium-calcineurin (CaN) pathway) and inhibiting its phosphorylation (through phosphorylation and inhibition of salt-inducible kinase SIK2). Insulin and metformin suppress hepatic glucose production at least partially by stimulating the activation of phosphodiesterase (PDE) and downregulation of cAMP signaling. Metformin also increases cellular AMP to inhibit adenylyl cyclase (AC) and thus suppresses cAMP synthesis. (C) Regulation of lipolysis in adipocyte. Glucagon and epinephrine increase lipolysis in adipocytes by stimulating PKA-dependent phosphorylation of lipid droplet-associated protein perilipin A, hormone-sensitive lipase (HSL), and adipose triglyceride lipase (ATGL). Insulin promotes glucose uptake and de novo lipogenesis, and inhibits lipolysis by activating PDE3B to suppress cAMP/PKA signaling. Metformin inhibits lipolysis by downregulation of the cAMP/PKA pathway in adipocytes, probably also via AMP and PDE activation. TAG, triacylglycerol; DAG, diacylglycerol; MAG, monoacylglycerol; FFA, free fatty acid.

  • Abbasi F, Carantoni M, Chen YD & Reaven GM 1998 Further evidence for a central role of adipose tissue in the antihyperglycemic effect of metformin. Diabetes Care 21 13011305. (doi:10.2337/diacare.21.8.1301)

    • Search Google Scholar
    • Export Citation
  • Abel ED, Peroni O, Kim JK, Kim YB, Boss O, Hadro E, Minnemann T, Shulman GI & Kahn BB 2001 Adipose-selective targeting of the GLUT4 gene impairs insulin action in muscle and liver. Nature 409 729733. (doi:10.1038/35055575)

    • Search Google Scholar
    • Export Citation
  • Ahren B 2009 Islet G protein-coupled receptors as potential targets for treatment of type 2 diabetes. Nature Reviews. Drug Discovery 8 369385. (doi:10.1038/nrd2782)

    • Search Google Scholar
    • Export Citation
  • Almahariq M, Mei FC & Cheng X 2014 Cyclic AMP sensor EPAC proteins and energy homeostasis. Trends in Endocrinology and Metabolism 25 6071. (doi:10.1016/j.tem.2013.10.004)

    • Search Google Scholar
    • Export Citation
  • Altarejos JY & Montminy M 2011 CREB and the CRTC co-activators: sensors for hormonal and metabolic signals. Nature Reviews. Molecular Cell Biology 12 141151. (doi:10.1038/nrm3072)

    • Search Google Scholar
    • Export Citation
  • Alto N, Carlisle Michel JJ, Dodge KL, Langeberg LK & Scott JD 2002 Intracellular targeting of protein kinases and phosphatases. Diabetes 51 S385388. (doi:10.2337/diabetes.51.2007.S385)

    • Search Google Scholar
    • Export Citation
  • Alves-Wagner AB, Mori RC, Sabino-Silva R, Fatima LA, Alves Ada S, Britto LR, Schaan BD & Machado UF 2015 Beta-adrenergic blockade increases GLUT4 and improves glycemic control in insulin-treated diabetic Wistar rats. Autonomic Neuroscience 193 108116. (doi:10.1016/j.autneu.2015.10.003)

    • Search Google Scholar
    • Export Citation
  • Ammala C, Ashcroft FM & Rorsman P 1993 Calcium-independent potentiation of insulin release by cyclic AMP in single beta-cells. Nature 363 356358. (doi:10.1038/363356a0)

    • Search Google Scholar
    • Export Citation
  • Antos CL, Frey N, Marx SO, Reiken S, Gaburjakova M, Richardson JA, Marks AR & Olson EN 2001 Dilated cardiomyopathy and sudden death resulting from constitutive activation of protein kinase a. Circulation Research 89 9971004. (doi:10.1161/hh2301.100003)

    • Search Google Scholar
    • Export Citation
  • Asensio C, Jimenez M, Kuhne F, Rohner-Jeanrenaud F & Muzzin P 2005 The lack of beta-adrenoceptors results in enhanced insulin sensitivity in mice exhibiting increased adiposity and glucose intolerance. Diabetes 54 34903495. (doi:10.2337/diabetes.54.12.3490)

    • Search Google Scholar
    • Export Citation
  • Beebe SJ, Oyen O, Sandberg M, Froysa A, Hansson V & Jahnsen T 1990 Molecular cloning of a tissue-specific protein kinase (C gamma) from human testis—representing a third isoform for the catalytic subunit of cAMP-dependent protein kinase. Molecular Endocrinology 4 465475. (doi:10.1210/mend-4-3-465)

    • Search Google Scholar
    • Export Citation
  • Beguin P, Nagashima K, Nishimura M, Gonoi T & Seino S 1999 PKA-mediated phosphorylation of the human K(ATP) channel: separate roles of Kir6.2 and SUR1 subunit phosphorylation. EMBO Journal 18 47224732. (doi:10.1093/emboj/18.17.4722)

    • Search Google Scholar
    • Export Citation
  • Berdeaux R & Stewart R 2012 cAMP signaling in skeletal muscle adaptation: hypertrophy, metabolism, and regeneration. American Journal of Physiology: Endocrinology and Metabolism 303 E1E17. (doi:10.1152/ajpendo.00555.2011)

    • Search Google Scholar
    • Export Citation
  • Berger A, Kablan A, Yao C, Ho T, Podyma B, Weinstein LS & Chen M 2016 Gsalpha deficiency in the ventromedial hypothalamus enhances leptin sensitivity and improves glucose homeostasis in mice on a high-fat diet. Endocrinology 157 600610. (doi:10.1210/en.2015-1700)

    • Search Google Scholar
    • Export Citation
  • Bergman RN & Ader M 2000 Free fatty acids and pathogenesis of type 2 diabetes mellitus. Trends in Endocrinology and Metabolism 11 351356. (doi:10.1016/S1043-2760(00)00323-4)

    • Search Google Scholar
    • Export Citation
  • Berthet J, Rall TW & Sutherland EW 1957 The relationship of epinephrine and glucagon to liver phosphorylase. IV. Effect of epinephrine and glucagon on the reactivation of phosphorylase in liver homogenates. Journal of Biological Chemistry 224 463475.

    • Search Google Scholar
    • Export Citation
  • Blanchet E, Van de Velde S, Matsumura S, Hao E, LeLay J, Kaestner K & Montminy M 2015 Feedback inhibition of CREB signaling promotes beta cell dysfunction in insulin resistance. Cell Reports 10 11491157. (doi:10.1016/j.celrep.2015.01.046)

    • Search Google Scholar
    • Export Citation
  • Brandon EP, Logue SF, Adams MR, Qi M, Sullivan SP, Matsumoto AM, Dorsa DM, Wehner JM, McKnight GS & Idzerda RL 1998 Defective motor behavior and neural gene expression in RIIbeta-protein kinase A mutant mice. Journal of Neuroscience 18 36393649.

    • Search Google Scholar
    • Export Citation
  • Burgers PP, Ma Y, Margarucci L, Mackey M, van der Heyden MA, Ellisman M, Scholten A, Taylor SS & Heck AJ 2012 A small novel A-kinase anchoring protein (AKAP) that localizes specifically protein kinase A-regulatory subunit I (PKA-RI) to the plasma membrane. Journal of Biological Chemistry 287 4378943797. (doi:10.1074/jbc.M112.395970)

    • Search Google Scholar
    • Export Citation
  • Carvalho E, Kotani K, Peroni OD & Kahn BB 2005 Adipose-specific overexpression of GLUT4 reverses insulin resistance and diabetes in mice lacking GLUT4 selectively in muscle. American Journal of Physiology: Endocrinology and Metabolism 289 E551561. (doi:10.1152/ajpendo.00116.2005)