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M Tiedge and S Lenzen

ABSTRACT

RINm5F insulinoma cells show a defective physiological insulin secretory response to glucose stimulation. The short chain carbonic acid sodium butyrate induced a growth arrest during a 72-h tissue culture period. In contrast to control RINm5F cells, 2 mm glucose increased insulin secretion by more than 70% in these sodium butyrate-treated cells (1 mm) without any further increase of the secretory rate between 2 and 20 mm glucose. This effect of sodium butyrate on insulin secretion was assessed in comparison with its effect on gene expression of the GLUT1 and GLUT2 glucose transporter, hexokinase type I and type II, glucokinase and insulin. Sodium butyrate at a 1 mm concentration decreased GLUT1 gene expression by nearly 50%, but did not induce gene expression of the low-affinity GLUT2 glucose transporter above the detection limit. Furthermore, sodium butyrate increased glucokinase gene expression by more than 50% and hexokinase type II gene expression by more than 100%, while insulin gene expression was increased only by 24%. Hexokinase type II enzyme activity was increased by more than 100% without a concomitant significant change of the glucokinase enzyme activity. Sodium butyrate (2 mm) caused effects comparable with those of 1 mm sodium butyrate. Thus the improved insulin secretory responsiveness of RINm5F insulinoma cells after sodium butyrate treatment at low non-physiological millimolar glucose concentrations can be interpreted as a result of an increased hexokinase-mediated metabolic flux rate through the glycolytic chain.

Free access

Heather C Denroche and C Bruce Verchere

Islet amyloid polypeptide (IAPP), the main component of islet amyloid in type 2 diabetes and islet transplants, is now recognized as a contributor to beta cell dysfunction. Increasingly, evidence warrants its investigation in type 1 diabetes owing to both its immunomodulatory and metabolic actions. Autoreactive T cells to IAPP-derived epitopes have been described in humans, suggesting that IAPP is an islet autoantigen in type 1 diabetes. In addition, although aggregates of IAPP have not been implicated in type 1 diabetes, they are potent pro-inflammatory stimuli to innate immune cells, and thus, could influence autoimmunity. IAPP aggregates also occur rapidly in transplanted islets and likely contribute to islet transplant failure in type 1 diabetes through sterile inflammation. In addition, since type 1 diabetes is a disease of both insulin and IAPP deficiency, clinical trials have examined the potential benefits of IAPP replacement in type 1 diabetes with the injectable IAPP analogue, pramlintide. Pramlintide limits postprandial hyperglycemia by delaying gastric emptying and suppressing hyperglucagonemia, underlining the possible role of IAPP in postprandial glucose metabolism. Here, we review IAPP in the context of type 1 diabetes: from its potential involvement in type 1 diabetes pathogenesis, through its role in glucose metabolism and use of IAPP analogues as therapeutics, to its potential role in clinical islet transplant failure and considerations in this regard for future beta cell replacement strategies.

Free access

Thierry Brun and Benoit R Gauthier

Blood glucose homeostasis is achieved by the regulation of insulin and glucagon secretion from the pancreatic islet β- and α-cells. Diabetes mellitus, which comprises a heterogeneous group of hyperglycaemic disorders, results mainly from inadequate mass and function of islet β-cells. Autoimmune destruction of β-cells causes type 1 diabetes, while type 2 is characterized by impaired insulin secretion and is often associated with diminished insulin action on its target tissues. Interestingly, similar to type 1 diabetes, a gradual loss of β-cell mass is observed in type 2 diabetes often requiring insulin therapy. Understanding the molecular mechanism that governs β-cell mass plasticity may provide a means to develop strategies to countera,ct β-cell death while increasing replication. Of particular interest is the islet-specific transcription factor paired box4 (Pax4) that was previously shown to be indispensable for the establishment of the β-cell lineage during development. However, recent accumulating evidence now suggest that Pax4 is also crucial for mature β-cell expansion and survival in response to physiological cues and that mutations or polymorphisms are associated with both type 1 and type 2 diabetes. In contrast, aberrant expression of Pax4 confers protection against apoptosis to insulinomas, whereas it promotes cell growth in lymphocytes. This review summarizes promising new published results supporting the important function of Pax4 in mature islet β-cell physiology and its contribution to pathophysiology when deregulated.

Free access

Mingtong Xu, Xiaochao Chen, Li Yan, Hua Cheng and Weiqing Chen

Association between the (AC)n dinucleotide repeat polymorphism at the 5′-end of the aldose reductase gene and the occurrence of diabetic nephropathy was conducted. We examined eight studies consisting of ten Caucasian type 1 diabetes mellitus case–control comparisons and eight studies consisting of nine type 2 diabetes mellitus case–control comparisons, which were based on our inclusion criterion and available in the literature. The meta-analysis demonstrated a large heterogeneity among the studies on the type 1 diabetic subjects and a significant association was observed between the (AC)n dinucleotide repeat polymorphism at the 5′-end of the aldose reductase gene and diabetic nephropathy. The Z−2 allele appeared to be a genetic risk factor for susceptibility to diabetic nephropathy with a random effects odds ratio (OR) of 1.40 (95% confidence interval, CI (1.07, 1.84)). The Z+2 allele showed a protective effect on diabetic nephropathy with a random effects OR of 0.77 (95% CI (0.65, 0.91)). The meta-analysis, however, showed no association between the genetic polymorphism and diabetic nephropathy in type 2 diabetic subjects. Neither the risk Z−2 allele nor the protective Z+2 allele in type 1 diabetic subjects appeared to have an effect on nephropathy in type 2 diabetic subjects, while their fixed effects OR was 1.09 (95% CI (0.96, 1.22)) and 0.88 (95% CI (0.67, 1.15)) respectively. The current meta-analysis demonstrated a correlation between the (AC)n dinucleotide repeat polymorphism and the occurrence of diabetic nephropathy in Caucasian type 1 diabetic subjects in contrast to type 2 diabetic subject population in which such an association could not be demonstrated.

Free access

B Lee, PG Bradford and SG Laychock

The inositol 1,4,5-trisphosphate receptor (InsP3R) is an intracellular Ca2+ channel that plays a role in the regulation of insulin secretion. In rat isolated pancreatic islets the expression of types I, II and III InsP3R mRNA was identified by reverse transcriptase-polymerase chain reaction and confirmed by cDNA cloning and sequencing. The islet ratios of types I, II and III InsP3R mRNA to beta-actin mRNA were 0.08 +/- 0.02, 0.08 +/- 0.03 and 0.25 +/- 0.04 respectively. Types I, II and III InsP3R mRNA were also expressed in rat (RINm5F) and mouse (betaHC9) pancreatic beta-cell lines, and rat cerebellum. Type III InsP3R mRNA was quantitatively the most abundant form in rat islets and RINm5F cells. In betaHC9 cells, types II and III InsP3R mRNA were expressed at similar levels, and in much greater abundance than type I mRNA. Type III was the least abundant InsP3R mRNA in cerebellum. Culture of betaHC9 cells for 5 days at 2.8 and 25 mM glucose, or RINm5F cells for 7 days at 5.5 and 20 mM glucose, resulted in significantly enhanced expression of type III, but not types I and II, InsP3R mRNA in the cells at the higher glucose concentrations. During short-term (0.5-2 h) incubations, betaHC9 cell type III InsP3R mRNA levels increased in response to glucose in a time- and concentration-dependent manner. Actinomycin D inhibited the glucose response. Alpha-ketoisocaproic acid also stimulated betaHC9 cell type III InsP3R mRNA expression in a concentration-dependent manner, whereas 2-deoxyglucose and 3-O-methylglucose were without effect. The different levels of expression of mRNA for three InsP3R isoforms in islets and insulinoma cells, and the influence of glucose and alpha-ketoisocaproic acid on the expression of type III mRNA, suggests that nutrient metabolism plays a role in the regulation of this gene and that the function of InsP3R subtypes may be unique with each playing a distinct role in beta-cell signal transduction and insulin secretion.

Free access

D T Furuya, A C Poletto, H S Freitas and U F Machado

Evidences have suggested that the endocannabinoid system is overactive in obesity, resulting in enhanced endocannabinoid levels in both circulation and visceral adipose tissue. The blockade of cannabinoid receptor type 1 (CB1) has been proposed for the treatment of obesity. Besides loss of body weight, CB1 antagonism improves insulin sensitivity, in which the glucose transporter type 4 (GLUT4) plays a key role. The aim of this study was to investigate the modulation of GLUT4-encoded gene (Slc2a4 gene) expression by CB1 receptor. For this, 3T3-L1 adipocytes were incubated in the presence of a highly selective CB1 receptor agonist (1 μM arachidonyl-2′-chloroethylamide) and/or a CB1 receptor antagonist/inverse agonist (0.1, 0.5, or 1 μM AM251, 1-(2,4-dichlorophenyl)-5-(4-iodophenyl)-4-methyl-N-1-piperidinyl-1H-pyrazole-3-carboxamide). After acute (2 and 4 h) and chronic (24 h) treatments, cells were harvested to evaluate: i) Slc2a4, Cnr1 (CB1 receptor-encoded gene), and Srebf1 type a (SREBP-1a type-encoded gene) mRNAs (real-time PCR); ii) GLUT4 protein (western blotting); and iii) binding activity of nuclear factor (NF)-κB and sterol regulatory element-binding protein (SREBP)-1 specifically in the promoter of Slc2a4 gene (electrophoretic mobility shift assay). Results revealed that both acute and chronic CB1 receptor antagonism greatly increased (∼2.5-fold) Slc2a4 mRNA and protein content. Additionally, CB1-induced upregulation of Slc2a4 was accompanied by decreased binding activity of NF-κB at 2 and 24 h, and by increased binding activity of the SREBP-1 at 24 h. In conclusion, these findings reveal that the blockade of CB1 receptor markedly increases Slc2a4/GLUT4 expression in adipocytes, a feature that involves NF-κB and SREBP-1 transcriptional regulation.

Free access

Cyrus C Martin, Brian P Flemming, Yingda Wang, James K Oeser and Richard M O'Brien

Islet-specific glucose-6-phosphatase catalytic subunit-related protein (IGRP/G6PC2) is a major autoantigen in both mouse and human type 1 diabetes. IGRP is selectively expressed in islet β cells and polymorphisms in the IGRP gene have recently been associated with variations in fasting blood glucose levels and cardiovascular-associated mortality in humans. Chromatin immunoprecipitation (ChIP) assays have shown that the IGRP promoter binds the islet-enriched transcription factors Pax-6 and BETA2. We show here, again using ChIP assays, that the IGRP promoter also binds the islet-enriched transcription factors MafA and Foxa2. Single binding sites for these factors were identified in the proximal IGRP promoter, mutation of which resulted in decreased IGRP fusion gene expression in βTC-3, Hamster insulinoma tumor (HIT), and Min6 cells. ChiP assays have shown that the islet-enriched transcription factor Pdx-1 also binds the IGRP promoter, but mutational analysis of four Pdx-1 binding sites in the proximal IGRP promoter revealed surprisingly little effect of Pdx-1 binding on IGRP fusion gene expression in βTC-3 cells. In contrast, in both HIT and Min6 cells mutation of these four Pdx-1 binding sites resulted in a ∼50% reduction in fusion gene expression. These data suggest that the same group of islet-enriched transcription factors, namely Pdx-1, Pax-6, MafA, BETA2, and Foxa2, directly or indirectly regulate expression of the two major autoantigens in type 1 diabetes.

Free access

MT Travers and MC Barber

Transcription of the acetyl-CoA carboxylase (ACC)-alpha gene is initiated from two promoters, promoter I (PI) and promoter II (PII) such that transcripts demonstrate heterogeneity in their 5' untranslated regions (UTR). Exons 1 and 2 (E1 and E2) are the primary exons in transcripts initiated from PI and PII respectively; E5 is the first coding exon present in all transcripts. In addition alternative exon splicing results in transcripts that either include or exclude a 47 nucleotide sequence corresponding to E4, such that E[1/4/5] and E[1/5] type transcripts result from PI activity, whereas transcripts containing E[2/4/5] or E[2/5] in the 5'UTR result from PII. In subcutaneous adipose tissue from non-pregnant non-lactating sheep approximately 60% of ACC-alpha transcripts are derived from PI, of which 85% are the E[1/5] type. Lactation resulted in an 88% reduction in total PI transcripts, of which the E[1/5] type was reduced 90% and the E[1/4/5] type 80%. By contrast lactation reduced the total levels of PII transcripts by only 50%. Culture of explants from the subcutaneous depot of lactating sheep with insulin plus dexamethasone for 72 h resulted in an 8-fold increase in both E[1/4/5] and E[1/5] types when compared with explants prior to culture. PII transcripts, by contrast, were increased 2-fold by culture in insulin plus dexamethasone and this was entirely attributed to an increase in the expression of the E[2/4/5] type. Dexamethasone acts to potentiate the action of insulin on PI and PII transcript abundance and this effect is greatest for PI transcripts. This study has demonstrated that repression of the ACC-alpha gene in adipose tissue during lactation is largely achieved through attenuation of PI transcript abundance and may be related, in part, to a change in the sensitivity of the apparatus that regulates PI transcript steady-state levels to insulin.

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G K Shooter, B Magee, M A Soos, G L Francis, K Siddle and J C Wallace

ABSTRACT

Insulin-like growth factor-I (IGF-I) analogues were produced with the aim of identifying IGF-I residues that contribute to the specificity of binding to the type 1 IGF receptor as opposed to the insulin receptor. Receptor binding properties of a series of A- and B-domain analogues were compared using rat L6 myoblasts, soluble human IGF type 1 receptors and soluble human insulin receptor isoforms HIR-A (−Ex11) and HIR-B (+Ex11). IGF-I analogues, [Leu8] IGF-I and [Phe59] IGF-I, were shown to exhibit respectively, a 28- and 17-fold decrease in affinity for the HIR-A with only a 6- and 5-fold decrease in affinity for the human IGF type 1 receptor. In contrast, the analogue [His4] IGF-I was equipotent to IGF-I in binding to the soluble type 1 IGF receptor while showing 7-fold and 4-fold increases in HIR-A and HIR-B binding respectively. Furthermore, [Leu62] IGF-I was 8-fold less potent than IGF-I in soluble IGF type 1 receptor binding but only showed a 2-fold decrease in HIR-A and HIR-B binding. Our study supports the conclusion that the co-evolution of the IGF-I and insulin receptor/ligand systems has resulted in subtle structural differences in the A- and B-regions of each ligand important for defining receptor binding specificity.

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Yanyan Cao, Yunsheng Li, Jaekyung Kim, Yulin Ren, Klaus Himmeldirk, Yi Liu, Yanrong Qian, Fengming Liu and Xiaozhuo Chen

Type 2 diabetes (T2D) has become an epidemic worldwide while T1D remains a great medical challenge. Insulin receptor (IR) signaling activators could alleviate hyperglycemia, reduce the burden on the pancreas, and contribute to prevention and treatment of both types of diabetes. Previously, we reported the synthesis and identification of a natural antidiabetic compound α-penta-galloyl-glucose (α-PGG). Subsequent studies led to the identification of an α-P6GG derivative, 6-chloro-6-deoxy-1,2,3,4-tetra-O-galloyl-α-d-glucopyranose (6Cl-TGQ). Here, we report that 6Cl-TGQ not only induced rapid and long-lasting glucose uptake comparable to insulin in adipocytes but also reduced high blood glucose levels to near normal and significantly decreased plasma insulin levels and improved glucose tolerance performance in high-fat diet-induced T2D mice when administered orally at 5 mg/kg once every other day. Moreover, a single gavage of 6Cl-TGQ at 10 mg/kg induced rapid and sharp decline of blood glucose in streptozotocin-induced T1D mice. Our studies further indicated that 6Cl-TGQ activated IR signaling in cell models and insulin-responsive tissues of mice. 6Cl-TGQ-induced Akt phosphorylation was completely blocked by IR and PI3K inhibitors, while the induced glucose uptake was blocked by the same compounds and a Glut4 inhibitor. Receptor binding studies indicated that 6Cl-TGQ bound to IR with a higher affinity than α-PGG. Importantly, 6Cl-TGQ, unlike insulin, selectively induced phosphorylation of IR without activating IGF1R or its signaling and did not increase cancer cell proliferation. These results indicate that 6Cl-TGQ is a potent orally efficacious compound with low carcinogenic potential and may contribute to the prevention and treatment of T1D and T2D.