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Haiyong Chen, Hui-Yao Lan, Dimitrios H Roukos, and William C Cho

MicroRNAs (miRNAs) are small molecules negatively regulating gene expression by diminishing their target mRNAs. Emerging studies have shown that miRNAs play diverse roles in diabetes mellitus. Type 1 diabetes (T1D) and T2D are two major types of diabetes. T1D is characterized by a reduction in insulin release from the pancreatic β-cells, while T2D is caused by islet β-cell dysfunction in response to insulin resistance. This review describes the miRNAs that control insulin release and production by regulating cellular membrane electrical excitability (ATP:ADP ratio), insulin granule exocytosis, insulin synthesis in β-cells, and β-cell fate and islet mass formation. This review also examines miRNAs involved the insulin resistance of liver, fat, and skeletal muscle, which change insulin sensitivity pathways (insulin receptors, glucose transporter type 4, and protein kinase B pathways). This review discusses the potential application of miRNAs in diabetes, including the use of gene therapy and therapeutic compounds to recover miRNA function in diabetes, as well as the role of miRNAs as potential biomarkers for T1D and T2D.

Free access

Zhengu Liu, Violeta Stanojevic, Luke J Brindamour, and Joel F Habener

Type 2 diabetes, often associated with obesity, results from a deficiency of insulin production and action manifested in increased blood levels of glucose and lipids that further promote insulin resistance and impair insulin secretion. Glucolipotoxicity caused by elevated plasma glucose and lipid levels is a major cause of impaired glucose-stimulated insulin secretion from pancreatic β-cells, due to increased oxidative stress, and insulin resistance. Glucagon-like peptide-1 (GLP1), an insulinotropic glucoincretin hormone, is known to promote β-cell survival via its actions on its G-protein-coupled receptor on β-cells. Here, we report that a nonapeptide, GLP1(28–36)amide, derived from the C-terminal domain of the insulinotropic GLP1, exerts cytoprotective actions on INS-1 β-cells and on dispersed human islet cells in vitro in conditions of glucolipotoxicity and increased oxidative stress independently of the GLP1 receptor. The nonapeptide appears to enter preferably stressed, glucolipotoxic cells compared with normal unstressed cells. It targets mitochondria and improves impaired mitochondrial membrane potential, increases cellular ATP levels, inhibits cytochrome c release, caspase activation, and apoptosis, and enhances the viability and survival of INS-1 β-cells. We propose that GLP1(28–36)amide might be useful in alleviating β-cell stress and might improve β-cell functions and survival.

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Neville H McClenaghan, Peter R Flatt, and Andrew J Ball

This study examined the effects of glucagon-like peptide-1 (GLP-1) on insulin secretion alone and in combination with sulphonylureas or nateglinide, with particular attention to KATP channel-independent insulin secretion. In depolarised cells, GLP-1 significantly augmented glucose-induced KATP channel-independent insulin secretion in a glucose concentration-dependent manner. GLP-1 similarly augmented the KATP channel-independent insulin-releasing effects of tolbutamide, glibenclamide or nateglinide. Downregulation of protein kinase A (PKA)- or protein kinase C (PKC)-signalling pathways in culture revealed that the KATP channel-independent effects of sulphonylureas or nateglinide were critically dependent upon intact PKA and PKC signalling. In contrast, GLP-1 exhibited a reduced but still significant insulin-releasing effect following PKA and PKC downregulation, indicating that GLP-1 can modulate KATP channel-independent insulin secretion by protein kinase-dependent and -independent mechanisms. The synergistic insulin-releasing effects of combinatorial GLP-1 and sulphonylurea/nateglinide were lost following PKA- or PKC-desensitisation, despite GLP-1 retaining an insulin-releasing effect, demonstrating that GLP-1 can induce insulin release under conditions where sulphonylureas and nateglinide are no longer effective. Our results provide new insights into the mechanisms of action of GLP-1, and further highlight the promise of GLP-1 or similarly acting analogues alone or in combination with sulphonylureas or meglitinide drugs in type 2 diabetes therapy.

Free access

Jennifer S ten Kulve, Dick J Veltman, Liselotte van Bloemendaal, Paul F C Groot, Henricus G Ruhé, Frederik Barkhof, Michaela Diamant, and Richard G Ijzerman

Glucagon-like peptide-1 (GLP1) affects appetite, supposedly mediated via the central nervous system (CNS). In this study, we investigate whether modulation of CNS responses to palatable food consumption may be a mechanism by which GLP1 contributes to the central regulation of feeding. Using functional MRI, we determined the effects of endogenous GLP1 and treatment with the GLP1 analogue liraglutide on CNS activation to chocolate milk receipt. Study 1 included 20 healthy lean individuals and 20 obese patients with type 2 diabetes (T2DM). Scans were performed on two occasions: during infusion of the GLP1 receptor antagonist exendin 9–39 (blocking actions of endogenous GLP1) and during placebo infusion. Study 2 was a randomised, cross-over intervention study carried out in 20 T2DM patients, comparing treatment with liraglutide to insulin, after 10 days and 12 weeks. Compared with lean individuals, T2DM patients showed reduced activation to chocolate milk in right insula (P = 0.04). In lean individuals, blockade of endogenous GLP1 effects inhibited activation in bilateral insula (P ≤ 0.03). Treatment in T2DM with liraglutide, vs insulin, increased activation to chocolate milk in right insula and caudate nucleus after 10 days (P ≤ 0.03); however, these effects ceased to be significant after 12 weeks. Our findings in healthy lean individuals indicate that endogenous GLP1 is involved in the central regulation of feeding by affecting central responsiveness to palatable food consumption. In obese T2DM, treatment with liraglutide may improve the observed deficit in responsiveness to palatable food, which may contribute to the induction of weight loss observed during treatment. However, no long-term effects of liraglutide were observed.

Free access

WW Lin and AM Oberbauer

IGF-I acts as a local proliferation and maturation factor for chondrocytes in the growth plate. However, the expression of different alternative IGF-I mRNA classes in the growth plate has not been characterized. Using quantitative reverse transcription PCR, the abundance of each alternative IGF-I mRNA class in resting, proliferative and hypertrophic chondrocytes was measured in rat costochondral growth plates. Class 1Ea mRNA was the most abundant IGF-I transcript overall and was highly expressed in proliferative chondrocytes at 2 and 4 weeks of age; by 6 weeks, the majority of 1Ea mRNA expression had shifted to hypertrophic chondrocytes. Class 1Eb mRNA was the second most abundant transcript and its distribution was uniform across all the cell types at 2 weeks of age. The expression pattern changed with increasing age such that at 6 weeks a gradient existed with hypertrophic chondrocytes expressing higher levels of 1Eb than resting chondrocytes. Class 2Ea mRNA was constitutively expressed at low levels across the growth plate at all ages, while class 2Eb mRNA expression was negligible. The distribution of total IGF-I mRNA also shifted across growth plate cell types as the animals aged from 2 to 6 weeks. These findings suggest that IGF-I class 1 mRNA plays the predominant role in the maturation of the growth plate.

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Qiaoli Cui, Yijing Liao, Yaojing Jiang, Xiaohang Huang, Weihong Tao, Quanquan Zhou, Anna Shao, Ying Zhao, Jia Li, Anran Ma, Zhihong Wang, Li Zhang, Zunyuan Yang, Yinan Liang, Minglin Wu, Zhenyan Yang, Wen Zeng, and Qinghua Wang

Glucagon-like peptide 1 (GLP-1) is an insulinotropic hormone and plays an important role in regulating glucose homeostasis. GLP-1 has a short half-life (t1/2<2 min) due to degrading enzyme dipeptidyl peptidase-IV and rapid kidney clearance, which limits its clinical application as a therapeutic reagent. We demonstrated recently that supaglutide, a novel GLP-1 mimetic generated by recombinant fusion protein techniques, exerted hypoglycemic and beta cell trophic effects in type 2 diabetes db/db mice. In the present study, we examined supaglutide’s therapeutic efficacy and pharmacokinetics in diabetic rhesus monkeys. We found that a single subcutaneous injection of supaglutide of tested doses transiently and significantly reduced blood glucose levels in a dose-dependent fashion in the diabetic monkeys. During a 4-weeks intervention period, treatment of supaglutide of weekly dosing dose-dependently decreased fasting and random blood glucose levels. This was associated with significantly declined plasma fructosamine levels. The repeated administration of supaglutide remarkably also decreased body weight in a dose-dependent fashion accompanied by decreased food intake. Intravenous glucose tolerance test results showed that supaglutide improved glucose tolerance. The intervention also showed enhanced glucose-stimulated insulin secretion and improved lipid profile in diabetic rhesus monkeys. These results reveal that supaglutide exerts beneficial effects in regulating blood glucose and lipid homeostasis in diabetic rhesus monkeys.

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M G Cavallo, F Dotta, L Monetini, S Dionisi, M Previti, L Valente, A Toto, U Di Mario, and P Pozzilli

Abstract

In the present study we have evaluated the expression of different beta-cell markers, islet molecules and autoantigens relevant in diabetes autoimmunity by a human insulinoma cell line (CM) in order to define its similarities with native beta cells and to discover whether it could be considered as a model for studies on immunological aspects of Type 1 diabetes.

First, the positivity of the CM cell line for known markers of neuroendocrine derivation was determined by means of immunocytochemical analysis using different anti-islet monoclonal antibodies including A2B5 and 3G5 reacting with islet gangliosides, and HISL19 binding to an islet glycoprotein. Secondly, the expression and characteristics of glutamic acid decarboxylase (GAD) and of GM2-1 ganglioside, both known to be islet autoantigens in diabetes autoimmunity and expressed by human native beta cells, were investigated in the CM cell line. The pattern of ganglioside expression in comparison to that of native beta cells was also evaluated. Thirdly, the binding of diabetic sera to CM cells reacting with islet cytoplasmic antigens (ICA) was studied by immunohistochemistry. The results of this study showed that beta cell markers identified by anti-islet monoclonal antibodies A2B5, 3G5 and HISL-19 are expressed by CM cells; similarly, islet molecules such as GAD and GM2-1 ganglioside are present and possess similar characteristics to those found in native beta cells; the pattern of expression of other gangliosides by CM cells is also identical to human pancreatic islets; beta cell autoantigen(s) reacting with antibodies present in islet cell antibodies (ICA) positive diabetic sera identified by ICA binding are also detectable in this insulinoma cell line.

We conclude that CM cells show close similarities to native beta cells with respect to the expression of neuroendocrine markers, relevant beta cell autoantigens in Type 1 diabetes (GAD, GM2-1, ICA antigen), and other gangliosides. Therefore, this insulinoma cell line may be considered as an ideal model for studies aimed at investigating autoimmune phenomena occurring in Type 1 diabetes.

Journal of Endocrinology (1996) 150, 113–120

Free access

Andréa M Caricilli, Paula H Nascimento, José R Pauli, Daniela M L Tsukumo, Lício A Velloso, José B Carvalheira, and Mário J A Saad

The aims of the present study were to investigate the expression of toll-like receptor 2 (TLR2) in muscle and white adipose tissue (WAT) of diet-induced obesity (DIO) mice, and also the effects of its inhibition, with the use of TLR2 antisense oligonucleotide (ASON), on insulin sensitivity and signaling. The expression of TLR2 was increased in muscle and WAT of DIO mice, compared with those that received standard chow. Inhibition of TLR2 in DIO mice, by TLR2 ASON, improved insulin sensitivity and signaling in muscle and WAT. In addition, data show that the inhibition of TLR2 expression prevents the activation of IKBKB, MAPK8, and serine phosphorylation of IRS1 in DIO mice, suggesting that TLR2 is a key modulator of the crosstalk between inflammatory and metabolic pathways. We, therefore, suggest that a selective interference with TLR2 presents an attractive opportunity for the treatment of insulin resistance in obesity and type 2 diabetes.

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D. Janjic and M. Asfari

ABSTRACT

To investigate further the role of cytokines in the pathogenesis of type I insulin-dependent diabetes mellitus, the effects of interleukin-1β (IL-1), tumour necrosis factor-α (TNF) and γ-interferon (IFN) were tested on rat insulinoma INS-1 cells. Whereas TNF and IFN had, respectively, a minor or no effect on insulin production, IL-1 caused a time- and dose-dependent decrease in insulin release and lowered the insulin content as well as the preproinsulin mRNA content of INS-1 cells. Both IL-1 and TNF exerted a cytostatic effect, estimated by a decrease in [3H]thymidine incorporation, while only IL-1 decreased cell viability as measured by the colorimetric 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) test.

The glutathione content of INS-1 cells was shown to be modulated by the presence of 2-mercaptoethanol in the culture medium, but was not affected by IL-1 or TNF.

In conclusion, INS-1 cell culture is considered to be a useful model for studying the effect of cytokines on insulin-producing cells. The differentiated features of these cells will permit several questions to be addressed regarding the mechanism of action of IL-1 and eventually other cytokines, both at the level of gene expression and of intracellular signalling.

Journal of Endocrinology (1992) 132, 67–76

Free access

B D Green, N Irwin, V A Gault, C J Bailey, F P M O’Harte, and P R Flatt

Glucagon-like peptide-1 (GLP-1) is a potent insulinotropic hormone proposed to play a role in both the pathophysiology and treatment of type 2 diabetes. This study has employed the GLP-1 receptor antagonist, exendin-4(9–39)amide (Ex(9–39)) to evaluate the role of endogenous GLP-1 in genetic obesity-related diabetes and related metabolic abnormalities using ob/ob and normal mice. Acute in vivo antagonistic potency of Ex(9–39) was confirmed in ob/ob mice by blockade of the insulin-releasing and anti-hyperglycaemic actions of intraperitoneal GLP-1. In longer term studies, ob/ob mice were given once daily injections of Ex(9–39) or vehicle for 11 days. Feeding activity, body weight, and both basal and glucose-stimulated insulin secretion were not significantly affected by chronic Ex(9–39) treatment. However, significantly elevated basal glucose concentrations and impaired glucose tolerance were evident at 11 days. These disturbances in glucose homeostasis were independent of changes of insulin sensitivity and reversed by discontinuation of the Ex(9–39) for 9 days. Similar treatment of normal mice did not affect any of the parameters measured. These findings illustrate the physiological extrapancreatic glucose-lowering actions of GLP-1 in ob/ob mice and suggest that the endogenous hormone plays a minor role in the metabolic abnormalities associated with obesity-related diabetes.