Chronic Methylglyoxal Infusion by Minipump Causes Pancreatic β-Cell Dysfunction and Induces Type 2 Diabetes in Sprague-Dawley Rats

The phenomenon of lipid-induced pancreatic β-cell dysfunction (“lipotoxicity”) has been very well documented in numerous in vitro experimental systems and has become widely accepted. In vivo demonstration of β-cell lipotoxicity, on the other hand, has not been consistently demonstrated, and there remains a lack of consensus regarding the in vivo effects of chronically elevated free fatty acids (FFA) on β-cell function. Much of the disagreement relates to how insulin secretion is quantified in vivo and in particular whether insulin secretion is assessed in relation to whole body insulin sensitivity, which is clearly reduced by elevated FFA. By correcting for changes in in vivo insulin sensitivity, we and others have shown that prolonged elevation of FFA impairs β-cell secretory function. Prediabetic animal models and humans with a positive family history of type 2 diabetes are more susceptible to this impairment, whereas those with severe impairment of β-cell function (such as individuals with type 2 diabetes) demonstrate no additional impairment of β-cell function when FFA are experimentally raised. Glucolipotoxicity (i.e., the combined β-cell toxicity of elevated glucose and FFA) has been amply demonstrated in vitro and in some animal studies but not in humans, perhaps because there are limitations in experimentally raising plasma glucose to sufficiently high levels for prolonged periods of time. We and others have shown that therapies directed toward diminishing oxidative stress and ER stress have the potential to reduce lipid-induced β-cell dysfunction in animals and humans. In conclusion, lipid-induced pancreatic β-cell dysfunction is likely to be one contributor to the complex array of genetic and metabolic insults that result in the relentless decline in pancreatic β-cell function in those destined to develop type 2 diabetes, and mechanisms involved in this lipotoxicity are promising therapeutic targets.

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Fatty acids and glucolipotoxicity in the pathogenesis of Type 2 diabetes

Biochemical Society Transactions ◽

10.1042/bst0360348 ◽

2008 ◽

Vol 36 (3) ◽

pp. 348-352 ◽

Cited By ~ 128

Author(s):

Miriam Cnop

Keyword(s):

Insulin Resistance ◽

Type 2 Diabetes ◽

Fatty Acids ◽

Cell Apoptosis ◽

Molecular Mechanisms ◽

Cell Loss ◽

Pancreatic Β Cell ◽

Β Cell ◽

Cell Dysfunction

The prevalence of Type 2 diabetes is increasing dramatically as a result of the obesity epidemic, and poses a major health and socio-economic burden. Type 2 diabetes develops in individuals who fail to compensate for insulin resistance by increasing pancreatic insulin secretion. This insulin deficiency results from pancreatic β-cell dysfunction and death. Western diets rich in saturated fats cause obesity and insulin resistance, and increase levels of circulating NEFAs [non-esterified (‘free’) fatty acids]. In addition, they contribute to β-cell failure in genetically predisposed individuals. NEFAs cause β-cell apoptosis and may thus contribute to progressive β-cell loss in Type 2 diabetes. The molecular pathways and regulators involved in NEFA-mediated β-cell dysfunction and apoptosis are beginning to be understood. We have identified ER (endoplasmic reticulum) stress as one of the molecular mechanisms implicated in NEFA-induced β-cell apoptosis. ER stress was also proposed as a mechanism linking high-fat-diet-induced obesity with insulin resistance. This cellular stress response may thus be a common molecular pathway for the two main causes of Type 2 diabetes, namely insulin resistance and β-cell loss. A better understanding of the molecular mechanisms contributing to pancreatic β-cell loss will pave the way for the development of novel and targeted approaches to prevent Type 2 diabetes.

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Retinol-Binding Protein 4 Activates STRA6 Provoking Pancreatic β Cell Dysfunction in Type 2 Diabetes

10.2337/figshare.13200527.v1 ◽

2020 ◽

Author(s):

Ada Admin ◽

Rong Huang ◽

Xinxiu Bai ◽

Xueyan Li ◽

Xiaohui Wang ◽

...

Keyword(s):

Type 2 Diabetes ◽

Cell Function ◽

Binding Protein ◽

Retinol Binding Protein ◽

Pancreatic Β Cell ◽

Β Cell ◽

Retinol Binding Protein 4 ◽

Cell Dysfunction ◽

Β Cell Function

Pancreatic β cell dysfunction plays a decisive role in progression of type 2 diabetes. Retinol binding protein 4 (RBP4) is a prominent adipokine in type 2 diabetes while its effect on β cell function remains elusive and the underlying mechanisms are unknown. Here, we found that elevated circulating RBP4 levels were inversely correlated with pancreatic β cell function in db/db mice across different glycemic stages. RBP4 directly suppressed glucose stimulated insulin secretion (GSIS) in primary isolated islets and INS-1E cells in a dose- and time-dependent manner. RBP4-transgenic overexpressing mice (RBP4-Tg) showed a dynamic decrease of GSIS which appeared as early as 8-week-old preceding the impairment of insulin sensitivity and glucose tolerance. Islets isolated from RBP4-Tg mice showed a significant decrease of GSIS. Mechanistically, we demonstrated that the stimulated by retinoic acid 6(STRA6), RBP4’s only known specific membrane receptor, is expressed in β cells and mediates the inhibitory effect of RBP4 on insulin synthesis via JAK2/STAT1/ISL-1 pathway. Moreover, decreasing circulating RBP4 level could effectively restore β cell dysfunction and ameliorate hyperglycemia in db/db mice. These observations revealed a role of RBP4 in pancreatic β cell dysfunction which provided new insight into the diabetogenic effect of RBP4.

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