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

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

Diabetes ◽

10.2337/db19-1241 ◽

2020 ◽

pp. db191241

Author(s):

Rong Huang ◽

Xinxiu Bai ◽

Xueyan Li ◽

Xiaohui Wang ◽

Lina Zhao

Keyword(s):

Type 2 Diabetes ◽

Binding Protein ◽

Retinol Binding Protein ◽

Pancreatic Β Cell ◽

Β Cell ◽

Retinol Binding Protein 4 ◽

Cell Dysfunction

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Circulating Retinol Binding Protein 4 is Inversely Associated with Pancreatic β Cell Function across the Spectrum of Glycemia

10.2337/dc20-1234/suppl.11985918.v1 ◽

2020 ◽

Author(s):

Rong Huang ◽

Songping Yin ◽

Yongxin Ye ◽

Nixuan Chen ◽

Shiyun Luo ◽

...

Keyword(s):

Type 2 Diabetes ◽

Insulin Secretion ◽

Glucose Tolerance ◽

Cell Function ◽

Retinol Binding Protein ◽

Β Cell ◽

Retinol Binding Protein 4 ◽

Β Cell Function ◽

Oral Minimal Model

OBJECTIVE: The aim of this study was to examine the association of circulating retinol binding protein 4 (RBP4) levels with β cell function across the spectrum of glucose tolerance from normal to overt type 2 diabetes. RESEARCH DESIGN AND METHODS: A total of 291 subjects aged 35-60 with normal glucose tolerance (NGT), newly diagnosed impaired fasting glucose or glucose tolerance (IFG/IGT) and type 2 diabetes were screened by standard 2-h oral glucose tolerance test (2-h OGTT) with the use of traditional measures to evaluate β cell function. 74 subjects from these participants were recruited in oral minimal model test and assessed β cell function with model-derived indices. Circulating RBP4 levels were measured by a commercially available ELISA kit. RESULTS: Circulating RBP4 levels were significantly and inversely correlated with β cell function indicated by the Stumvoll first-phase and second-phase insulin secretion indexes, but not with HOMA-β, calculated from the 2-h OGTT in 291 subjects across the spectrum of glycemia. The inverse association was also observed in subjects involved in the oral minimal model test with β cell function assessed by both direct measures and model-derived measures, after adjustment for potential confounders. Moreover, RBP4 emerged as an independent factor of the disposition index-total insulin secretion (DI-PhiT). CONCLUSION: Circulating RBP4 levels are inversely and independently correlated with β cell function across the spectrum of glycemia, providing another possible explanation of the linkage between RBP4 and the pathogenesis of type 2 diabetes.

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Circulating Retinol-Binding Protein 4 Is Inversely Associated With Pancreatic β-Cell Function Across the Spectrum of Glycemia

Diabetes Care ◽

10.2337/dc19-2432 ◽

2020 ◽

Vol 43 (6) ◽

pp. 1258-1265

Author(s):

Rong Huang ◽

Songping Yin ◽

Yongxin Ye ◽

Nixuan Chen ◽

Shiyun Luo ◽

...

Keyword(s):

Cell Function ◽

Binding Protein ◽

Retinol Binding Protein ◽

Pancreatic Β Cell ◽

Β Cell ◽

Retinol Binding Protein 4 ◽

Β Cell Function

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Lipid-induced pancreatic β-cell dysfunction: focus on in vivo studies

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00416.2010 ◽

2011 ◽

Vol 300 (2) ◽

pp. E255-E262 ◽

Cited By ~ 133

Author(s):

Adria Giacca ◽

Changting Xiao ◽

Andrei I. Oprescu ◽

Andre C. Carpentier ◽

Gary F. Lewis

Keyword(s):

Type 2 Diabetes ◽

Insulin Secretion ◽

Cell Function ◽

Pancreatic Β Cell ◽

Β Cell ◽

Cell Dysfunction ◽

Β Cell Function

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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Circulating Retinol Binding Protein 4 is Inversely Associated with Pancreatic β Cell Function across the Spectrum of Glycemia

10.2337/dc20-1234/suppl.11985918 ◽

2020 ◽

Author(s):

Rong Huang ◽

Songping Yin ◽

Yongxin Ye ◽

Nixuan Chen ◽

Shiyun Luo ◽

...

Keyword(s):

Type 2 Diabetes ◽

Insulin Secretion ◽

Glucose Tolerance ◽

Cell Function ◽

Retinol Binding Protein ◽

Β Cell ◽

Retinol Binding Protein 4 ◽

Β Cell Function ◽

Oral Minimal Model

OBJECTIVE: The aim of this study was to examine the association of circulating retinol binding protein 4 (RBP4) levels with β cell function across the spectrum of glucose tolerance from normal to overt type 2 diabetes. RESEARCH DESIGN AND METHODS: A total of 291 subjects aged 35-60 with normal glucose tolerance (NGT), newly diagnosed impaired fasting glucose or glucose tolerance (IFG/IGT) and type 2 diabetes were screened by standard 2-h oral glucose tolerance test (2-h OGTT) with the use of traditional measures to evaluate β cell function. 74 subjects from these participants were recruited in oral minimal model test and assessed β cell function with model-derived indices. Circulating RBP4 levels were measured by a commercially available ELISA kit. RESULTS: Circulating RBP4 levels were significantly and inversely correlated with β cell function indicated by the Stumvoll first-phase and second-phase insulin secretion indexes, but not with HOMA-β, calculated from the 2-h OGTT in 291 subjects across the spectrum of glycemia. The inverse association was also observed in subjects involved in the oral minimal model test with β cell function assessed by both direct measures and model-derived measures, after adjustment for potential confounders. Moreover, RBP4 emerged as an independent factor of the disposition index-total insulin secretion (DI-PhiT). CONCLUSION: Circulating RBP4 levels are inversely and independently correlated with β cell function across the spectrum of glycemia, providing another possible explanation of the linkage between RBP4 and the pathogenesis of type 2 diabetes.

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Circulating Retinol Binding Protein 4 is Inversely Associated with Pancreatic β Cell Function across the Spectrum of Glycemia

10.2337/figshare.11985918 ◽

2020 ◽

Author(s):

Rong Huang ◽

Songping Yin ◽

Yongxin Ye ◽

Nixuan Chen ◽

Shiyun Luo ◽

...

Keyword(s):

Type 2 Diabetes ◽

Insulin Secretion ◽

Glucose Tolerance ◽

Cell Function ◽

Retinol Binding Protein ◽

Β Cell ◽

Retinol Binding Protein 4 ◽

Β Cell Function ◽

Oral Minimal Model

OBJECTIVE: The aim of this study was to examine the association of circulating retinol binding protein 4 (RBP4) levels with β cell function across the spectrum of glucose tolerance from normal to overt type 2 diabetes. RESEARCH DESIGN AND METHODS: A total of 291 subjects aged 35-60 with normal glucose tolerance (NGT), newly diagnosed impaired fasting glucose or glucose tolerance (IFG/IGT) and type 2 diabetes were screened by standard 2-h oral glucose tolerance test (2-h OGTT) with the use of traditional measures to evaluate β cell function. 74 subjects from these participants were recruited in oral minimal model test and assessed β cell function with model-derived indices. Circulating RBP4 levels were measured by a commercially available ELISA kit. RESULTS: Circulating RBP4 levels were significantly and inversely correlated with β cell function indicated by the Stumvoll first-phase and second-phase insulin secretion indexes, but not with HOMA-β, calculated from the 2-h OGTT in 291 subjects across the spectrum of glycemia. The inverse association was also observed in subjects involved in the oral minimal model test with β cell function assessed by both direct measures and model-derived measures, after adjustment for potential confounders. Moreover, RBP4 emerged as an independent factor of the disposition index-total insulin secretion (DI-PhiT). CONCLUSION: Circulating RBP4 levels are inversely and independently correlated with β cell function across the spectrum of glycemia, providing another possible explanation of the linkage between RBP4 and the pathogenesis of type 2 diabetes.

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Circulating Retinol Binding Protein 4 is Inversely Associated with Pancreatic β Cell Function across the Spectrum of Glycemia

10.2337/figshare.11985918.v1 ◽

2020 ◽

Author(s):

Rong Huang ◽

Songping Yin ◽

Yongxin Ye ◽

Nixuan Chen ◽

Shiyun Luo ◽

...

Keyword(s):

Type 2 Diabetes ◽

Insulin Secretion ◽

Glucose Tolerance ◽

Cell Function ◽

Retinol Binding Protein ◽

Β Cell ◽

Retinol Binding Protein 4 ◽

Β Cell Function ◽

Oral Minimal Model

OBJECTIVE: The aim of this study was to examine the association of circulating retinol binding protein 4 (RBP4) levels with β cell function across the spectrum of glucose tolerance from normal to overt type 2 diabetes. RESEARCH DESIGN AND METHODS: A total of 291 subjects aged 35-60 with normal glucose tolerance (NGT), newly diagnosed impaired fasting glucose or glucose tolerance (IFG/IGT) and type 2 diabetes were screened by standard 2-h oral glucose tolerance test (2-h OGTT) with the use of traditional measures to evaluate β cell function. 74 subjects from these participants were recruited in oral minimal model test and assessed β cell function with model-derived indices. Circulating RBP4 levels were measured by a commercially available ELISA kit. RESULTS: Circulating RBP4 levels were significantly and inversely correlated with β cell function indicated by the Stumvoll first-phase and second-phase insulin secretion indexes, but not with HOMA-β, calculated from the 2-h OGTT in 291 subjects across the spectrum of glycemia. The inverse association was also observed in subjects involved in the oral minimal model test with β cell function assessed by both direct measures and model-derived measures, after adjustment for potential confounders. Moreover, RBP4 emerged as an independent factor of the disposition index-total insulin secretion (DI-PhiT). CONCLUSION: Circulating RBP4 levels are inversely and independently correlated with β cell function across the spectrum of glycemia, providing another possible explanation of the linkage between RBP4 and the pathogenesis of type 2 diabetes.

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