Abstract
Objective: Type 2 diabetes (T2D) occurs by deterioration in pancreatic β-cell function and/or progressive loss of pancreatic β-cell mass under the context of insulin resistance. α7 nicotinic acetylcholine receptor (nAChR) may contribute to insulin sensitivity but its role in the pathogenesis of T2D remains undefined. We investigated whether the systemic lack of α7 nAChR was sufficient to impair glucose homeostasis. Methods: We used an α7 nAChR knock-out (α7−/−) mouse model fed a standard chow diet. The effects of the lack of α7 nAChR on islet mass, insulin secretion, glucose and insulin tolerance, body composition, and food behaviour were assessed in vivo and ex vivo experiments. Results: Young α7−/− mice display a chronic mild high glycemia combined with an impaired glucose tolerance and a marked deficit in β-cell mass. In addition to these metabolic disorders, old mice developed adipose tissue inflammation, elevated plasma free fatty acid concentrations and presented glycolytic muscle insulin resistance in old mice. Finally, α7−/− mice, fed a chow diet, exhibited a late-onset excessive gain in body weight through increased fat mass associated with higher food intake. Conclusion: Our work highlights the important role of α7 nAChR in glucose homeostasis. The constitutive lack of α7 nAChR suggests a novel pathway influencing the pathogenesis of T2D.
Highlights
Type 2 diabetes (TD2) is a major health problem that will affect 592 million people in the world by 2035 [1]
Using Real-Time quantitative PCR (RT-qPCR), we found that mouse adipose tissue, liver, and pancreatic islets expressed the α7 nicotinic acetylcholine receptor (nAChR) (Figure 1a–c)
Evaluation of glucose homeostasis revealed that 1/ the lack of α7 nAChR in 10-week-old mice leads to a reduced β-cell mass and chronic mild high glycemia without islet inflammation; 2/10-week-old α7−/− mice exhibit impaired glucose tolerance and a tendency for higher insulin sensitivity, whereas 25-week-old α7−/− mice showed both glucose intolerance and skeletal muscle insulin resistance, and 3/10 to 25-week-old α7−/− mice gained more weight through a marked increase of fat mass associated with higher food intake
Summary
Type 2 diabetes (TD2) is a major health problem that will affect 592 million people in the world by 2035 [1]. T2D is characterized by an inability to control glucose homeostasis in response to metabolic demand. The pathogenesis of T2D is mainly caused by insulin resistance and pancreatic β cell dysfunction [2]. In patients suffering pre-diabetes or diabetes, insulin resistance affects glucose uptake in response to insulin mainly in their skeletal muscle, liver and adipose tissue, leading to development of high glycemia [3]. T2D only occurs by deterioration in pancreatic β-cell function and/or progressive loss of pancreatic β-cell mass under the context of insulin resistance [4]. Reduction of functional β-cell mass is a fundamental feature of T2D. The factors promoting β-cell mass dysfunction in patients at different stage in their adult lives are poorly understood
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