| Project Detail |
Background and rationale:Pancreatic islets in obese individuals with impaired glucose metabolism are characterized by increased production of incompletely processed pro-insulin. Our recent studies show that defective pro-insulin processing per se leads to massive obesity due to impaired central satiety. Furthermore, amyloid formation in the islets, metabolic stress and aging enhance macrophage-derived IL-1ß. Moreover, we have shown that IL-1ß has a dual effect on insulin secretion with an initial acute stimulatory effect that increases insulin and amyloid-precursor secretion followed by a second phase in which chronic stimulation impairs the processing of pro-insulin and decreases ß-cell function. Finally, IL-1 antagonism in patients with type 2 diabetes improves insulin processing. Therefore, in prediabetes, islet inflammation may promote hyperinsulinemia and impair pro-insulin processing, thereby contributing to the development of obesity and eventually diabetes. Overall objectives: The overall hypothesis of this study is that metabolic stress and aging promote islet inflammation, which will initially induce hyperinsulinemia observed in prediabetes and impair the processing of pro-insulin. Accumulation of islet amyloid will further enhance islet inflammation and incompletely processed pro-insulin will promote hyperphagia. This will support the development of obesity and eventually decrease insulin secretion. Interrupting these deleterious processes may preserve ß-cell function and delay obesity-associated diabetes. Impact: With these studies, we aim to assign a novel role for islet inflammation in the development of diabetes and obesity. It should demonstrate that inflammation initially drives hyperinsulinemia and impairs processing of pro-insulin. This dysfunction will promote hyperphagia and precipitate ß-cell exhaustion and diabetes. Therefore, islet inflammation may not only be a mere consequence of metabolic stress due to over-nutrition and insulin resistance, but may also further promote obesity and precipitate diabetes. This introduces the novel concept that islet inflammation contributes to body weight regulation. This could lead to therapeutic approaches using a judicious combination of exogenous brain permeable insulin, and anti-inflammatory treatments, or by developing a blocking agent targeted to a specific proinsulin-processing product in order to prevent obesity and diabetes. |
