Diet‐induced β‐cell insulin resistance results in reversible loss of functional β‐cell mass

What is it about?

Pancreatic islet/β-cell insulin signaling has been proposed to be of importance for an appropriate β-cell function and survival. Consequently β-cell insulin resistance is likely to constitute an important factor causing and/or contributing to β-cell dysfunction and type 2 diabetes (T2DM) development. Although convincing in genetic models, the relevance of β-cell insulin resistance in diet-induced T2DM remains unclear. Exemplified by different combinations of Western-style diet in diabetes-prone male mice we show that β-cell insulin resistance occurs early during T2DM progression and is due to a combination of lipotoxicity and increased β-cell work-load. Within eight weeks of a high-fat-high-sucrose diet mice became obese, developed impaired insulin and glucose tolerances and displayed non-compensatory insulin release, at least in part, due to reduced expression of syntaxin-1A. By using reporter islets transplanted to the anterior chamber of the eye we demonstrate a concomitant loss of functional β-cell mass. When mice were changed from diabetogenic diet to normal chow diet the diabetes phenotype was reversed, suggesting a remarkable plasticity of functional β-cell mass in the early phase of T2DM development. Our data reinforce the relevance of diet composition as an environmental factor determining different routes of diabetes progression in a given genetic background. Employing the in vivo reporter islet monitoring approach will allow defining key time-points in the dynamics of reversible loss of functional β-cell mass and thus the investigation of the underlying molecular mechanisms involved in the progression towards T2DM manifestation.

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