Although necessary, insulin resistance alone is not sufficient for T2DM development since the pancreas has the capacity to adapt by increasing both beta-cell mass and insulin secretion. Due to these compensatory mechanisms, normoglycemia can be maintained despite reduced insulin sensitivity in the periphery. However, inadequate insulin secretion is a crucial component of T2DM pathophysiology . Obesity contributes to beta-cell decompensation and impaired insulin secretion through the related insulin resistant state and various glucotoxic and lipotoxic effects on the pancreas. Lipotoxicity can cause beta-cell dysfunction depending on the degree of FFA exposure and on the underlying genetic predisposition for T2DM. In vitro , prolonged exposure of beta-cells to high FFA concentrations increases FFA oxidation and causes accumulation of intracellular metabolites (. citrate and ceramide) which impair glucose-stimulated insulin secretion and promote apoptosis [97, 104]. Clinical studies confirmed that, sustained high FFA plasma levels can impair insulin secretion in predisposed (family history of T2DM) individuals . On the contrary, pharmacological inhibition of lipolysis in non-diabetic individuals with strong family history of T2DM can improve insulin secretion . Similarly, glucotoxicity can impair beta-cell function depending on the duration and degree of hyperglycemia. In vitro , prolonged beta-cell exposure to high glucose concentrations causes glucose desensitization, impairs insulin gene transcription and induces apoptosis . Clinical studies also reported that reduced beta-cell sensitivity to glucose plays a predominant role in patients with impaired glucose tolerance [107, 108].
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