Impaired glucose tolerance and mild diabetes induce β-cell dysfunction in mice

Severe chronic hyperglycaemia ( > 15 mM) causes impaired glycolytic and mitochondrial metabolism in pancreatic β-cells, leading to dramatically reduced insulin secretion and content. However, patients with type 2 diabetes often experience many years of reduced β-cell function and impaired glucose tolerance preceding diabetes diagnosis. It is postulated that β-cell function may be compromised by relatively small changes in glycaemia, initiating a gradual decline that underlies diabetes progression. We therefore investigated the extent to which impaired glucose tolerance and chronic mild hyperglycaemia are detrimental to β-cells. We show that chronic elevation of blood glucose of just 2-3 mM is sufficient to impair β-cell function, causing marked changes in metabolic gene expression and reducing insulin content, metabolic enzyme activity, mitochondrial oxidative phosphorylation and insulin secretion. Smaller but significant changes are produced by impaired glucose tolerance. These findings demonstrate that altered β-cell metabolism is an early event in type 2 diabetes development and highlight a need for therapeutic intervention during prediabetes.