β-Cells in Type 2 Diabetes: A Loss of Function and Mass

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Abstract
Type 2 diabetes mellitus manifests itself in individuals who lose the ability to produce sufficient amounts of insulin to maintain normoglycaemia in the face of insulin resistance. The ability to secrete adequate amounts of insulin depends on β-cell function and mass. Chronic hyperglycaemia is detrimental to pancreatic β-cells, causing impaired insulin secretion and playing an essential role in the regulation of β-cell turnover. This paper will address the effect of chronically elevated glucose levels on β-cell turnover and function. In previous studies we have shown that elevated glucose concentrations induce apoptosis in human β-cells due to an interaction between constitutively expressed Fas ligand and upregulated Fas. Human β-cells produce interleukin (IL)-1β in response to high glucose concentrations, independently of an immune-mediated process. This was antagonized by the IL-1 receptor antagonist (IL-1Ra), a naturally occurring anti-inflammatory cytokine also found in the β-cell. Therefore the balance of IL-1β and IL-1Ra may play a crucial role in the pathogenesis of diabetes. Inhibition of glucotoxicity represents a promising therapeutic stratagem in diabetes therapy to preserve functional β-cell mass.