Relevance of fatty acid modulation of GSIS in the pathogenesis of insulin resistance and type 2 diabetes

While on the one hand fatty acid-mediated increases in insulin secretion may be important in ensuring adequate insulin release in situations where both FFA and glucose are elevated, on the other hand chronic over-exposure to fatty acids could lead to hypersecretion of insulin and hyperinsulinaemia. Boden (1997) propose that in non-diabetic and moderately insulin-resistant subjects, FFA stimulation of gluconeogenesis is counteracted by the FFA stimulation of insulin secretion, and is thereby an important counter-regulatory mechanism for maintaining circulating glucose concentration. However, in the development of type 2 diabetes in obese subjects, FFAs fail to stimulate the required compensatory insulin response, resulting in peripheral under-utilisation and hepatic overproduction of glucose, with resultant hyperglycaemia.

It has been proposed that chronic over-exposure to FFA and LC acyl CoA results in the accumulation of lipid components within the beta-cell, with lipotoxicity and apoptosis leading to possible failure in insulin biosynthesis and secretion (Roduit et al., 2004). This beta cell failure typifies severe type 2 diabetes and explains the fact that many of these subjects ultimately require insulin treatment to bring their glucose intolerance under control. A model of beta-cell lipotoxicity based on over-expression of SREBP-1c in INS-1 cells has been developed (Yamashita et al., 2004). This model showed lipotoxicity was associated with enhanced expression of lipogenic genes, e.g. acetyl CoA carboxylase, TAG accumulation, and a reduction in the ATP : ADP ratio. Such investigations provide evidence for possible mechanisms involved in the chronic effects of over-provision of dietary lipid on insulin resistance, although studies are required to elucidate the mechanisms involved when this stage of insulin resistance is reached.

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