The aetiology of non-insulin-dependent diabetes mellitus: is abnormal suppression of hepatic gluconeogenesis the primary event?
Despite intensive research effort, the aetiology of non-insulin dependent diabetes mellitus remains unknown. In this disorder, hyperglycaemia results from three defects: impaired suppression of hepatic glucose production; reduced peripheral clearance of glucose; and impaired glucose-mediated insulin secretion. It has been proposed that reduced peripheral glucose clearance is the primary or inherited defect and that hyperinsulinaemia secondary to this eventually leads to beta cell exhaustion and impaired insulin secretion. Other authors have proposed that the initial defect is an abnormality in the first phase of insulin secretion. In this paper it is proposed that the primary abnormality is failure of hepatic gluconeogenesis to suppress adequately and that the resulting excess glucose flux results in peripheral insulin resistance and in a defect of glucose-mediated insulin secretion. This hypothesis is supported by recent data showing the glucose per se can induce defects in insulin action and insulin secretion.
Proietto
J
J
University of Melbourne, Department of Medicine, Royal Melbourne Hospital, Parkville, Vic, Australia.
D003924:Diabetes Mellitus, Type 2 / Q000209:etiology*; D005943:Gluconeogenesis / Q000502:physiology*; D006801:Humans; D007333:Insulin Resistance / Q000502:physiology; D007515:Islets of Langerhans / Q000503:physiopathology; D008099:Liver / Q000378:metabolism; D008954:Models, Biological