Insulin and Proinsulin Secretion in Type 2 Diabetes

Diabetes is a disease that is now regarded as approaching epidemic proportions. It is estimated that there are at least 1.4 million diabetics in the UK alone and that this number will double by the year 2010. In addition, there are probably a further 1 million who have the disease but are, as yet, unaware of this. In the United States, the number of diabetics is estimated at around 17 million. The overwhelming majority of patients have type 2 diabetes, a disease traditionally regarded as being of “maturity onset” and associated with certain racial minorities, obesity, hypertension and high triglycerides as well as being strongly influenced by family history. The last ten years have seen the emergence of an alarming trend, with the occurrence of type 2 diabetes in children, adolescents and adults of normal weight.

Type 2 diabetes is essentially a disease of insulin resistance. However, it is well recognised that, from an early stage, the disease is also characterised by changes in pancreatic β-cell function. Such changes can be assessed by measuring the release of insulin and its molecular precursors in response to a glucose challenge. Insulin is released from the β-cells of the Islets of Langerhans in the pancreas in response to the rise in blood glucose that follows a carbohydrate containing meal. It is synthesised initially as a high molecular weight precursor, proinsulin. This molecule is cleaved at two specific sites to yield two short polypeptide chains linked by two disulphide bridges (Figure 1).

Diabetes produces fundamental changes in the secretion of insulin and its precursor molecules. The accurate quantification of Insulin, Proinsulin and C-peptide is required in the understanding of the pathophysiology of diabetes and in the development of new therapies.

Under normal circumstances, only trace amounts of “intact” proinsulin or the intermediate metabolites of processing (“split” proinsulins) survive to be released into peripheral blood. When the pancreas is subjected to repeated or increased stimulation by glucose, as occurs in insulin resistance, this molecular processing becomes less efficient and increasing proportions of intact and split proinsulins (particularly 32,33 split and des 31, 32 proinsulin) appear in peripheral blood. The measurement of insulin precursors in peripheral blood can provide important information with regard to both the diagnosis and monitoring of type 2 diabetes.