Laboratory of Molecular Biophysics Laboratory Journal 2000 Dr. K. A. Watson

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Kimberly A. Watson

Type II diabetes: structural and computational studies of cell signalling proteins in pancreatic ß-cells.

Type II diabetes is a familial disease affecting approximately 8% of the UK population aged 60-69 yrs and accounts for over 11% of our national health care budget. It is characterised by insulin resistance that causes abnormalities in carbohydrate and lipid metabolism, resulting in hyperglycaemia. Diabetes is the leading cause of blindness, amputation of the legs and kidney failure. Type II is often considered a 'mild' form of the disease, however, such diabetics are 2-3 times more likely to suffer heart attack and stroke than non-diabetics. Although the causes of Type II are not fully known, key proteins have been identified whose importance in insulin secretion and glucose homeostatis is becoming apparent.

The problem of maintaining good glycaemic control can be approached through an understanding of proteins involved in glycogen metabolism and insulin secretion. Calcium ions play a key role in the intracellular signalling of insulin production in the ß-cell. A central component of extracellular signalling in the ß-cell is the ATP sensitive K⁺ channel. Decreased ß -cell function is a major factor in Type II diabetes. It is likely that understanding the control of insulin and glucose at the molecular level, in particular via Ca²⁺ signalling pathways, will be an essential part of future drug development for Type II diabetes.

We are using X-ray crystallography, various biophysical methods, and computational approaches to study the structure and function of the targets that play a role in glucose homeostasis. Currently, our studies are focused on proteins involved in liver and muscle glycogen metabolism (phosphorylase and glycogen synthase), the pancreatic ß-cell K⁺-ATP sensitive channel regulatory subunit (SUR1), and other signalling proteins of the pancreatic ß-cell (CD38, -endosulfine).

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