Type 2 diabetes, also known as adult-onset diabetes, is a metabolic disorder resulting from the body’s inability to produce enough, or properly use, insulin. Affecting roughly 90% of all diabetes patients, this disorder usually sets in slowly after age 40 and mostly strikes overweight individuals. While its underlying roots are unknown, one of the causes of Type 2 diabetes lies in the process by which insulin sets off a chain of intracellular signals leading to nutrient absorption.
Normally, insulin binds with a receptor molecule on a cell membrane, rather like a ship docking, setting off signals that stimulate an array of events including the induction of glucose transport and cell growth. In Type 2 and sometimes Type 1 diabetes, this signalling system is inefficient, and the cell’s ability to respond to insulin is impaired - a condition known as insulin resistance.
Three agents affecting insulin action have been identified: free fatty acids, TNF-alpha and a protein called leptin, first found to affect insulin function by Prof. Menachem Rubinstein of Weizmann’s Molecular Genetics Department.
Leptin first made headlines in 1994, when scientists discovered that daily leptin injections cause genetically obese mice to eat less and lose weight. However, working with human liver cells, Rubinstein and colleagues Drs. Batya Cohen and Daniela Novick found that excessive leptin actually disrupts insulin function.
The team found that when leptin binds to liver cells, the resulting biochemical cascade prevents a key insulin receptor from being phosphorylated (the process in which phosphate molecules attach to a protein). This failure results in impaired insulin performance - particularly affecting its ability to slow down the creation of new glucose in the blood, thus raising blood sugar levels in the body.
Unlike the much-publicized obese mice, which had a genetic mutation causing leptin deficiency, obese humans are known to have high blood leptin levels. Rubinstein’s study may therefore explain why overweight people are five times more likely to develop diabetes than people of normal weight, as well as pointing the way toward new treatments. These findings also sound a warning bell regarding the use of leptin in weight-reducing drugs, since it may be an accelerating factor in the development of diabetes.