A new insight towards the treatment of Diabetes

GENEVA, Switzerland, December 9, 1999 Pierre Maechler and Claes Wollheim of the Medical School at the University of Geneva has identified a new molecule that plays a role in the regulation of insulin secretion. The work will be published in the December 9^, 1999 issue of Nature. This discovery opens new possibilities towards novel therapeutics for diabetes.

Over the last five years, Prof Wollheim s laboratory has established several methods permitting the elucidation of the role of mitochondria in metabolism-secretion coupling in the beta cell. To this end, ??_m, [Ca²⁺]_m, cytosolic [ATP] and insulin secretion were measured singly and in combination in intact and permeabilized cells. These methods, as well as the measurement of Ca²⁺ in the endoplasmic reticulum, have helped to clarify the initial events in the impairment of insulin secretion caused by oxidative stress. In order to study the link between [Ca²⁺]_c, mitochondrial activation and the exocytosis of insulin, we have permeabilized cells with ?-toxin. This approach renders possible the clamping of cytosolic [ATP] and [Ca²⁺]_c at permissive concentrations, as well as the direct stimulation of mitochondrial metabolism by various substrates. Mitochondrial activation using the TCA cycle intermediate succinate was associated with a marked stimulation of insulin release. These results suggested that insulin secretion caused by mitochondrial substrates involves the generation of factors which require both a rise of [Ca²⁺]_m and a supply of carbons for the TCA cycle.

Molecules derived from mitochondrial metabolism were then screened for their secretagogue activity in permeabilized beta cells. This screening suggested glutamate to be a candidate for the putative messenger. Glutamate is formed in the mitochondria from the TCA cycle intermediate ?-ketoglutarate by glutamate dehydrogenase. In the beta cell glutamate was found to be generated by the mitochondria during glucose elevation. In permeabilized cells, under conditions of permissive clamped [Ca²⁺]_c, added glutamate directly stimulates insulin exocytosis independently of mitochondrial function. These results suggest that glutamate, in contrast to succinate, acts downstream of mitochondrial metabolism.

These results demonstrate that glutamate acts as an intracellular messenger, coupling glucose metabolism to insulin secretion.

For more information, please contact Dr. Pierre Maechler; Email: pierre.maechler@medecine.unige.ch;tel: + 41 22 702 55 54