IMPAIRED PHOSPHOINOSITIDE METABOLISM IN GLUCOSE-INCOMPETENT ISLETS OFNEONATALLY STREPTOZOTOCIN-DIABETIC RATS

The effects of nutrient and neurotransmitter stimuli on insulin releas e, loss of phosphoinositides (PI), and production of inositol phosphat es (InsP) were investigated in islets from neonatally streptozotocin-i njected (nSTZ) rats. In islets from nSTZ rats, insulin secretory respo nses to 16.7 mM D-glucose and 10.0 mM D-glyceraldehyde were reduced co mpared with controls. Contents in phosphatidylinositol 4-monophosphate [PtdIns(4)P] and phosphatidylinositol 4,5-bisphosphate [PtdIns(4,5)P- 2], but not in phosphatidylinositol, were diminished. Glucose effects on breakdown of PtdIns(4)P and PtdIns(4,5)P-2 and on total InsP accumu lation were both reduced. D-Glucose was unable to increase the levels of both inositol trisphosphate isomers, Ins(1,3,4)P-3 and Ins(1,4,5)P- 3. Glyceraldehyde also failed to promote InsP formation. By contrast, the ability of 1.0 mM carbachol or 300 nM cholecystokinin to stimulate insulin secretion and InsP generation was still observed. Thus a dist urbed coupling between nutrient recognition and activation of phosphol ipase C, possibly together with a shortage of available polyphosphoino sitides, could be responsible for the altered islet PI turnover in the nSTZ rats. It is proposed that such defects may contribute to the imp airment of glucose-stimulated insulin secretion in this model of non-i nsulin-dependent diabetes mellitus.