IMPAIRED GLUCOSE-INDUCED INSULIN-RESPONSE IN TRANSGENIC MICE OVEREXPRESSING THE L-PHOSPHOFRUCTOKINASE GENE

The selective impairment of glucose-induced insulin secretion in NIDDM can be attributed to defects in the glucose-signaling system. An alte ration in the activity of phosphofructokinase (PFK), a key enzyme in t he glycolytic pathway, may play a role in the abnormal glucose-induced insulin secretion. In this study, we evaluated insulin secretion in t ransgenic (Tg) mice overexpressing the liver-type subunit of phosphofr uctokinase (PFKL). Three independently derived Tg-PFKL lines showed ra ndom and postprandial hyperglycemia, with diminished acute insulin res ponse following intravenous glucose tolerance load. Isolated islets of Tg-PFKL mice exhibited a shift to the right of the glucose insulin do se curve. However, the maximal insulin secretory capacity, as well as the potentiation effect by arginine, were retained. PFK activity in Tg -PFKL, islets was increased by 30-70%, because of the overexpression o f PFKL. Conceivably, a selective overexpression of the PFKL isoform in Tg-PFKL mice altered the enzymatic properties of the tetrameric PFK a nd thereby affected glucose metabolism. A similar phenomenon was previ ously observed in transfected PC12-PFKL cells. The data show that over expression of PFKL in transgenic mice was associated with diminished g lucose-induced insulin response and suggest a mechanism to explain the role of beta-cell PFK activity in glucose-induced insulin secretion.