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 alteration in the activity of phosphofructokinase (PFK), a key enzyme in the glycolytic pathway, may play a role in the abnormal glucose-induced insulin secretion. In this study, we evaluated insulin secretion in transgenic (Tg) mice overexpressing the liver-type subunit of phosphofructokinase (PFKL). Three independently derived Tg-PFKL lines showed random and postprandial hyperglycemia with diminished acute insulin response following intravenous glucose tolerance load. Isolated islets of Tg-PFKL mice exhibited a shift to the right of the glucose insulin dose 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 of PFKL. Conceivably, a selective overexpression of the PFKL isoform in Tg-PFKL mice altered the enzymatic properties of the tetrameric PFK and thereby affected glucose metabolism. A similar phenomenon was previously observed in transfected PC12-PFKL cells. The data show that overexpression of PFKL in transgenic mice was associated with diminished glucose-induced insulin response and suggest a mechanism to explain the role of beta-cell PFK activity in glucose-induced insulin secretion.
Knobler
H
H
Division of Endocrinology, Kaplan Hospital Rehovot, Israel. knobler@inter.net.il
Weiss
Y
Y
Peled
M
M
Groner
Y
Y
D000367:Age Factors; D000818:Animals; D001786:Blood Glucose / Q000502:physiology*; D001835:Body Weight; D005247:Feeding Behavior / Q000502:physiology; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000378:metabolism; D007527:Isoenzymes / Q000502:physiology; D051379:Mice; D008822:Mice, Transgenic; D010732:Phosphofructokinase-1 / Q000502:physiology*; D012636:Secretory Rate
D001786:Blood Glucose; D007328:Insulin; D007527:Isoenzymes; D010732:Phosphofructokinase-1