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1 Department of Biochemistry, Boston University School of Medicine, Boston, Massachusetts, United States; Obesity Research Center, Evans Department of Medicine, Boston University Medical Center, Boston, Massachusetts, United States; Department of Pathology, Boston University School of Medicine, Boston, Massachusetts, United States
2 Rolf Luft Research Center for Diabetes and Endocrinology, Karolinska University Hospital, Stockholm, Sweden
3 Boston, United States; Department of Biochemistry, Boston University School of Medicine, Boston, Massachusetts, United States
4 Department of Biochemistry, Boston University School of Medicine, Boston, Massachusetts, United States
5 Obesity Research Center, Evans Department of Medicine, Boston University Medical Center, Boston, Massachusetts, United States
6 Department of Pharmacology, Southern Illinois University School of Medicine, Springfield, Illinois, United States
7 The Rolf Luft Research Center for Diabetes and Endocrinology, Karolinska Institutet, Stockholm, Stockholm Region, Sweden
8 Department of Biochemistry, Boston University School of Medicine, Boston, Massachusetts, United States; Obesity Research Center, Evans Department of Medicine, Boston University Medical Center, Boston, Massachusetts, United States
* To whom correspondence should be addressed. E-mail: tornheim{at}bu.edu.
Phosphofructokinase is a key enzyme of glycolysis that exists as homo- and heterotetramers of three subunit isoforms, M, L and C. Mice with a disrupting tag inserted near the distal promoter of the phosphofructokinase-M gene showed tissue-dependent differences in loss of that isoform: 99% in brain and 95-98% in islets, but only 50-75% in skeletal muscle and little if any loss in heart. This correlated with the continued presence of proximal transcripts specifically in muscle tissues. These data strongly support the proposed two promoter system of the gene, with ubiquitous use of the distal promoter and additional use of the proximal promoter selectively in muscle. Interestingly, the mice were glucose intolerant and had somewhat elevated fasting and fed blood glucose levels; however, they did not have an abnormal insulin tolerance test, consistent with the less pronounced loss of phosphofructokinase-M in muscle. Isolated perifused islets showed about 50% decreased glucose-stimulated insulin secretion and reduced amplitude and regularity of secretory oscillations. Oscillations in cytoplasmic free Ca2+ and the rise in the ATP/ADP ratio appeared normal. Secretory oscillations still occurred in the presence of diazoxide and high KCl, indicating an oscillation mechanism not requiring dynamic Ca2+ changes. The results suggest the importance of phosphofructokinase-M for insulin secretion, although glucokinase is the overall rate-limiting glucose sensor. Whether the Ca2+ oscillations and residual insulin oscillations in this mouse model are due to the residual 2-5% phosphofructokinase-M or to other phosphofructokinase isoforms present in islets or involve another metabolic oscillator remains to be determined.
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