Upregulated hexokinase activity in isolated islets from diabetic 90% pancreatectomized rats.
Glucokinase is the beta-cell glucose sensor, i.e., the site in glucose metabolism that determines the glucose set-point (sensitivity) for insulin secretion. Hexokinase is also present, but it normally contributes little to glucose metabolism because of end-product inhibition by glucose 6-phosphate. There is a lowered glucose set-point for insulin secretion in 90% pancreatectomized (Px) diabetic rats. We investigated the mechanism by measuring hexokinase and glucokinase activity in islet extracts. Glucokinase activity was minimally raised in Px islets (Vmax 125% of sham-operated control rats). In contrast, hexokinase Vmax was 250% of the control value, suggesting that the increased hexokinase activity caused the beta-cell glucose hypersensitivity. Additional evidence was obtained with a 40-h fast that was performed because of a previous observation that the inhibitory effect of fasting on insulin secretion was impaired in Px rats. Glucokinase activity fell normally in the Px rats (32 +/- 4% reduction in sham vs. 37 +/- 4% in Px rats) as opposed to hexokinase activity, which was unaffected in either group. In summary, a feature of hyperglycemia is upregulated islet hexokinase activity. The result is that hexokinase assumes partial control over the glucose set-point for insulin secretion. As such, regulatory effects on insulin secretion, such as fasting, that are mediated through glucokinase activity may be altered.
Hosokawa
H
H
Division of Endocrinology, Diabetes, Metabolism, and Molecular Medicine, New England Medical Center, Tufts University School of Medicine, Boston, Massachusetts, USA.
Hosokawa
Y A
YA
Leahy
J L
JL
D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000097:blood / Q000201:enzymology*; D004305:Dose-Response Relationship, Drug; D005215:Fasting; D005947:Glucose / Q000378:metabolism* / Q000494:pharmacology; D006593:Hexokinase / Q000378:metabolism*; D007515:Islets of Langerhans / Q000187:drug effects / Q000201:enzymology* / Q000378:metabolism; D007700:Kinetics; D008297:Male; D010180:Pancreatectomy; D010766:Phosphorylation; D051381:Rats; D017207:Rats, Sprague-Dawley; D012016:Reference Values; D015431:Weight Loss
D001786:Blood Glucose; D006593:Hexokinase; D005947:Glucose