Regulation of skeletal muscle hexokinase II by insulin in nondiabetic and NIDDM subjects.
Impaired muscle glucose phosphorylation to glucose-6-phosphate by hexokinases (HKs)-I and -II may contribute to insulin resistance in NIDDM and obesity. HK-II expression is regulated by insulin. We tested the hypothesis that basal and insulin-stimulated expression of HK-II is decreased in NIDDM and obese subjects. Skeletal muscle HK-I and HK-II activities were measured in seven lean and six obese normal subjects and eight patients with NIDDM before and at 3 and 5 h of a hyperinsulinemic (80 mU x m(-2) x min(-1)) euglycemic clamp. To assess whether changes in HK-II expression seen during a glucose clamp are likely to be physiologically relevant, we also measured HK-I and HK-II activity in 10 lean normal subjects before and after a high-carbohydrate meal. After an overnight fast, total HK, HK-I, and HK-II activities were similar in lean and obese control subjects; but HK-II was lower in NIDDM patients than in lean subjects (1.42 +/- 0.16 [SE] vs. 2.33 +/- 0.24 nmol x min(-1) x mg(-1) molecular weight, P < 0.05) and accounted for a lower proportion of total HK (33 +/- 3 vs. 47 +/- 3%, P < 0.025). HK-II (but not HK-I) activity increased during the clamp in lean and obese subjects by 34 and 36% after 3 h and by 14 and 22% after 5 h of hyperinsulinemia; no increase was found in the NIDDM patients. In the lean subjects, muscle HK-II activity also increased by 15% 4 h after the meal, from 2.47 +/- 0.19 basally to 2.86 +/- 0.28 nmol x min(-1) x mg(-1) protein (P < 0.05). During the clamps, muscle HK-II activity correlated with muscle citrate synthase activity in the normal subjects (r = 0.58, P < 0.05) but not in the NIDDM patients. A weak relationship was noted between muscle HK-II activity and glucose disposal rate at the end of the clamp when all three groups were combined (r = 0.49, P < 0.05). In summary, NIDDM patients have lower muscle HK-II activity basally and do not increase the activity of this enzyme in response to a 5-h insulin stimulus. This defect may contribute to their insulin resistance. In nondiabetic obese subjects, muscle HK-II expression and its regulation by insulin are normal.
Kruszynska
Y T
YT
Department of Endocrinology and Metabolism, University of California, San Diego, Veterans Administration Medical Center, La Jolla 92093, USA.
Mulford
M I
MI
Baloga
J
J
Yu
J G
JG
Olefsky
J M
JM
D000328:Adult; D001786:Blood Glucose / Q000378:metabolism; D002950:Citrate (si)-Synthase / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000201:enzymology*; D005260:Female; D015309:Glucose Clamp Technique; D006593:Hexokinase / Q000378:metabolism*; D006801:Humans; D006946:Hyperinsulinism / Q000201:enzymology; D007328:Insulin / Q000097:blood / Q000494:pharmacology*; D007333:Insulin Resistance; D008297:Male; D008875:Middle Aged; D018482:Muscle, Skeletal / Q000187:drug effects* / Q000201:enzymology*; D009765:Obesity / Q000201:enzymology; D010084:Oxidation-Reduction
D001786:Blood Glucose; D007328:Insulin; D002950:Citrate (si)-Synthase; D006593:Hexokinase