Mechanism by which metformin reduces glucose production in type 2 diabetes

Citation
Rs. Hundal et al., Mechanism by which metformin reduces glucose production in type 2 diabetes, DIABETES, 49(12), 2000, pp. 2063-2069
Citations number
44
Categorie Soggetti
Endocrynology, Metabolism & Nutrition","Endocrinology, Nutrition & Metabolism
Journal title
DIABETES
ISSN journal
00121797 → ACNP
Volume
49
Issue
12
Year of publication
2000
Pages
2063 - 2069
Database
ISI
SICI code
0012-1797(200012)49:12<2063:MBWMRG>2.0.ZU;2-G
Abstract
To examine the mechanism by which metformin lowers endogenous glucose produ ction in type 2 diabetic patients, we studied seven type 2 diabetic subject s, with fasting hyperglycemia (15.5 +/- 1.3 mmol/l), before and after 3 mon ths of metformin treatment. Seven healthy subjects, matched for sex, age, a nd BMI,served as control subjects. Rates of net hepatic glycogenolysis, est imated by C-13 nuclear magnetic resonance spectroscopy, were combined with estimates of contributions to glucose production of gluconeogenesis and gly cogenolysis, measured by labeling of blood glucose by H-2 from ingested (H2 O)-H-2. Glucose production was measured using [6,6-H-2(2)]glucose. The rate of glucose production was twice as high in the diabetic subjects as in con trol subjects (0.70 +/- 0.05 vs. 0.36 +/- 0.03 mmol m(-2) min(-1), P < 0.00 01). Metformin reduced that rate by 24% (to 0.53 +/- 0.03 mmol.m(-2).min(-1 ), P = 0.0009) and fasting plasma glucose concentration by 30% (to 10.8 +/- 0.9 mmol/l, P = 0.0002). The rate of gluconeogenesis was three times highe r in the diabetic subjects than in the control subjects (0.59 +/- 0.03 vs. 0.18 +/- 0.03 mmol.m(-2). min(-1)) and metformin reduced that rate by 36% ( to 0.38 +/- 0.03 mmol.m(-2).min(-1), P = 0.01). By the (H2O)-H-2 method, th ere was a twofold increase in rates of gluconeogenesis in diabetic subjects (0.42 +/- 0.04 mmol.m(-2).min(-1)), which decreased by 33% after metformin treatment (0.28 +/- 0.03 mmol.m(-2).min(-1), P = 0.0002). There was no gly cogen cycling in the control subjects, but in the diabetic subjects, glycog en cycling contributed to 25% of glucose production and explains the differ ences between the two methods used, In conclusion, patients with poorly con trolled type 2 diabetes have increased rates of endogenous glucose producti on, which can be attributed to increased rates of gluconeogenesis. Metformi n lowered the rate of glucose production in these patients through a reduct ion in gluconeogenesis.