The acute effect of metformin on glucose production in the conscious dog is primarily attributable to inhibition of glycogenolysis

被引:23
作者
Chu, CA
Wiernsperger, N
Muscato, N
Knauf, M
Neal, DW
Cherrington, AD
机构
[1] Vanderbilt Univ, Sch Med, Dept Physiol & Mol Biophys, Nashville, TN 37232 USA
[2] Grp Lyonnaise Ind Pharmaceut, LIPHA, Lyon, France
来源
METABOLISM-CLINICAL AND EXPERIMENTAL | 2000年 / 49卷 / 12期
关键词
D O I
10.1053/meta.2000.18561
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
Although metformin has been used worldwide to treat type 2 diabetes for several decades, its mechanism of action on glucose homeostasis remains controversial. To further assess the effect of metformin on glucose metabolism, 10 42-hour-fasted conscious dogs were studied in the absence ([Con] n = 5) and presence ([Met] n = 5) of a portal infusion of metformin (0.15 mg . kg(-1) . min(-1)) over 300 minutes. Hepatic glucose production was measured by both arteriovenous-difference and tracer methods. All dogs were maintained on a pancreatic clamp and in a euglycemic state to ensure that any changes in glucose metabolism would result directly from the effects of metformin. The arterial metformin level was 21 +/- 3 mug/mL during the test period. Net hepatic glucose output (NHGO) decreased in Met dogs from 1.9 +/- 0.2 to 0.7 +/- 0.1 mg . kg(-1) . min(-1)(P < .05). NHGO remained unchanged in Con dogs (1.7 +/- 0.3 to 1.5 +/- 0.3 mg . kg(-1)min(-1)). Tracer-determined glucose production paralleled NHGO. The net hepatic glycogenolytic rate decreased from 1.0 +/- 0.2 to -0.3 +/- 0.2 mg . kg(-1) . min(-1)(P < .05) in Met dogs, but remained unchanged in Con dogs (0.8 +/- 0.2 to 0.8 +/- 0.3 mg kg-l min-l). No significant change in gluconeogenic flux was found in either the Met group (1.2 +/- 0.3 to 1.3 +/- 0.3 mg . kg(-1) . min(-1)) or the Con group (1.3 +/- 0.4 to 1.0 +/- 0.3 mg . kg(-1) . min(-1)). No significant changes were observed in glucose utilization or glucose clearance in either group. In conclusion, in the normal fasted dog, (1) the primary acute effect of metformin on glucose metabolism was an inhibition of hepatic glucose production and not a stimulation of glucose utilization; and (2) the inhibition of glucose production was attributable to a decrease in hepatic glycogenolysis and not to an alteration in gluconeogenic flux. Copyright (C) 2000 by W.B. Saunders Company.
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页码:1619 / 1626
页数:8
相关论文
共 22 条
[1]   METFORMIN DECREASES GLUCONEOGENESIS BY ENHANCING THE PYRUVATE-KINASE FLUX IN ISOLATED RAT HEPATOCYTES [J].
ARGAUD, D ;
ROTH, H ;
WIERNSPERGER, N ;
LEVERVE, XM .
EUROPEAN JOURNAL OF BIOCHEMISTRY, 1993, 213 (03) :1341-1348
[2]  
CHRISTIANSEN MP, 1997, DIABETES S1, V46, pA244
[3]   Comparison of the direct and indirect effects of epinephrine on hepatic glucose production [J].
Chu, CA ;
Sindelar, DK ;
Neal, DW ;
Allen, EJ ;
Donahue, EP ;
Cherrington, AD .
JOURNAL OF CLINICAL INVESTIGATION, 1997, 99 (05) :1044-1056
[4]   Direct effects of catecholamines on hepatic glucose production in conscious dog are due to glycogenolysis [J].
Chu, CA ;
Sindelar, DK ;
Neal, DW ;
Cherrington, AD .
AMERICAN JOURNAL OF PHYSIOLOGY-ENDOCRINOLOGY AND METABOLISM, 1996, 271 (01) :E127-E137
[5]   Metabolic effects of metformin on glucose and lactate metabolism in noninsulin-dependent diabetes mellitus [J].
Cusi, K ;
Consoli, A ;
DeFronzo, RA .
JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM, 1996, 81 (11) :4059-4067
[6]   MECHANISM OF METFORMIN ACTION IN OBESE AND LEAN NONINSULIN-DEPENDENT DIABETIC SUBJECTS [J].
DEFRONZO, RA ;
BARZILAI, N ;
SIMONSON, DC .
JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM, 1991, 73 (06) :1294-1301
[7]   Effects of metformin on the pathways of glucose utilization after oral glucose in non-insulin-dependent diabetes mellitus patients [J].
Fery, F ;
Plat, L ;
Balasse, EO .
METABOLISM-CLINICAL AND EXPERIMENTAL, 1997, 46 (02) :227-233
[8]   PREDOMINANT ROLE OF GLUCONEOGENESIS IN THE HEPATIC GLYCOGEN REPLETION OF DIABETIC RATS [J].
GIACCARI, A ;
ROSSETTI, L .
JOURNAL OF CLINICAL INVESTIGATION, 1992, 89 (01) :36-45
[9]   Effect of prior exercise on the partitioning of an intestinal glucose load between splanchnic bed and skeletal muscle [J].
Hamilton, KS ;
Gibbons, FK ;
Bracy, DP ;
Lacy, DB ;
Cherrington, AD ;
Wasserman, DH .
JOURNAL OF CLINICAL INVESTIGATION, 1996, 98 (01) :125-135
[10]   METFORMIN IMPROVES PERIPHERAL BUT NOT HEPATIC INSULIN ACTION IN OBESE PATIENTS WITH TYPE-II DIABETES [J].
HOTHERNIELSEN, O ;
SCHMITZ, O ;
ANDERSEN, PH ;
BECKNIELSEN, H ;
PEDERSEN, O .
ACTA ENDOCRINOLOGICA, 1989, 120 (03) :257-265