Causal linkage between insulin suppression of lipolysis and suppression of liver glucose output in dogs

被引:251
作者
Rebrin, K [1 ]
Steil, GM [1 ]
Mittelman, SD [1 ]
Bergman, RN [1 ]
机构
[1] UNIV SO CALIF, SCH MED, DEPT PHYSIOL & BIOPHYS, LOS ANGELES, CA 90033 USA
关键词
adipose tissue; insulin action; hepatic glucose output; free fatty acids; lipolysis;
D O I
10.1172/JCI118846
中图分类号
R-3 [医学研究方法]; R3 [基础医学];
学科分类号
1001 ;
摘要
Suppression of hepatic glucose output (HGO) has been shown to be primarily mediated by peripheral rather than portal insulin concentrations; however, the mechanism by which peripheral insulin suppresses HGO has not yet been determined. Previous findings by our group indicated a strong correlation between free fatty acids (FFA) and HGO, Suggesting that;insulin suppression of HGO is mediated via suppression of lipolysis. To directly test the hypothesis that insulin suppression of HGO is causally linked to the suppression of adipose tissue lipolysis, we performed euglycemic-hyperinsulinemic glucose clamps in conscious dogs (n=8) in which FFA were either allowed to fall or were prevented from falling with Liposyn plus heparin infusion (LI; 0.5 ml/min 20% Liposyn plus 25 U/min heparin with a 250 U prime). Endogenous insulin and glucagon were suppressed with somatostatin (1 mu g/min/kg), and insulin was infused at a rate of either 0.125 or 0.5 mU/min/kg. Two additional experiments were performed at the 0.5 mU/min/kg insulin dose: a double Liposyn infusion (2xLI; 1.0 ml/min 20% Liposyn, heparin as above), and a glycerol infusion (19 mg/min). With the 0.125 mU/min/kg insulin infusion, FFA fell 40% and HGO fell 33%; preventing the fall in FFA with LI entirely prevented this decline in HGO. With 0.5 mU/min/kg insulin infusion, FFA levels fell 64% while HGO declined 62%. Preventing the fall in FFA at this higher insulin dose largely prevented the fall in HGO; however, steady state HGO still declined by 18%. Doubling the LI infusion did not further affect HGO, suggesting that the effect of FFA on HGO is saturable. Elevating plasma glycerol levels did not alter insulin's ability to suppress HGO. These data directly support the concept that insulin suppression of HGO is not direct, but rather is mediated via insulin suppression of adipose tissue lipolysis. Thus, resistance to insulin control of hepatic glucose production in obesity and/or non-insulin-dependent diabetes mellitus may reflect resistance of the adipocyte to insulin suppression of lipolysis.
引用
收藏
页码:741 / 749
页数:9
相关论文
共 49 条
  • [1] PERIPHERAL EFFECTS OF INSULIN DOMINATE SUPPRESSION OF FASTING HEPATIC GLUCOSE-PRODUCTION
    ADER, M
    BERGMAN, RN
    [J]. AMERICAN JOURNAL OF PHYSIOLOGY, 1990, 258 (06): : E1020 - E1032
  • [2] ANDERSEN L, 1993, CLIN CHEM, V39, P578
  • [3] BERGMAN RN, 1993, ADV EXP MED BIOL, V334, P181
  • [4] BERGMEYR HU, 1983, METHODS ENZYMATIC AN
  • [5] ACUTE ELEVATION OF FREE FATTY-ACID LEVELS LEADS TO HEPATIC INSULIN RESISTANCE IN OBESE SUBJECTS
    BEVILACQUA, S
    BONADONNA, R
    BUZZIGOLI, G
    BONI, C
    CIOCIARO, D
    MACCARI, F
    GIORICO, MA
    FERRANNINI, E
    [J]. METABOLISM-CLINICAL AND EXPERIMENTAL, 1987, 36 (05): : 502 - 506
  • [6] MECHANISMS OF FATTY ACID-INDUCED INHIBITION OF GLUCOSE-UPTAKE
    BODEN, G
    CHEN, XH
    RUIZ, J
    WHITE, JV
    ROSSETTI, L
    [J]. JOURNAL OF CLINICAL INVESTIGATION, 1994, 93 (06) : 2438 - 2446
  • [7] GLYCEROL TURNOVER AND OXIDATION IN MAN
    BORTZ, WM
    HAFF, AC
    HOLMES, WL
    PAUL, P
    [J]. JOURNAL OF CLINICAL INVESTIGATION, 1972, 51 (06) : 1537 - +
  • [8] DYNAMICS OF HEPATIC AND PERIPHERAL INSULIN EFFECTS SUGGEST COMMON RATE-LIMITING STEP INVIVO
    BRADLEY, DC
    POULIN, RA
    BERGMAN, RN
    [J]. DIABETES, 1993, 42 (02) : 296 - 306
  • [9] REGULATION OF FREE FATTY-ACID METABOLISM BY GLUCAGON
    CARLSON, MG
    SNEAD, WL
    CAMPBELL, PJ
    [J]. JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM, 1993, 77 (01) : 11 - 15
  • [10] INSULIN REGULATION OF RENAL GLUCOSE-METABOLISM IN CONSCIOUS DOGS
    CERSOSIMO, E
    JUDD, RL
    MILES, JM
    [J]. JOURNAL OF CLINICAL INVESTIGATION, 1994, 93 (06) : 2584 - 2589