Diabetes, Vol 46, Issue 7 1111-1119, Copyright © 1997 by American Diabetes Association

ARTICLES

Fatty acids mediate the acute extrahepatic effects of insulin on hepatic glucose production in humans

GF Lewis, M Vranic, P Harley and A Giacca
Department of Medicine, University of Toronto, Ontario, Canada. glewis@torhosp.toronto.on.ca

We have shown previously in humans that insulin partly suppresses hepatic glucose production (HGP) by an extrahepatic (indirect) mechanism. In the present study, we investigated the role of free fatty acids (FFAs) in mediating the extrahepatic effects of insulin in humans and determined the extent to which insulin can regulate HGP by a non-FFA-mediated effect. Sixteen healthy men received an intravenous tolbutamide infusion for 3 h, and pancreatic insulin secretion was calculated by deconvolution of peripheral C-peptide levels. On a subsequent occasion, equimolar exogenous insulin was infused by peripheral vein. In both studies, glucose was clamped at euglycemia. We have previously validated this method and shown no independent insulin-like activity of tolbutamide. During the clamp, 9 of the 16 subjects received a low dose of heparin and Intralipid to prevent the insulin-induced suppression of FFAs, while 7 subjects received a high dose of heparin and Intralipid to raise FFAs approximately 2.5-fold. In both the high- and low-dose groups, peripheral insulin was higher and calculated portal insulin lower with peripheral versus portal insulin delivery. In the low-dose group, HGP decreased by 68.3 +/- 2.1% with portal insulin delivery and 64.7 +/- 3.7% with peripheral insulin delivery (NS). In the high-dose group, HGP decreased by 58.0 +/- 4.5% with portal insulin and 48.3 +/- 5.0% with peripheral insulin (P < 0.05). Four individuals who participated in the high-dose group underwent an additional peripheral insulin study in which the same dose of exogenous insulin was infused as in the high-dose group but in the absence of heparin and Intralipid. During this latter study, FFA levels declined by approximately 90% during hyperinsulinemia, and HGP was suppressed by 71.8 +/- 5.6%, which was a much greater suppression (P < 0.01) than when FFA levels were raised in these subjects during the equivalent rate insulin infusion. In summary, the previously observed greater suppression of HGP with equimolar peripheral versus portal insulin is eliminated or reversed, depending on plasma FFA levels, if FFAs are prevented from decreasing, suggesting an important role of FFAs in mediating the extrahepatic effects of insulin on HGP. However, the effect of FFA clamping is relatively small with a significant degree of suppression of HGP (by approximately 50%), which remains even when FFAs are elevated above basal levels, suggesting that in the physiological range FFAs only partially influence the suppression of HGP in humans. This suggests that other mechanisms, most likely hepatic, dominate the acute insulin-induced suppression of glucose production.
CiteULike    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

				H. V. Lin, J.-Y. Kim, A. Pocai, L. Rossetti, L. Shapiro, P. E. Scherer, and D. Accili Adiponectin Resistance Exacerbates Insulin Resistance in Insulin Receptor Transgenic/Knockout Mice Diabetes, August 1, 2007; 56(8): 1969 - 1976. [Abstract] [Full Text] [PDF]

				H.-Y. Liu, Q. F. Collins, Y. Xiong, F. Moukdar, E. G. Lupo Jr., Z. Liu, and W. Cao Prolonged Treatment of Primary Hepatocytes with Oleate Induces Insulin Resistance through p38 Mitogen-activated Protein Kinase J. Biol. Chem., May 11, 2007; 282(19): 14205 - 14212. [Abstract] [Full Text] [PDF]

				J. Girard The Inhibitory Effects of Insulin on Hepatic Glucose Production Are Both Direct and Indirect Diabetes, December 1, 2006; 55(Supplement_2): S65 - S69. [Abstract] [Full Text] [PDF]

				Q. F. Collins, Y. Xiong, E. G. Lupo Jr., H.-Y. Liu, and W. Cao p38 Mitogen-activated Protein Kinase Mediates Free Fatty Acid-induced Gluconeogenesis in Hepatocytes J. Biol. Chem., August 25, 2006; 281(34): 24336 - 24344. [Abstract] [Full Text] [PDF]

				E. Prodi and S. Obici Minireview: The Brain as a Molecular Target for Diabetic Therapy Endocrinology, June 1, 2006; 147(6): 2664 - 2669. [Abstract] [Full Text] [PDF]

				K. F. Petersen, S. Dufour, D. Befroy, M. Lehrke, R. E. Hendler, and G. I. Shulman Reversal of Nonalcoholic Hepatic Steatosis, Hepatic Insulin Resistance, and Hyperglycemia by Moderate Weight Reduction in Patients With Type 2 Diabetes Diabetes, March 1, 2005; 54(3): 603 - 608. [Abstract] [Full Text] [PDF]

				R. C. Camacho, R. R. Pencek, D. B. Lacy, F. D. James, and D. H. Wasserman Suppression of Endogenous Glucose Production by Mild Hyperinsulinemia During Exercise Is Determined Predominantly by Portal Venous Insulin Diabetes, February 1, 2004; 53(2): 285 - 293. [Abstract] [Full Text]

				C. B. Jensen, H. Storgaard, J. J. Holst, F. Dela, S. Madsbad, and A. A. Vaag Insulin Secretion and Cellular Glucose Metabolism after Prolonged Low-Grade Intralipid Infusion in Young Men J. Clin. Endocrinol. Metab., June 1, 2003; 88(6): 2775 - 2783. [Abstract] [Full Text] [PDF]

				T. K. T. Lam, A. Carpentier, G. F. Lewis, G. van de Werve, I. G. Fantus, and A. Giacca Mechanisms of the free fatty acid-induced increase in hepatic glucose production Am J Physiol Endocrinol Metab, May 1, 2003; 284(5): E863 - E873. [Abstract] [Full Text] [PDF]

				N. Gupta, H. Sandhu, T. Goh, K. Shah, S. R. Wiesenthal, H. Yoshii, V. Chong, T. K. T. Lam, C. A. Haber, W. Williams, et al. Insulin inhibits glucose production by a direct effect in diabetic depancreatized dogs during euglycemia Am J Physiol Endocrinol Metab, November 1, 2002; 283(5): E1002 - E1007. [Abstract] [Full Text] [PDF]

				T. K. T. Lam, H. Yoshii, C. A. Haber, E. Bogdanovic, L. Lam, I. G. Fantus, and A. Giacca Free fatty acid-induced hepatic insulin resistance: a potential role for protein kinase C-delta Am J Physiol Endocrinol Metab, October 1, 2002; 283(4): E682 - E691. [Abstract] [Full Text] [PDF]

				M. Hawkins, I. Gabriely, R. Wozniak, K. Reddy, L. Rossetti, and H. Shamoon Glycemic Control Determines Hepatic and Peripheral Glucose Effectiveness in Type 2 Diabetic Subjects Diabetes, July 1, 2002; 51(7): 2179 - 2189. [Abstract] [Full Text] [PDF]

				Y. Sun, S. Liu, S. Ferguson, L. Wang, P. Klepcyk, J. S. Yun, and J. E. Friedman Phosphoenolpyruvate Carboxykinase Overexpression Selectively Attenuates Insulin Signaling and Hepatic Insulin Sensitivity in Transgenic Mice J. Biol. Chem., June 21, 2002; 277(26): 23301 - 23307. [Abstract] [Full Text] [PDF]

				R. L. Dobbins, L. S. Szczepaniak, J. Myhill, Y. Tamura, H. Uchino, A. Giacca, and J. D. McGarry The Composition of Dietary Fat Directly Influences Glucose-Stimulated Insulin Secretion in Rats Diabetes, June 1, 2002; 51(6): 1825 - 1833. [Abstract] [Full Text] [PDF]

				G. F. Lewis, A. Carpentier, K. Adeli, and A. Giacca Disordered Fat Storage and Mobilization in the Pathogenesis of Insulin Resistance and Type 2 Diabetes Endocr. Rev., April 1, 2002; 23(2): 201 - 229. [Abstract] [Full Text] [PDF]

				E. E. Blaak and A. J.M. Wagenmakers The Fate of [U-13C]Palmitate Extracted by Skeletal Muscle in Subjects With Type 2 Diabetes and Control Subjects Diabetes, March 1, 2002; 51(3): 784 - 789. [Abstract] [Full Text] [PDF]

				M. Mensink, E. E. Blaak, M. A. van Baak, A. J.M. Wagenmakers, and W. H.M. Saris Plasma Free Fatty Acid Uptake and Oxidation Are Already Diminished in Subjects at High Risk for Developing Type 2 Diabetes Diabetes, November 1, 2001; 50(11): 2548 - 2554. [Abstract] [Full Text] [PDF]

				V. Rigalleau, C. Binnert, K. Minehira, N. Stefanoni, P. Schneiter, E. Henchoz, O. Matzinger, C. Cayeux, E. Jéquier, and L. Tappy In Normal Men, Free Fatty Acids Reduce Peripheral but Not Splanchnic Glucose Uptake Diabetes, April 1, 2001; 50(4): 727 - 732. [Abstract] [Full Text]

				J. E. Gerich, C. Meyer, H. J. Woerle, and M. Stumvoll Renal Gluconeogenesis: Its importance in human glucose homeostasis Diabetes Care, February 1, 2001; 24(2): 382 - 391. [Abstract] [Full Text]

				S. D. Mittelman and R. N. Bergman Inhibition of lipolysis causes suppression of endogenous glucose production independent of changes in insulin Am J Physiol Endocrinol Metab, September 1, 2000; 279(3): E630 - E637. [Abstract] [Full Text] [PDF]

				A. Carpentier, S. D. Mittelman, R. N. Bergman, A. Giacca, and G. F. Lewis Acute enhancement of insulin secretion by FFA in humans is lost with prolonged FFA elevation Am J Physiol Endocrinol Metab, June 1, 1999; 276(6): E1055 - E1066. [Abstract] [Full Text] [PDF]

				G. F. Lewis, A. Carpentier, D. Bilinski, A. Giacca, and M. Vranic Counterregulatory Response to Hypoglycemia Differs According to the Insulin Delivery Route, But Does Not Affect Glucose Production in Normal Humans J. Clin. Endocrinol. Metab., March 1, 1999; 84(3): 1037 - 1046. [Abstract] [Full Text]

				K. Zierler Whole body glucose metabolism Am J Physiol Endocrinol Metab, March 1, 1999; 276(3): E409 - E426. [Abstract] [Full Text] [PDF]

				C. Meyer, J. Dostou, V. Nadkarni, and J. Gerich Effects of physiological hyperinsulinemia on systemic, renal, and hepatic substrate metabolism Am J Physiol Renal Physiol, December 1, 1998; 275(6): F915 - F921. [Abstract] [Full Text] [PDF]

				G. F. Lewis, M. Vranic, and A. Giacca Role of free fatty acids and glucagon in the peripheral effect of insulin on glucose production in humans Am J Physiol Endocrinol Metab, July 1, 1998; 275(1): E177 - E186. [Abstract] [Full Text] [PDF]

				R. H. McCall, S. R. Wiesenthal, Z. Q. Shi, K. Polonsky, and A. Giacca Insulin acutely suppresses glucose production by both peripheral and hepatic effects in normal dogs Am J Physiol Endocrinol Metab, February 1, 1998; 274(2): E346 - E356. [Abstract] [Full Text] [PDF]