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Inhibition of lipolysis causes suppression of endogenous glucose production independent of changes in insulin

Published on Sep 1, 2000in American Journal of Physiology-endocrinology and Metabolism 4.02
· DOI :10.1152/ajpendo.2000.279.3.E630
Steven D. Mittelman29
Estimated H-index: 29
(SC: University of Southern California),
Richard N. Bergman103
Estimated H-index: 103
(SC: University of Southern California)
Abstract
We have shown that insulin controls endogenous glucose production (EGP) indirectly, via suppression of adipocyte lipolysis. Free fatty acids (FFA) and EGP are suppressed proportionately, and when the decline in FFA is prevented during insulin infusion, suppression of EGP is also prevented. The present study tested the hypothesis that suppression of lipolysis under conditions of constant insulin would yield a suppression of EGP. N 6-cyclohexyladenosine (CHA) was used to selectively suppress adipocyte lipolysis during euglycemic clamps in conscious male dogs. FFA suppression by CHA caused suppression of EGP. Liposyn control experiments, which maintained FFA levels above basal during CHA infusion, completely prevented the decline in EGP, whereas glycerol control experiments, which maintained glycerol levels close to basal, did not prevent a decline in EGP. These controls suggest that the EGP suppression was secondary to the suppression of FFA levels specifically. A difference in the sensitivity of FFA and EG...
  • References (36)
  • Citations (69)
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References36
Newest
Published on Feb 1, 1999in Journal of Clinical Investigation 13.25
Xinhua Chen23
Estimated H-index: 23
,
Nayyar Iqbal21
Estimated H-index: 21
,
Guenther Boden63
Estimated H-index: 63
We have quantitatively determined gluconeogenesis (GNG) from all precursors, using a novel method employing 2H20 to address the question of whether changes in plasma free fatty acids (FFA) affect GNG in healthy, nonobese subjects. In the first study (n = 6), plasma FFA were lowered at 16 to 20 hours with nicotinic acid (NA) and were then allowed to rise at 20 to 24 hours (FFA rebound after administration of NA). FFA decreased from 387 μM at 16 hours to 43 μM at 20 hours, and then rebounded to 1,...
226 Citations Source Cite
Published on May 1, 1998in Diabetes 7.27
Garry M. Steil40
Estimated H-index: 40
,
Kerstin Rebrin21
Estimated H-index: 21
+ 1 AuthorsRichard N. Bergman103
Estimated H-index: 103
The contribution of portal insulin delivery to the disappearance of glucose administered intravenously was assessed in the present study. Paired insulin-modified intravenous glucose tolerance tests (IVGTTs) were performed in dogs in which insulin was administered into the portal vein or into a peripheral vein. Peripheral insulin levels were matched in the paired IVGTTs by adjusting the portal insulin dose in proportion to first-pass hepatic insulin extraction. Two sets of IVGTTs were performed. ...
24 Citations Source Cite
Published on Dec 15, 1997in Journal of Clinical Investigation 13.25
Steven D. Mittelman29
Estimated H-index: 29
,
You-Yin Fu1
Estimated H-index: 1
+ 2 AuthorsRichard N. Bergman103
Estimated H-index: 103
Suppression of endogenous glucose production (EGP) is one of insulin's primary metabolic effects and failure of this action is a major contributor to fasting hyperglycemia of type 2 diabetes mellitus. Classically, insulin was thought to suppress the liver directly, via hyperinsulinemia in the portal vein. Recently, however, we and others have demonstrated that at least part, and possibly most of insulin's action to suppress EGP is normally mediated via an extrahepatic (i.e., indirect) mechanism....
84 Citations Source Cite
Published on Oct 1, 1997in Diabetes 7.27
Yolanta T. Kruszynska10
Estimated H-index: 10
(UCSD: University of California, San Diego),
Mim I Mulford1
Estimated H-index: 1
(UCSD: University of California, San Diego)
+ 2 AuthorsJerrold M. Olefsky106
Estimated H-index: 106
(UCSD: University of California, San Diego)
Impaired suppression of plasma nonesterified fatty acids (NEFAs) after glucose ingestion may contribute to glucose intolerance, but the mechanisms are unclear. Evidence that insulin inhibits hepatic glucose output (HGO), in part by suppressing plasma NEFA levels, suggests that impaired suppression of plasma NEFA after glucose ingestion would impair HGO suppression and increase the systemic delivery of glucose. To test this hypothesis, we studied glucose kinetics (constant intravenous [3-H]glucos...
41 Citations Source Cite
Published on Jul 1, 1997in Diabetes 7.27
Gary F. Lewis46
Estimated H-index: 46
,
Mladen Vranic44
Estimated H-index: 44
+ 1 AuthorsAdria Giacca42
Estimated H-index: 42
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 deconvolutio...
107 Citations Source Cite
Published on Mar 15, 1997in Journal of Clinical Investigation 13.25
Marilyn Ader28
Estimated H-index: 28
,
Ta-Chen Ni2
Estimated H-index: 2
,
Richard N. Bergman103
Estimated H-index: 103
Glucose tolerance is determined by both insulin action and insulin-independent effects, or “glucose effectiveness,” which includes glucose-mediated stimulation of glucose uptake (R d ) and suppression of hepatic glucose output (HGO). Despite its importance to tolerance, controversy surrounds accurate assessment of glucose effectiveness. Furthermore, the relative contributions of glucose’s actions on R d and HGO under steady state and dynamic conditions are unclear. We performed hyperglycemic cla...
77 Citations Source Cite
Published on Mar 1, 1997in The Journal of Clinical Endocrinology and Metabolism 5.79
Françoise Fery18
Estimated H-index: 18
,
Laurence Plat5
Estimated H-index: 5
+ 1 AuthorsEdmond Balasse23
Estimated H-index: 23
The role played by circulating free fatty acids (FFA) and fat oxidation in the regulation of whole body glucose production and uptake in the basal state is still a matter of debate. This question was analyzed in nine normal overnight fasted volunteers in whom glucose kinetics ([3-3H]glucose infusion) and substrate oxidation rates (indirect calorimetry) were measured during 10.5 h both under placebo conditions and during experimental antilipolysis induced by Acipimox given orally during the last ...
25 Citations Source Cite
Published on Jan 1, 1997in Diabetes 7.27
Duna Massillon7
Estimated H-index: 7
(Yeshiva University),
Nir Barzilai69
Estimated H-index: 69
+ 2 AuthorsLuciano Rossetti75
Estimated H-index: 75
(Yeshiva University)
The distal enzymatic step in the process of glucose output is catalyzed by the glucose-6-phosphatase (Glc-6-Pase) complex. The recently cloned catalytic unit of this complex has been shown to be regulated by insulin, dexamethasone, cAMP, and glucose. Using a combination of intralipid and/or nicotinic acid infusions and a pancreatic clamp technique, we maintained plasma free fatty acids (FFAs) at three different levels (0.26 ± 0.07, 0.56 ± 0.09, and 1.59 ± 0.12 mmol/1) in the presence of well-con...
111 Citations Source Cite
Published on Nov 1, 1996in Metabolism-clinical and Experimental 5.96
Ki-Up Lee46
Estimated H-index: 46
,
Joong Y. Park10
Estimated H-index: 10
+ 4 AuthorsSung W. Park4
Estimated H-index: 4
Abstract Increased availability of free fatty acids (FFA) may play a role in the pathogenesis of insulin resistance in the liver. We examined the effects of an antilipolytic nicotinic acid analog (acipimox) on hepatic glucose metabolism in basal and hyperinsulinemic states in normal rats. Acipimox decreased plasma FFA levels profoundly and enhanced the ability of insulin to suppress hepatic glucosa production (HGP) and to stimulate peripheral glucose utilization. In the basal state, acipimox inh...
22 Citations Source Cite
Published on Aug 1, 1996in Journal of Clinical Investigation 13.25
Kerstin Rebrin21
Estimated H-index: 21
,
Garry M. Steil40
Estimated H-index: 40
+ 1 AuthorsRichard N. Bergman103
Estimated H-index: 103
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 l...
225 Citations Source Cite
Cited By69
Newest
Published on Mar 13, 2019in Drug Safety 3.64
Lee S. Nguyen1
Estimated H-index: 1
(University of Paris),
M. Vautier3
Estimated H-index: 3
(University of Paris)
+ 4 AuthorsJoe-Elie Salem9
Estimated H-index: 9
(University of Paris)
Inhibitors of mechanistic target of rapamycin (mTOR inhibitors) are used as antiproliferative immunosuppressive drugs and have many clinical applications in various drug combinations. Experience in transplantation studies has been gained regarding the side effect profile of these drugs and the potential benefits and limitations compared with other immunosuppressive agents. This article reviews the adverse effects of mTOR inhibitors in solid organ transplantation, with special attention given to ...
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Published on Jul 14, 2017in The EMBO Journal 10.56
Alexandros Vegiopoulos15
Estimated H-index: 15
(DKFZ: German Cancer Research Center),
Maria Rohm4
Estimated H-index: 4
(University of Oxford),
Stephan Herzig28
Estimated H-index: 28
Abstract Adipose tissue represents a critical component in healthy energy homeostasis. It fulfills important roles in whole‐body lipid handling, serves as the body9s major energy storage compartment and insulation barrier, and secretes numerous endocrine mediators such as adipokines or lipokines. As a consequence, dysfunction of these processes in adipose tissue compartments is tightly linked to severe metabolic disorders, including obesity, metabolic syndrome, lipodystrophy, and cachexia. While...
38 Citations Source Cite
Published on Jul 1, 2017in Trends in Endocrinology and Metabolism 10.77
Paul M. Titchenell8
Estimated H-index: 8
(UPenn: University of Pennsylvania),
Mitchell A. Lazar113
Estimated H-index: 113
(UPenn: University of Pennsylvania),
Morris J. Birnbaum89
Estimated H-index: 89
(UPenn: University of Pennsylvania)
During insulin-resistant states such as type 2 diabetes mellitus (T2DM), insulin fails to suppress hepatic glucose production but promotes lipid synthesis leading to hyperglycemia and hypertriglyceridemia. Defining the downstream signaling pathways underlying the control of hepatic metabolism by insulin is necessary for understanding both normal physiology and the pathogenesis of metabolic disease. We summarize recent literature highlighting the importance of both hepatic and extrahepatic mechan...
29 Citations Source Cite
Published on Jul 1, 2017in Chromatographia 1.40
Chuanqin Hu3
Estimated H-index: 3
(BTBU: Beijing Technology and Business University),
Yousheng Wang (BTBU: Beijing Technology and Business University)+ 2 AuthorsBaoguo Sun (BTBU: Beijing Technology and Business University)
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Published on Jul 1, 2017in Diabetes 7.27
Richard N. Bergman103
Estimated H-index: 103
(Cedars-Sinai Medical Center),
Malini S. Iyer6
Estimated H-index: 6
(Cedars-Sinai Medical Center)
On the basis of studies that investigated the intraportal versus systemic insulin infusion and transendothelial transport of insulin, we proposed the “single gateway hypothesis,” which supposes an indirect regulation of hepatic glucose production by insulin; the rate-limiting transport of insulin across the adipose tissue capillaries is responsible for the slow suppression of free fatty acids (FFAs), which in turn is responsible for delayed suppression of hepatic endogenous glucose production (E...
5 Citations Source Cite
Published on Nov 1, 2016in Diabetes 7.27
Malini S. Iyer6
Estimated H-index: 6
(Cedars-Sinai Medical Center),
Richard N. Bergman103
Estimated H-index: 103
(Cedars-Sinai Medical Center)
+ 5 AuthorsCathryn M. Kolka15
Estimated H-index: 15
(Cedars-Sinai Medical Center)
Activation of the sympathetic nervous system (SNS) constitutes a putative mechanism of obesity-induced insulin resistance. Thus, we hypothesized that inhibiting the SNS by using renal denervation (RDN) will improve insulin sensitivity (S I ) in a nonhypertensive obese canine model. S I was measured using euglycemic-hyperinsulinemic clamp (EGC), before (week 0 [w0]) and after 6 weeks of high-fat diet (w6-HFD) feeding and after either RDN (HFD + RDN) or sham surgery (HFD + sham). As expected, HFD ...
9 Citations Source Cite
Published on Mar 3, 2016in Expert Opinion on Drug Safety 3.16
Pedro Ventura-Aguiar2
Estimated H-index: 2
,
Josep M. Campistol62
Estimated H-index: 62
(University of Barcelona),
Fritz Diekmann25
Estimated H-index: 25
ABSTRACTIntroduction: Mammalian target of rapamycin (mTOR) inhibitors (sirolimus and everolimus) are a class of immunosuppressive drugs approved for solid organ transplantation (SOT). By inhibiting the ubiquitous mTOR pathway, they present a peculiar safety profile. The increased incidence of serious adverse events in early studies halted the enthusiasm as a kidney sparing alternative to calcineurin inhibitors (CNI).Areas covered: Herein we review mTOR inhibitors safety profile for adult organ t...
28 Citations Source Cite
Published on Jan 1, 2016
Published on Jan 1, 2016
Isabel R. Hsu9
Estimated H-index: 9
,
Edward Zuniga5
Estimated H-index: 5
,
Richard N. Bergman103
Estimated H-index: 103