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Central Role of the Adipocyte in the Metabolic Syndrome
Published on Jan 1, 2001in Journal of Investigative Medicine 2.03
· DOI :10.2310/6650.2001.34108
Richard N. Bergman104
Estimated H-index: 104
(University of Southern California),
Gregg W. Van Citters8
Estimated H-index: 8
(University of Southern California)
+ 4 AuthorsMartin Ellmerer25
Estimated H-index: 25
(University of Southern California)
Abstract
Abstract Insulin resistance is associated with a plethora of chronic illnesses, including Type 2 diabetes, dyslipidemia, clotting dysfunction, and colon cancer. The relationship between obesity and insulin resistance is well established, and an increase in obesity in Western countries is implicated in increased incidence of diabetes and other diseases. Central, or visceral, adiposity has been particularly associated with insulin resistance; however, the mechanisms responsible for this association are unclear. Our laboratory has been studying the physiological mechanisms relating visceral adiposity and insulin resistance. Moderate fat feeding of the dog yields a model reminiscent of the metabolic syndrome, including visceral adiposity, hyperinsulinemia, and insulin resistance. We propose that insulin resistance of the liver derives from a relative increase in the delivery of free fatty acids (FFA) from the omental fat depot to the liver (via the portal vein). Increased delivery results from 1) more stored lipids in omental depot, 2) severe insulin resistance of the central fat depot, and 3) possible regulation of visceral lipolysis by the central nervous system. The significance of portal FFA delivery results from the importance of FFA in the control of liver glucose production. Insulin regulates liver glucose output primarily via control of adipocyte lipolysis. Thus, because FFA regulate the liver, it is expected that visceral adiposity will enhance delivery of FFA to the liver and make the liver relatively insulin resistant. It is of interest how the intact organism compensates for insulin resistance secondary to visceral fat deposition. While part of the compensation is enhanced B-cell sensitivity to glucose, an equally important component is reduced liver insulin clearance, which allows for a greater fraction of B-cell insulin secretion to bypass liver degradation, to enter the systemic circulation, and to result in hyperinsulinemic compensation. The signal(s) resulting in B-cell up-regulation and reduced liver insulin clearance with visceral adiposity is (are) unknown, but it appears that the glucagon-like peptide (GLP-1) hormone plays an important role. The integrated response of the organism to central adiposity is complex, involving several organs and tissue beds. An investigation into the integrated response may help to explain the features of the metabolic syndrome.
  • References (29)
  • Cited By (173)
Cite
References29
Published on Feb 24, 2001in Presse Medicale 0.92
Barbier D1
Estimated H-index: 1
113 Citations
Steven D. Mittelman28
Estimated H-index: 28
(University of Southern California),
Richard N. Bergman104
Estimated H-index: 104
(University of Southern California)
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 adipo...
69 Citations Source Cite
M. Ader1
Estimated H-index: 1
,
Richard N. Bergman104
Estimated H-index: 104
(University of Southern California)
Insulin may suppress hepatic glucose production directly, or indirectly via suppression of release of gluconeogenic substrates from extrasplanchnic tissues. To compare these mechanisms, we performed insulin dose-response experiments in conscious dogs at euglycemia, during somatostatin infusion, and intraportal glucagon replacement. Insulin was sequentially infused either intraportally (0.05, 0.20, 0.40, 1.0, 1.4, and/or 3.0; protocol I) or systemically at half the intraportal rate (0.025, 0.10, ...
117 Citations Source Cite
Published on Mar 15, 1996in Journal of Clinical Investigation 13.25
Garry M. Steil49
Estimated H-index: 49
,
Marilyn Ader28
Estimated H-index: 28
+ 2 AuthorsRichard N. Bergman104
Estimated H-index: 104
In vitro, insulin transport across endothelial cells has been reported to be saturable, suggesting that the transport process is receptor mediated. In the present study, the transport of insulin across capillary endothelial cells was investigated in vivo. Euglycemic glucose clamps were performed in anesthetized dogs (n = 16) in which insulin was infused to achieve concentrations in the physiological range (1.0 mU/kg per min + 5 mU/kg priming bolus; n = 8) or pharmacologic range (18 mU/kg per min...
106 Citations Source Cite
Published on Oct 1, 1991in Diabetes 7.27
Ilpo Puhakainen6
Estimated H-index: 6
,
Veikko A. Koivisto50
Estimated H-index: 50
,
Hannele Yki-Järvinen94
Estimated H-index: 94
Increased gluconeogenesis has been suggested to account for all of the increase in basal glucose production in patients with non-insulin-dependent diabetes mellitus (NIDDM). We studied the effect of inhibition of gluconeogenesis with ethanol on total hepatic glucose output (HGO) in patients with NIDDM. Fourteen patients with NIDDM (mean ± SE age 61 ± 2 yr, fasting plasma glucose 11.4 ± 0.8 mM; body mass index 27 ± 1 kg/m2) were studied twice after an overnight fast, once during ethanol administr...
70 Citations Source Cite
Published on Sep 1, 1991in Journal of Clinical Investigation 13.25
Guenther Boden59
Estimated H-index: 59
,
F Jadali1
Estimated H-index: 1
+ 5 AuthorsC Smith1
Estimated H-index: 1
Abstract We have examined the onset and duration of the inhibitory effect of an intravenous infusion of lipid/heparin on total body carbohydrate and fat oxidation (by indirect calorimetry) and on glucose disappearance (with 6,6 D2-glucose and gas chromatography-mass spectrometry) in healthy men during euglycemic hyperinsulinemia. Glycogen synthase activity and concentrations of acetyl-CoA, free CoA-SH, citrate, and glucose-6-phosphate were measured in muscle biopsies obtained before and after in...
412 Citations Source Cite
Published on Oct 1, 1999in Diabetologia 6.02
Marianthe Hamilton-Wessler11
Estimated H-index: 11
(University of Southern California),
Marilyn Ader28
Estimated H-index: 28
(University of Southern California)
+ 4 AuthorsRichard N. Bergman104
Estimated H-index: 104
(University of Southern California)
Aims/hypothesis. The provision of stable, reproducible basal insulin is crucial to diabetes management. This study in dogs examined the metabolic effects and interstitial fluid (ISF) profiles of fatty acid acylated insulin, LysB29-tetradecanoyl, des-(B30) human insulin (NN304). Methods. Euglycaemic clamps were carried out under inhalant anaesthesia during equimolar intravenous infusions (3.6 pmol · min–1· kg–1 for 480 min) of human insulin or NN304 (n = 8 per group). Results. Steady-state total ...
66 Citations Source Cite
Published on Dec 1, 1994in Journal of Clinical Investigation 13.25
A. Alzaid10
Estimated H-index: 10
(Riyadh Military Hospital),
Sean F. Dinneen31
Estimated H-index: 31
+ 3 AuthorsRobert A. Rizza80
Estimated H-index: 80
Abstract Insulin concentrations in humans continuously change and typically increase only when glucose also increases such as with eating. In this setting, it is not known whether the severity of hepatic and extrahepatic insulin resistance is comparable and whether the ability of glucose to regulate its own uptake and release is defective in non-insulin-dependent diabetes mellitus (NIDDM). To address this question, NIDDM and nondiabetic subjects were studied when glucose concentrations were clam...
77 Citations Source Cite
Published on Jan 1, 1984in Metabolism-clinical and Experimental 5.96
David J. Evans5
Estimated H-index: 5
(Medical College of Wisconsin),
Raymond G. Hoffman15
Estimated H-index: 15
(Medical College of Wisconsin)
+ 1 AuthorsAhmed H. Kissebah40
Estimated H-index: 40
(Medical College of Wisconsin)
Abstract The relationship of body fat distribution to metabolic profiles was determined in 80 healthy premenopausal white women of a wide range of obesity levels [percentage of ideal body weight (% IBW) 92–251]. Distribution of fat between the upper and lower body was assessed from the waist/hips girth ratio (WHR), which varied from 0.64 to 1.02. In 23 women, in vivo insulin sensitivity was also determined from the steady-state plasma glucose (SSPG) level at comparable insulin levels of approxim...
335 Citations Source Cite
Published on Jan 2, 1998in Journal of Biological Chemistry 4.01
Duna Massillon1
Estimated H-index: 1
(University of Pennsylvania),
Wei Chen1
Estimated H-index: 1
(University of Pennsylvania)
+ 5 AuthorsLuciano Rossetti1
Estimated H-index: 1
(University of Pennsylvania)
Abstract Hepatic gene expression of P-enolpyruvate carboxykinase (PEPCK) and glucose-6-phosphatase (Glc-6-Pase) is regulated in response to changes in the availability of substrates, in particular glucose (Glc; Massillon, D., Barzilai, N., Chen, W., Hu, M., and Rossetti, L. (1996) J. Biol. Chem. 271, 9871–9874). We investigated the mechanism(s) in conscious rats. Hyperglycemia per se caused a rapid and marked increase in Glc-6-Pase mRNA abundance and protein levels. By contrast, hyperglycemia de...
75 Citations Source Cite
Cited By173
Published on Jan 1, 2008
Sang Jun Lee (University of Toledo)
Published on Jan 1, 2007
Guido Lastra22
Estimated H-index: 22
(University of Missouri),
Camila Manrique23
Estimated H-index: 23
(University of Missouri),
James R. Sowers78
Estimated H-index: 78
(University of Missouri)
Obesity, Type 2 Diabetes Mellitus (T2DM) and Cardiovascular Disease (CVD) are worldwide leading causes of morbidity and mortality. Once considered as separate metabolic and hemodynamic/cardiovascular entities respectively, it has become nowadays clear that the relationship between these conditions is not coincidental, and has common pathophysiological features that allows considering both obesity and T2DM as part of the cardiovascular diseases spectrum. Furthermore, from a clinical standpoint it...
1 Citations Source Cite
Published on Jan 1, 2007
Scott M. Grundy163
Estimated H-index: 163
(University of Texas Southwestern Medical Center)
Serum cholesterol, which normally consists predominantly of low-density lipoprotein (LDL) cholesterol (LDLC), is influenced by the liver’s expression of LDL receptors; the latter is regulated by the cholesterol content of liver cells. The process whereby cholesterol passes from peripheral tissues through high-density lipoprotein (HDL) and back to the liver is called reverse cholesterol transport. Cumulative data suggest that the risk of coronary heart disease declines to a total serum cholestero...
Source Cite
Published on Jan 1, 2014
Danijela Gasevic15
Estimated H-index: 15
(Simon Fraser University),
Simi Kohli7
Estimated H-index: 7
(Simon Fraser University)
+ 1 AuthorsScott A. Lear38
Estimated H-index: 38
(Simon Fraser University)
Given the increase in ethnic diversity worldwide, and especially in high-income countries such as Australia, Canada, the United Kingdom, and the United States, there has been significant interest in exploring the ethnic differences in disease risk factors and chronic diseases. This chapter summarizes the ethnic differences in abdominal adipose tissue distribution, devoting particular attention to subcutaneous and visceral adipose tissue. Additionally, this chapter reviews ethnic differences in t...
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Published on Jan 1, 2008
Obesity is one of the major risk factors of atherosclerosis and arterial stiffness. Recent evidence suggests detrimental effect of fat mass rather than overall body mass. Abdominal fat has been indicated to have more negative impact than other fat depots. We evaluated the impact of regional fat distribution on atherosclerosis and compared the variances explained by 11-different adiposity measures on atherosclerosis and arterial stiffness among bi-racial women in menopausal transition. All analys...
Sachin Patil6
Estimated H-index: 6
(Michigan State University),
Zheng Li8
Estimated H-index: 8
(Michigan State University),
Christina Chan34
Estimated H-index: 34
(Michigan State University)
Tissue engineering is a rapidly expanding, multi-disciplinary field in biomedicine. It provides the ability to manipulate living cells and biomaterials for the purpose of restoring, maintaining, and enhancing tissue and organ function. Scientists have engineered various tissues in the body, from skin substitutes to artificial nerves to heart tissues, with varying degrees of success. Although the field of tissue engineering has come a long way since its first successful demonstration by Bisceglie...
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Published on May 18, 2011
A thesis submitted to the Department of Clinical Microbiology, School of Medical Sciences, Kwame Nkrumah University of Science and Technology, in partial fulfillment of the requirements for the degree of Master of Philosophy, May-2011
Published on Jan 24, 2006in Annals of the New York Academy of Sciences 4.28
Marianne O. Larsen16
Estimated H-index: 16
(University of Copenhagen),
Bidda Rolin17
Estimated H-index: 17
(Novo Nordisk)
+ 2 AuthorsOve Svendsen19
Estimated H-index: 19
(University of Copenhagen)
: High-fat diet and obesity are known to be of major importance for development of type 2 diabetes in humans. High-fat feeding can induce syndromes of glucose intolerance and/or insulin resistance in several species, and the Gottingen minipig might be a useful model for studying the effect of dietary high-fat intake and obesity on glucose homeostasis and the susceptibility to diabetes. The present study was designed as a pilot study to investigate the effects of obesity caused by high-fat high-e...
44 Citations Source Cite
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