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Longitudinal compensation for fat-induced insulin resistance includes reduced insulin clearance and enhanced beta-cell response.

Published on Dec 1, 2000in Diabetes7.20
· DOI :10.2337/diabetes.49.12.2116
Steven D. Mittelman29
Estimated H-index: 29
,
G W Van Citters2
Estimated H-index: 2
+ 4 AuthorsRichard N. Bergman103
Estimated H-index: 103
Cite
Abstract
Central adiposity is highly correlated with insulin resistance, which is an important risk factor for type 2 diabetes and other chronic diseases. However, in normal individuals, central adiposity can be tolerated for many years without development of impaired glucose tolerance or diabetes. Here we examine longitudinally the mechanisms by which glucose tolerance can be maintained in the face of substantial insulin resistance. Normal dogs were fed a diet enriched with moderate amounts of fat (2 g x kg(-1) x day(-1)), similar to that seen in modern "cafeteria" diets, and the time course of metabolic changes in these animals was examined over 12 weeks. Trunk adiposity as assessed by magnetic resonance imaging increased from 12 to 19%, but body weight remained unchanged. Insulin sensitivity (SI) as determined by frequently sampled intravenous glucose tolerance tests was measured over a 12-week period. SI decreased 35% by week 1 and remained impaired for the entire 12 weeks. Intravenous glucose tolerance was reduced transiently for 1 week, recovered to baseline, and then again began to decline after 8 weeks. First-phase insulin response began to increase after week 2, peaked by week 6 (190% of basal), and then declined. The increase in insulin response was due partially to enhanced beta-cell function (22%) but due also to an approximately 50% reduction in insulin clearance. This compensation by insulin clearance was also confirmed with insulin clamps performed in fat-fed versus control dogs. The present study confirms the ability of the normal individual to compensate for fat-induced insulin resistance by enhanced insulin response, such that the product of insulin sensitivity x secretion is little changed. However, the compensation is due as much to reduced insulin clearance as increased beta-cell sensitivity to glucose. Reduced hepatic extraction of insulin may be the first line of defense providing a higher proportion of secreted insulin to the periphery and sparing the beta-cells during compensation for the insulin-resistant state.
  • References (40)
  • Citations (164)
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References40
Newest
Published on Jan 2, 2007in Acta Paediatrica2.27
F. Cerutti23
Estimated H-index: 23
(UNITO: University of Turin),
Sacchetti C10
Estimated H-index: 10
(UNITO: University of Turin)
+ 3 AuthorsGiovanni Pacini52
Estimated H-index: 52
(National Research Council)
Obesity is characterized by variable degrees of hyperinsulinaemia, which has been attributed to either β-cell hypersecretion or reduced hepatic insulin extraction, or both. To investigate this controversial issue, a 4-h frequently sampled i.v. glucose tolerance test (glucose dose 12.8 g m -2 ) was performed in 13 normotolerant, grossly obese adolescents (10 F/3 M; 13 ± 1 y; body mass index 32 ± 0.9; pubertal stage 4-5; obesity duration 7.8 ± 3 y) and in a comparable group of 8 healthy, normal-we...
Karl J. Kaiyala20
Estimated H-index: 20
,
Ronald L. Prigeon30
Estimated H-index: 30
(UW: University of Washington)
+ 3 AuthorsMichael W. Schwartz101
Estimated H-index: 101
(UW: University of Washington)
The ability to increase β-cell function in the face of reduced insulin sensitivity is essential for normal glucose tolerance. Because high-fat feeding reduces both insulin sensitivity and glucose tolerance, we hypothesized that it also reduces β-cell compensation. To test this hypothesis, we used intravenous glucose tolerance testing with minimal model analysis to measure glucose tolerance (K g), insulin sensitivity (SI), and the acute insulin response to glucose (AIRg) in nine dogs fed a chow d...
Published on Jul 1, 1999in Metabolism-clinical and Experimental6.51
Yun-Ping Zhou6
Estimated H-index: 6
(U of C: University of Chicago),
Brian N. Cockburn12
Estimated H-index: 12
(U of C: University of Chicago)
+ 1 AuthorsKenneth S. Polonsky86
Estimated H-index: 86
(U of C: University of Chicago)
Abstract The biochemical mechanisms responsible for basal hyperinsulinemia in insulin-resistant states have not been fully defined. We therefore studied pancreatic β-cell function in vitro to characterize the relative importance of fuel metabolism or secretion via a constitutive pathway in the maintenance of high basal insulin secretion in Zucker diabetic fatty (ZDF) and Zucker fatty (ZF) rats. Insulin secretion from ZF (10 ± 1.8 ν 5 ± 0.6 pmol/ng DNA/h) and ZDF (30 ± 4 ν 7 ± 0.8 pmol/ng DNA/h) ...
Published on Apr 1, 1999in Diabetes7.20
Stephanie R. Wiesenthal5
Estimated H-index: 5
,
Harmanjit Sandhu5
Estimated H-index: 5
+ 7 AuthorsAdria Giacca42
Estimated H-index: 42
Hyperinsulinemia is a common finding in obesity and results from insulin hypersecretion and impaired hepatic insulin extraction. In vitro studies have shown that free fatty acids (FFAs), which are often elevated in obesity, can impair insulin binding and degradation in isolated rat hepatocytes. To investigate whether FFAs impair hepatic insulin extraction (E(H)) in vivo, either saline (SAL) or 10% Intralipid (0.03 ml x kg(-1) x min(-1)) plus heparin (0.44 U x kg(-1) x min(-1)) (IH) was infused i...
Published on Apr 1, 1999in The Journal of Clinical Endocrinology and Metabolism5.61
Steven C. Elbein37
Estimated H-index: 37
(University of Arkansas for Medical Sciences),
Sandra J. Hasstedt40
Estimated H-index: 40
(UofU: University of Utah)
+ 1 AuthorsSteven E. Kahn91
Estimated H-index: 91
(UW: University of Washington)
Both defective insulin secretion and insulin resistance have been reported in relatives of type 2 diabetic subjects. We tested 120 members of 26 families with a type 2 diabetic sibling pair with a tolbutamide-modified, frequently sampled iv glucose tolerance test to determine the insulin sensitivity index (SI) and acute insulin response to glucose (AIRglucose). A measure ofβ -cell compensation for insulin sensitivity was calculated as the product SI × AIRglucose, based on the demonstrated hyperb...
Published on Jan 1, 1999in Annals of Clinical and Laboratory Science0.96
L Jovanovic1
Estimated H-index: 1
,
B Gondos1
Estimated H-index: 1
The increasing prevalence of obesity, which has reached epidemic proportions, raises the likelihood that a similar increase in diabetes will follow. Linkage between the two conditions is clear. Overweight is not only an important risk factor for the development of diabetes, but also has a significant impact on progression and complications. Diagnostic criteria for the recognition of diabetes and for monitoring of the disease process will become increasingly important. The role of laboratory eval...
Published on Aug 19, 1998in Diabetologia7.11
Andrea Mari55
Estimated H-index: 55
(National Research Council)
A new modelling analysis was developed to assess insulin sensitivity with a tracer-modified intravenous glucose tolerance test (IVGTT). IVGTTs were performed in 5 normal (NGT) and 7 non-insulin-dependent diabetic (NIDDM) subjects. A 300 mg/kg glucose bolus containing [6,6-2H2]glucose was given at time 0. After 20 min, insulin was infused for 5 min (NGT, 0.03; NIDDM, 0.05 U/kg). Concentrations of tracer, glucose, insulin and C-peptide were measured for 240 min. A circulatory model for glucose kin...
Giovanni Pacini52
Estimated H-index: 52
(National Research Council),
Giancarlo Tonolo31
Estimated H-index: 31
(University of Sassari)
+ 5 AuthorsR. Nosadini17
Estimated H-index: 17
(University of Sassari)
The minimal model is widely used to evaluate insulin action on glucose disappearance from frequently sampled intravenous glucose tolerance tests (FSIGT). The common protocols are a regular (rFSIGT, single injection of 0.3 g/kg of glucose) and an insulin-modified test (mFSIGT, with an additional insulin administration at 20 min). This study compared the insulin sensitivity index (SI) and glucose effectiveness (SG) obtained in the same individual (16 normal subjects) with the two tests. SI was 7.1...
Published on Feb 1, 1998in Nature43.07
Dominic J. Withers2
Estimated H-index: 2
(HHMI: Howard Hughes Medical Institute),
Julio Sanchez Gutierrez1
Estimated H-index: 1
(HHMI: Howard Hughes Medical Institute)
+ 9 AuthorsGerald I. Shulman142
Estimated H-index: 142
(Yale University)
Human type 2 diabetes is characterized by defects in both insulin action and insulin secretion. It has been difficult to identify a single molecular abnormality underlying these features. Insulin-receptor substrates (IRS proteins) may be involved in type 2 diabetes: they mediate pleiotropic signals initiated by receptors for insulin and other cytokines1. Disruption of IRS-1 in mice retards growth, but diabetes does not develop because insulin secretion increases to compensate for the mild resist...
Published on Sep 1, 1997in Journal of Clinical Investigation12.28
Ele Ferrannini10
Estimated H-index: 10
,
Andrea Natali47
Estimated H-index: 47
+ 3 AuthorsGertrude Mingrone3
Estimated H-index: 3
Insulin resistance and insulin hypersecretion are established features of obesity. Their prevalence, however, has only been inferred from plasma insulin concentrations. We measured insulin sensitivity (as the whole-body insulin-mediated glucose uptake) and fasting posthepatic insulin delivery rate (IDR) with the use of the euglycemic insulin clamp technique in a large group of obese subjects in the database of the European Group for the Study of Insulin Resistance (1,146 nondiabetic, normotensiv...
Cited By164
Newest
Published on Apr 10, 2019in Applied Physiology, Nutrition, and Metabolism3.46
Richard Viskochil3
Estimated H-index: 3
(UMass: University of Massachusetts Amherst),
Kate Lyden14
Estimated H-index: 14
(UMass: University of Massachusetts Amherst)
+ 3 AuthorsBarry Braun36
Estimated H-index: 36
(UMass: University of Massachusetts Amherst)
Higher insulin following sedentary behavior may be due to increased insulin secretion (IS), decreased hepatic insulin extraction (HIE), or a combination of both. Ten healthy adults completed glucos...
Published on Oct 1, 2018in Diabetes7.20
Laura C. Page2
Estimated H-index: 2
(Duke University),
Amalia Gastaldelli64
Estimated H-index: 64
(National Research Council)
+ 2 AuthorsJenny Tong32
Estimated H-index: 32
(UC: University of Cincinnati)
Emerging evidence supports the importance of ghrelin to defend against starvation-induced hypoglycemia. This effect may be mediated by inhibition of glucose-stimulated insulin secretion as well as reduced insulin sensitivity. However, administration of ghrelin during meal consumption also stimulates the release of glucagon-like peptide 1 (GLP-1), an incretin important in nutrient disposition. The objective of this study was to evaluate the interaction between ghrelin and GLP-1 on parameters of g...
Isaac Asare-Bediako2
Estimated H-index: 2
(Cedars-Sinai Medical Center),
Rebecca L. Paszkiewicz4
Estimated H-index: 4
(Cedars-Sinai Medical Center)
+ 6 AuthorsRichard N. Bergman103
Estimated H-index: 103
(Cedars-Sinai Medical Center)
Hyperinsulinemia, accompanied by reduced first-pass hepatic insulin extraction (FPE) and increased secretion, is a primary response to insulin resistance. Different in vivo methods are used to esti...
Published on Aug 1, 2018in Diabetes7.20
Isaac Asare-Bediako2
Estimated H-index: 2
(Cedars-Sinai Medical Center),
Rebecca L. Paszkiewicz4
Estimated H-index: 4
(Cedars-Sinai Medical Center)
+ 5 AuthorsRichard N. Bergman103
Estimated H-index: 103
(Cedars-Sinai Medical Center)
Although the β-cells secrete insulin, the liver, with its first-pass insulin extraction (FPE), regulates the amount of insulin allowed into circulation for action on target tissues. The metabolic clearance rate of insulin, of which FPE is the dominant component, is a major determinant of insulin sensitivity (SI). We studied the intricate relationship among FPE, SI, and fasting insulin. We used a direct method of measuring FPE, the paired portal/peripheral infusion protocol, where insulin is infu...
Published on Jul 1, 2018in Domestic Animal Endocrinology2.30
S. Lindåse4
Estimated H-index: 4
(SLU: Swedish University of Agricultural Sciences),
Cecilia E. Müller9
Estimated H-index: 9
(SLU: Swedish University of Agricultural Sciences)
+ 1 AuthorsJ. Bröjer9
Estimated H-index: 9
(SLU: Swedish University of Agricultural Sciences)
Abstract Information about the effect of nonstructural carbohydrates (NSCs) in forage on the postprandial glucose and insulin response in horses is scarce. This is of interest as postprandial hyperinsulinemia in horses is a risk factor for laminitis. In addition, insulin sensitivity (IS) differs between breeds. The aim was to evaluate the postprandial glucose and insulin response to haylage diets with different NSC content in horses of 2 different breeds and to evaluate the relationship between ...
Published on Jan 1, 2018in Obesity3.97
Josiane L. Broussard7
Estimated H-index: 7
(CU: University of Colorado Boulder),
Josiane L. Broussard6
Estimated H-index: 6
(CU: University of Colorado Boulder)
+ 3 AuthorsCathryn M. Kolka15
Estimated H-index: 15
(Cedars-Sinai Medical Center)
Diets high in saturated fat induce obesity and insulin resistance and impair insulin access to skeletal muscle, leading to reduced insulin levels at the muscle cell surface available to bind insulin receptors and induce glucose uptake. In contrast, diets supplemented with polyunsaturated fat improve insulin sensitivity (SI) and reduce the risk for type 2 diabetes. It was hypothesized that a diet high in polyunsaturated fat would preserve SI and insulin access to muscle, as compared with a diet h...
Published on Dec 1, 2017in Diabetes & Metabolism4.01
Yasuhiro Matsubayashi2
Estimated H-index: 2
(Niigata University),
Akihiro Yoshida1
Estimated H-index: 1
(Niigata University)
+ 7 AuthorsSone Hirohito48
Estimated H-index: 48
(Niigata University)
Abstract Aim Hepatic insulin clearance (HIC) is important in regulating plasma insulin levels. Diminished HIC causes inappropriate hyperinsulinaemia, and both obesity and fatty liver (FL), which are known to decrease HIC, can be found either together in the same patient or on their own. The mechanism by which obesity reduces HIC is presumed to be mediated by FL. However, few reports have examined the role of FL in the relationship between obesity and HIC in type 2 diabetes (T2D) patients. Theref...
Published on Dec 1, 2017in Scientific Reports4.01
Hideyoshi Kaga3
Estimated H-index: 3
(Juntendo University),
Yoshifumi Tamura19
Estimated H-index: 19
(Juntendo University)
+ 11 AuthorsShigeki Aoki48
Estimated H-index: 48
(Juntendo University)
Hyperinsulinemia observed in obese subject is caused at least in part by low metabolic clearance rate of insulin (MCRI). However, the determinants of MCRI in non-obese subjects are not fully understood. To investigate the correlates of MCRI in healthy non-obese men (BMI <25 kg/m2), we studied 49 non-obese Japanese men free of cardiometabolic risk factors. Using a 2-step hyperinsulinemic euglycemic clamp, we evaluated MCRI and insulin sensitivity. We also calculated the rate of glucose disappeara...
Published on Oct 1, 2017in Diabetes7.20
Francesca Piccinini3
Estimated H-index: 3
(Cedars-Sinai Medical Center),
David Polidori25
Estimated H-index: 25
(Janssen Pharmaceutica)
+ 1 AuthorsRichard N. Bergman103
Estimated H-index: 103
(Cedars-Sinai Medical Center)
African Americans (AAs) tend to have higher plasma insulin concentrations than European Americans (EAs); the increased insulin concentrations have been attributed to increased secretion and/or decreased insulin clearance by liver or other tissues. This work characterizes the contributions of hepatic versus extrahepatic insulin degradation related to ethnic differences between AAs and EAs. By using a recently developed mathematical model that uses insulin and C-peptide measurements from the insul...
Published on Sep 1, 2017in Journal of Veterinary Internal Medicine2.29
S. Lindåse4
Estimated H-index: 4
(SLU: Swedish University of Agricultural Sciences),
Katarina Nostell7
Estimated H-index: 7
(SLU: Swedish University of Agricultural Sciences)
+ 1 AuthorsJ. Bröjer9
Estimated H-index: 9
(SLU: Swedish University of Agricultural Sciences)
Background A hyperbolic relationship between β-cell response and insulin sensitivity (IS) has been described in several species including rodents, dogs, and humans. This relationship has not been elucidated in the horse. Hypothesis/Objectives To determine whether the hyperbolic relationship between β-cell response and IS exists in horses by using indices of β-cell response from the oral sugar test (OST) and IS measurements from the euglycemic hyperinsulinemic clamp (EHC). A second aim was to com...