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Paradoxical effect of troglitazone in normal animals: enhancement of adipocyte but reduction of liver insulin sensitivity.

Published on Dec 1, 2000in Diabetes 7.20
· DOI :10.2337/diabetes.49.12.2087
Melvin K. Dea9
Estimated H-index: 9
,
G W Van Citters2
Estimated H-index: 2
+ 3 AuthorsRichard N. Bergman103
Estimated H-index: 103
Cite
Abstract
Troglitazone is an antidiabetic agent that improves the ability of adipocytes to store triglycerides by enhancing their insulin sensitivity. Although potent in insulin-resistant states, the effect of troglitazone on lipid and glucose turnover in normal animals has not been assessed. Euglycemic clamps were performed as an insulin dose response in normal mongrel dogs (n = 6). Somatostatin was infused without hormone replacement (zero insulin) for 90 min. Insulin was then either portally replaced (1.8 pmol x min(-1) x kg(-1), overreplaced (5.4 pmol x min(-1) x kg(-1)), or overreplaced peripherally to match the systemic levels of the portal overreplacement dose (2.3 pmol x min(-1) x kg(-1)) for 180 min. A total of 600 mg troglitazone was then given orally each day for 3 weeks and continued throughout a second experimental phase, at which point the euglycemic clamps were repeated. In concordance with previous studies, endogenous glucose production (EGP) was similar whether insulin was delivered portally or peripherally, both before and during troglitazone treatment. Although free fatty acids (FFAs) at zero insulin were not affected, there was a leftward shift of the insulin-FFA dose response curve secondary to a suppression of FFA release into plasma. EGP was paradoxically elevated by troglitazone treatment because of an elevation of both gluconeogenesis and glycogenolysis. In conclusion, troglitazone reduced hepatic sensitivity to FFAs. Because EGP is a primary determinant of fasting blood glucose, we hypothesize that a protective mechanism exists in normal animals, preventing hypoglycemia during insulin sensitization with troglitazone.
  • References (23)
  • Citations (5)
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References23
Newest
Published on Apr 1, 1999in Diabetes 7.20
Agneta L. Sunehag24
Estimated H-index: 24
,
Morey W. Haymond66
Estimated H-index: 66
+ 2 AuthorsDennis M. Bier44
Estimated H-index: 44
Very low birth weight (VLBW) infants are dependent on total parenteral nutrition (TPN) to prevent hypoglycemia and provide a sufficient energy intake. However, diminished tolerance for parenteral glucose delivered at high rates frequently provokes hyperglycemia. We hypothesized that when their glucose supply is reduced to prevent hyperglycemia, VLBW infants can maintain normoglycemia via gluconeogenesis from glycerol and amino acids. Twenty infants born at 27 +/- 0.2 (mean +/- SE) gestational we...
94 Citations Source Cite
Published on Oct 20, 1998in Diabetologia 7.11
Marilyn Ader28
Estimated H-index: 28
(SC: University of Southern California),
Joyce M. Richey16
Estimated H-index: 16
(SC: University of Southern California),
Richard N. Bergman103
Estimated H-index: 103
(SC: University of Southern California)
To determine whether long-term insulin deficiency alters insulin movement across the endothelium, plasma and lymph dynamics were assessed in dogs after alloxan (50 mg/kg; n = 8) or saline injection (n = 6). Glucose tolerance (KG) and acute insulin response were assessed by glucose injection before and 18 days after treatment. Two days later, hyperglycaemic (16.7 mmol/l) hyperinsulinaemic (60 pmol · min−1· kg−1) glucose clamps were carried out in a subset of dogs (n = 5 for each group), with simu...
13 Citations Source Cite
Published on Apr 1, 1998in Atherosclerosis 4.25
Geneviève Martin18
Estimated H-index: 18
(Pasteur Institute),
Kristina Schoonjans19
Estimated H-index: 19
(Pasteur Institute)
+ 1 AuthorsJohan Auwerx134
Estimated H-index: 134
(Pasteur Institute)
It is currently thought that the effects of PPARgamma activation on glucose homeostasis may be due to the effect of this nuclear receptor on the production of adipocyte-derived signalling molecules, which affect muscle glucose metabolism. Potential signalling molecules derived from adipocytes and modified by PPARgamma activation include TNFalpha and leptin, which both interfere with glucose homeostasis. In addition to its effects on these proteins, PPARgamma also profoundly affects fatty acid me...
118 Citations Source Cite
Published on Apr 1, 1998in Diabetes 7.20
Bruce M. Spiegelman165
Estimated H-index: 165
The past several years have seen an explosive increase in our understanding of the transcriptional basis of adipose cell differentiation. In particular, a key role has been illustrated for PPAR-gamma, a member of the nuclear hormone receptor superfamily. PPAR-gamma has also been recently identified as the major functional receptor for the thiazolidinedione class of insulin-sensitizing drugs. This review examines the evidence that has implicated this transcription factor in the processes of adipo...
1,503 Citations Source Cite
Published on Feb 1, 1998in Annals of Internal Medicine 19.32
David G. Maggs9
Estimated H-index: 9
(Yale University),
Thomas A. Buchanan70
Estimated H-index: 70
(SC: University of Southern California)
+ 11 AuthorsJerrold M. Olefsky106
Estimated H-index: 106
(UCSD: University of California, San Diego)
BACKGROUND: Troglitazone is a new insulin-sensitizing agent used to treat type 2 diabetes mellitus. The mechanism by which troglitazone exerts its effect on systemic glucose metabolism is unknown. OBJECTIVE: To determine the effects of 6 months of troglitazone monotherapy on glucose metabolism in patients with type 2 diabetes mellitus. DESIGN: Randomized, double-blind, placebo-controlled trial. SETTING: Six general clinical research centers at university hospitals. PATIENTS: 93 patients (mean ag...
264 Citations Source Cite
Published on Jan 1, 1998in Drug Safety 3.53
Gilbert Re65
Estimated H-index: 65
,
Mark E. Cooper109
Estimated H-index: 109
,
Henry Krum91
Estimated H-index: 91
(Monash University)
Diabetes mellitus is associated with alterations in a number of key metabolic pathways. Despite theoretical concerns, clinically significant alterations in the pharmacokinetic properties of commonly prescribed drugs are relatively uncommon. Indeed, dose adjustment is rarely required in the setting of well controlled diabetes mellitus. However, significant alterations in drug handling may occur in the context of poor metabolic control or in the presence of complications such as nephropathy.
15 Citations Source Cite
Published on Dec 15, 1997in Journal of Clinical Investigation 12.28
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 Aug 1, 1997in Diabetes 7.20
Didier Auboeuf32
Estimated H-index: 32
(French Institute of Health and Medical Research),
Jennifer Rieusset33
Estimated H-index: 33
(French Institute of Health and Medical Research)
+ 7 AuthorsHubert Vidal69
Estimated H-index: 69
(French Institute of Health and Medical Research)
Members of the peroxisome proliferator–activated receptor (PPAR) family might be involved in pathologies with altered lipid metabolism. They participate in the control of the expression of genes involved in lipid metabolism and adipocyte differentiation. In addition, thiazolidinediones improve insulin resistance in vivo by activating PPARγ. However, little is known regarding their tissue distribution and relative expression in humans. Using a quantitative and sensitive reverse transcription (RT)...
647 Citations Source Cite
Published on Jul 1, 1997in Diabetes 7.20
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 Nov 1, 1996in Diabetes 7.20
Kathleen Berkowitz4
Estimated H-index: 4
,
Ruth Peters47
Estimated H-index: 47
+ 6 AuthorsThomas A. Buchanan70
Estimated H-index: 70
We conducted a randomized placebo-controlled study to determine the effects of the thiazolidinedione compound troglitazone on whole-body insulin sensitivity (S I ), pancreatic β-cell function, and glucose tolerance in 42 Latino women with impaired glucose tolerance (IGT) and a history of gestational diabetes mellitus (GDM), characteristics that carry an 80% risk of developing NIDDM within 5 years. After baseline oral (OGTT) and intravenous (IVGTT) glucose tolerance testing, subjects were assigne...
90 Citations Source Cite
Cited By5
Newest
Kazutaka Aoki15
Estimated H-index: 15
,
Junji Matsui10
Estimated H-index: 10
+ 13 AuthorsKumpei Tokuyama34
Estimated H-index: 34
Phosphoinositide 3-kinase (PI3K) p85 α-deficient mice exhibit hypoglycemia as a result of increased insulin sensitivity and glucose uptake in peripheral tissues. Although PI3K is central to the metabolic actions of insulin, its mechanism of action in liver is not well understood. In the present study, we investigated hepatic insulin signaling and glucose homeostasis in p85 α-deficient and wild-type mice. In the livers of p85 α-deficient mice, p50α played a compensatory role in insulin-stimulated...
10 Citations Source Cite
Published on Nov 1, 2008in Diabetes, Obesity and Metabolism 6.13
V. Hulstrøm1
Estimated H-index: 1
(UCPH: University of Copenhagen),
Kurt Højlund39
Estimated H-index: 39
(OUH: Odense University Hospital)
+ 2 AuthorsKlaus Levin20
Estimated H-index: 20
(OUH: Odense University Hospital)
Patients with type 2 diabetes (T2D) and their first-degree relatives (FDRs) are characterized by hypoadiponectinaema and insulin resistance. In T2D patients, plasma adiponectin and insulin sensitivity (SI) increase in response to thiazolidinediones (TZDs). These findings suggest a role for adiponectin in the regulation of SI. We studied the relationship between plasma adiponectin and glucose and lipid metabolism and the effect of troglitazone (200 mg/day) for 12 weeks in 19 normoglycaemic, obese...
8 Citations Source Cite
Published on Jan 1, 2006in Diabetologia 7.11
S. Shadid1
Estimated H-index: 1
(Mayo Clinic),
Michael Dennis Jensen27
Estimated H-index: 27
(Mayo Clinic)
Aims/hypothesis Plasma NEFA concentrations are largely determined by adipose tissue lipolysis. Insulin suppression of lipolysis is commonly impaired with insulin resistance and improves with thiazolidinedione treatment of type 2 diabetes. The present studies were designed to assess the effects of thiazolidinedione on NEFA (oleate) metabolism that are independent of improved glycaemic control.
23 Citations Source Cite
Published on Sep 1, 2003in Molecular Pharmacology 3.85
Àgatha Cabrero14
Estimated H-index: 14
,
Mireia Jové11
Estimated H-index: 11
+ 3 AuthorsManuel Vázquez-Carrera36
Estimated H-index: 36
Cardiac expression of genes involved in fatty acid metabolism may suffer alterations depending on the substrate availability. We studied how troglitazone, an antidiabetic drug that selectively activates peroxisome proliferator-activated receptor γ (PPARγ), affected the expression of several of these genes. A single-day troglitazone administration (100 mg/kg/day) did not significantly alter plasma free fatty acids or triglyceride levels. In contrast, a 10-day period of troglitazone treatment sign...
25 Citations Source Cite
Published on Jan 1, 2001in Journal of Investigative Medicine 1.99
Richard N. Bergman103
Estimated H-index: 103
(SC: University of Southern California),
Gregg W. Van Citters8
Estimated H-index: 8
(SC: University of Southern California)
+ 4 AuthorsMartin Ellmerer25
Estimated H-index: 25
(SC: University of Southern California)
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 associatio...
176 Citations Source Cite