TY - JOUR
T1 - Effects of pioglitazone on intramyocellular fat metabolism in patients with type 2 diabetes mellitus
AU - Bajaj, Mandeep
AU - Baig, Rais
AU - Suraamornkul, Swangjit
AU - Hardies, Lou Jean
AU - Coletta, Dawn K.
AU - Cline, Gary W.
AU - Monroy, Adriana
AU - Koul, Shailja
AU - Sriwijitkamol, Apiradee
AU - Musi, Nicolas
AU - Shulman, Gerald I.
AU - DeFronzo, Ralph A.
N1 - Funding Information:
Disclosure Summary: M.B. has received research grant support from Takeda Pharmaceuticals, Novartis, Eli Lilly, and Amylin. M.B. consults for Takeda Pharmaceuticals and has received lecture fees from Takeda Pharmaceuticals, Merck, Novartis, Sanofi-Aventis, and Pfizer. R.A.D. has received research grant support from Takeda Pharmaceuticals, Amylin, Eli Lilly, Novartis, and Pfizer. R.A.D. consults for Takeda Pharmaceuticals, Amylin, Eli Lilly, Roche, Novartis, ISIS, and Johnson & Johnson. R.A.D. has received lecture fees from Amylin, Eli Lilly, and Takeda Pharmaceuticals. R.B., S.S., L.J.H., D.K.C., G.W.C., A.M., S.K., A.S., N.M., and G.I.S. have nothing to declare.
Funding Information:
This work was supported by National Institutes of Health Grant DK-24092 , a Veterans Administration Merit Award, a grant from Takeda Pharmaceuticals, and General Clinical Research Center Grant MO1-RR01346 .
PY - 2010/4
Y1 - 2010/4
N2 - Context: Lipotoxicity (increased tissue fat content) has been implicated in the development of muscle insulin resistance and type 2 diabetes mellitus (T2DM). Objective: The aim was to study the effect of pioglitazone on intramyocellular fat metabolism. Research Design: Twenty-four T2DM subjects (glycosylated hemoglobin = 8.3 ± 0.4%) participated in three similar study protocols before and after 4 months of 45 mg/d pioglitazone treatment: 1) 3-h euglycemic insulin (80 mU/m2 · min) clamp with measurement of intramyocellular fat with proton nuclear magnetic resonance; 2) vastus lateralis muscle biopsy for measurement of LCFACoAs 60 min before start of the insulin clamp; and 3) muscle biopsy for measurement of diacylglycerol 60 min before start of the insulin clamp. Results: In all three protocols, pioglitazone similarly reduced (all P < 0.05) the glycosylated hemoglobin (Δ = 0.8-1.2%), fasting plasma glucose (39-76 mg/dl), fasting free fatty acid (132-236 μmol/liter), and increased insulin-stimulated glucose disposal (by 25-56%). Intramyocellular fat (protocol I) declined from 1.5 to 0.9% (P < 0.05) and correlated with the increase in glucose disposal rate (r = 0.65; P < 0.05). Long chain-fatty acyl-coenzyme A decreased from 12.5 to 8.1 nmol/g (P < 0.05) and correlated with the increase in disposal rate (r = 0.76; P < 0.05). Pioglitazone therapy had no effect on muscle diacylglycerol content. Conclusions: Pioglitazone improves insulin resistance in T2DM in association with mobilization of fat and toxic lipid metabolites out of muscle.
AB - Context: Lipotoxicity (increased tissue fat content) has been implicated in the development of muscle insulin resistance and type 2 diabetes mellitus (T2DM). Objective: The aim was to study the effect of pioglitazone on intramyocellular fat metabolism. Research Design: Twenty-four T2DM subjects (glycosylated hemoglobin = 8.3 ± 0.4%) participated in three similar study protocols before and after 4 months of 45 mg/d pioglitazone treatment: 1) 3-h euglycemic insulin (80 mU/m2 · min) clamp with measurement of intramyocellular fat with proton nuclear magnetic resonance; 2) vastus lateralis muscle biopsy for measurement of LCFACoAs 60 min before start of the insulin clamp; and 3) muscle biopsy for measurement of diacylglycerol 60 min before start of the insulin clamp. Results: In all three protocols, pioglitazone similarly reduced (all P < 0.05) the glycosylated hemoglobin (Δ = 0.8-1.2%), fasting plasma glucose (39-76 mg/dl), fasting free fatty acid (132-236 μmol/liter), and increased insulin-stimulated glucose disposal (by 25-56%). Intramyocellular fat (protocol I) declined from 1.5 to 0.9% (P < 0.05) and correlated with the increase in glucose disposal rate (r = 0.65; P < 0.05). Long chain-fatty acyl-coenzyme A decreased from 12.5 to 8.1 nmol/g (P < 0.05) and correlated with the increase in disposal rate (r = 0.76; P < 0.05). Pioglitazone therapy had no effect on muscle diacylglycerol content. Conclusions: Pioglitazone improves insulin resistance in T2DM in association with mobilization of fat and toxic lipid metabolites out of muscle.
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U2 - 10.1210/jc.2009-0911
DO - 10.1210/jc.2009-0911
M3 - Article
C2 - 20157197
AN - SCOPUS:77951628147
SN - 0021-972X
VL - 95
SP - 1916
EP - 1923
JO - Journal of Clinical Endocrinology and Metabolism
JF - Journal of Clinical Endocrinology and Metabolism
IS - 4
ER -