Effects of pioglitazone on intramyocellular fat metabolism in patients with type 2 diabetes mellitus.
BACKGROUND
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.


METHODS
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/m(2) . min) clamp with measurement of intramyocellular fat with proton nuclear magnetic resonance; 2) vastus lateralis muscle biopsy for measurement of LC-FACoAs 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 (Delta = 0.8-1.2%), fasting plasma glucose (39-76 mg/dl), fasting free fatty acid (132-236 mumol/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.
Bajaj
Mandeep
M
Diabetes Division, Department of Medicine, University of Texas Health Science Center, San Antonio, Texas 77030, USA. mandeepbajaj@hotmail.com
Baig
Rais
R
Suraamornkul
Swangjit
S
Hardies
Lou Jean
LJ
Coletta
Dawn K
DK
Cline
Gary W
GW
Monroy
Adriana
A
Koul
Shailja
S
Sriwijitkamol
Apiradee
A
Musi
Nicolas
N
Shulman
Gerald I
GI
DeFronzo
Ralph A
RA
D000214:Acyl Coenzyme A / Q000378:metabolism; D000328:Adult; D000368:Aged; D002851:Chromatography, High Pressure Liquid; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy* / Q000378:metabolism*; D004075:Diglycerides / Q000378:metabolism; D005230:Fatty Acids, Nonesterified / Q000097:blood; D005260:Female; D015309:Glucose Clamp Technique; D006442:Glycated Hemoglobin / Q000378:metabolism; D006801:Humans; D007004:Hypoglycemic Agents / Q000627:therapeutic use*; D007333:Insulin Resistance / Q000502:physiology; D050356:Lipid Metabolism / Q000187:drug effects*; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D008875:Middle Aged; D032342:Muscle Cells / Q000187:drug effects / Q000378:metabolism*; D018482:Muscle, Skeletal / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D000077205:Pioglitazone; D053719:Tandem Mass Spectrometry; D045162:Thiazolidinediones / Q000627:therapeutic use*; D014280:Triglycerides / Q000378:metabolism
D000214:Acyl Coenzyme A; D004075:Diglycerides; D005230:Fatty Acids, Nonesterified; D006442:Glycated Hemoglobin; D007004:Hypoglycemic Agents; D000077205:Pioglitazone; D045162:Thiazolidinediones; D014280:Triglycerides