Chronic treatment with pioglitazone does not protect obese patients with diabetes mellitus type II from free fatty acid-induced insulin resistance.
BACKGROUND
Thiazolidinediones increase peripheral insulin sensitivity and decrease plasma free fatty acids (FFA). However, their exact mechanism of action has not been fully elucidated.


OBJECTIVE
We studied the protective effect of pioglitazone on FFA-induced insulin resistance and the effects on intramyocellular glycosphingolipids.


METHODS
We studied glucose metabolism in the basal state and during a hyperinsulinemic euglycemic clamp by using stable isotopes. Studies were performed at baseline and after 4 months of treatment with pioglitazone. Patients were then studied on a third occasion during infusion of a lipid emulsion to increase plasma FFA to pretreatment levels. All studies were combined with muscle biopsies to measure intramyocellular ceramide and glycosphingolipids.


METHODS
Patients were obese with poorly controlled type 2 diabetes mellitus.


METHODS
Patients were treated with 30 mg pioglitazone once daily.


METHODS
The change in peripheral insulin sensitivity after treatment with pioglitazone and during the infusion of the lipid emulsion was the main outcome measure.


RESULTS
Peripheral glucose uptake (Rd) increased significantly, but returned to baseline levels after increasing plasma FFA to pretreatment levels. Insulin-mediated suppression of FFA was increased significantly. Intramyocellular ceramide concentrations were higher during the hyperinsulinemic clamp after treatment with pioglitazone, but not in the basal state. The intramyocellular content of glycosphingolipids and plasma concentrations of ceramide and glycosphingolipids did not change.


CONCLUSIONS
Pioglitazone increases Rd and insulin-mediated suppression of plasma FFA, but does not protect patients with type 2 diabetes mellitus from FFA-induced insulin resistance. This effect of pioglitazone is not attained via a decrease in intramyocellular concentrations of ceramide or glycosphingolipids.
Serlie
Mireille J
MJ
Department of Endocrinology and Metabolism, Academic Medical Center, F5-169, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands. m.j.serlie@amc.uva.nl
Allick
Gideon
G
Groener
Johanna E
JE
Ackermans
Mariette T
MT
Heijligenberg
Rik
R
Voermans
Barbara C
BC
Aerts
Johannes M
JM
Meijer
Alfred J
AJ
Sauerwein
Hans P
HP
D052242:Adiponectin / Q000097:blood; D002518:Ceramides / Q000097:blood; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000188:drug therapy*; D005230:Fatty Acids, Nonesterified / Q000502:physiology*; D005260:Female; D005947:Glucose / Q000378:metabolism; D005963:Glucosylceramides / Q000097:blood; D006801:Humans; D007004:Hypoglycemic Agents / Q000627:therapeutic use*; D007333:Insulin Resistance; D008297:Male; D009765:Obesity / Q000150:complications*; D000077205:Pioglitazone; D012044:Regression Analysis; D045162:Thiazolidinediones / Q000627:therapeutic use*
D052242:Adiponectin; D002518:Ceramides; D005230:Fatty Acids, Nonesterified; D005963:Glucosylceramides; D007004:Hypoglycemic Agents; D045162:Thiazolidinediones; D005947:Glucose; D000077205:Pioglitazone