The effect of pioglitazone on the liver: role of adiponectin.
OBJECTIVE
Diabetic hyperglycemia results from insulin resistance of peripheral tissues and glucose overproduction due to increased gluconeogenesis (GNG). Thiazolidinediones (TZDs) improve peripheral insulin sensitivity, but the effect on the liver is less clear. The goal of this study was to examine the effect of TZDs on GNG.


METHODS
Twenty sulfonylurea-treated type 2 diabetic subjects were randomly assigned (double-blind study) to receive pioglitazone (PIO group; 45 mg/day) or placebo (Plc group) for 4 months to assess endogenous glucose production (EGP) (3-(3)H-glucose infusion), GNG (D2O technique), and insulin sensitivity by two-step hyperinsulinemic-euglycemic clamp (240 and 960 pmol/min per m2).


RESULTS
Fasting plasma glucose (FPG) (10.0 +/- 0.8 to 7.7 +/- 0.7 mmol/l) and HbA1c (9.0 +/- 0.4 to 7.3 +/- 0.6%) decreased in the PIO and increased in Plc group (P < 0.05 PIO vs. Plc). Insulin sensitivity increased approximately 40% during high insulin clamp after pioglitazone (P < 0.01) and remained unchanged in the Plc group (P < 0.05 PIO vs. Plc). EGP did not change, while GNG decreased in the PIO group (9.6 +/- 0.7 to 8.7 +/- 0.6 micromol x min(-1) x kg(ffm)(-1)) and increased in the Plc group (8.0 +/- 0.5 to 9.6 +/- 0.8) (P < 0.05 PIO vs. Plc). Change in FPG correlated with change in GNG flux (r = 0.63, P < 0.003) and in insulin sensitivity (r = 0.59, P < 0.01). Plasma adiponectin increased after pioglitazone (P < 0.001) and correlated with delta FPG (r = -0.54, P < 0.03), delta GNG flux (r = -0.47, P < 0.05), and delta insulin sensitivity (r = 0.65, P < 0.005). Plasma free fatty acids decreased after pioglitazone and correlated with delta GNG flux (r = 0.54, P < 0.02). From stepwise regression analysis, the strongest determinant of change in FPG was change in GNG flux.


CONCLUSIONS
Pioglitazone improves FPG, primarily by reducing GNG flux in type 2 diabetic subjects.
Gastaldelli
Amalia
A
Stable Isotope Lab, Institute of Clinical Physiology-CNR, via Moruzzi 1, 56100 Pisa, Italy. amalia@ifc.cnr.it
Miyazaki
Yoshinori
Y
Mahankali
Archana
A
Berria
Rachele
R
Pettiti
Maura
M
Buzzigoli
Emma
E
Ferrannini
Eleuterio
E
DeFronzo
Ralph A
RA
D050153:Abdominal Fat / Q000187:drug effects; D052242:Adiponectin / Q000097:blood; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy*; D005943:Gluconeogenesis / Q000187:drug effects; D005947:Glucose / Q000096:biosynthesis; D015309:Glucose Clamp Technique; D005951:Glucose Tolerance Test; D006801:Humans; D007328:Insulin / Q000097:blood; D008099:Liver / Q000187:drug effects*; D008112:Liver Glycogen; D008875:Middle Aged; D047495:PPAR gamma / Q000819:agonists; D000077205:Pioglitazone; D013453:Sulfonylurea Compounds / Q000627:therapeutic use; D045162:Thiazolidinediones / Q000627:therapeutic use*
D052242:Adiponectin; D007328:Insulin; D008112:Liver Glycogen; D047495:PPAR gamma; D013453:Sulfonylurea Compounds; D045162:Thiazolidinediones; D005947:Glucose; D000077205:Pioglitazone