The effect of rosiglitazone on the liver: decreased gluconeogenesis in patients with type 2 diabetes.
OBJECTIVE
Diabetic hyperglycemia results from insulin resistance of peripheral tissues and glucose overproduction due to increased gluconeogenesis (GNG). Thiazolidinediones have been shown to improve glycemic control and increase peripheral insulin sensitivity. Whether chronic thiazolidinedione treatment is associated with a decrease in GNG has not been determined.


METHODS
We studied 26 diet-treated type 2 diabetic patients randomly assigned to rosiglitazone (RSG; 8 mg/d; n = 13) or placebo (n = 13) for 12 wk. At baseline and 12 wk, we measured endogenous glucose production (by [3H]glucose infusion) and GNG (by the [2H]2O technique) after a 15-h fast. Peripheral insulin sensitivity was evaluated by a two-step (240 and 960 pmol/min/m(-2)) euglycemic insulin clamp.


RESULTS
Compared with placebo, RSG reduced fasting plasma glucose (9.7 +/- 0.7 to 7.4 +/- 0.3 mmol/liter; P < 0.001), fasting fractional GNG (-15 +/- 4%; P = 0.002), and fasting GNG flux (-3.9 +/- 1.2 micromol/min/kg fat-free mass; P = 0.004), with no effect on glycogenolytic flux. Changes in GNG flux and fasting glucose were tightly correlated (r = 0.83; P < 0.0001). During both clamp steps, RSG enhanced insulin-mediated glucose clearance (by 26% and 31%; P = 0.01 and P < 0.02, respectively). In a subgroup of patients studied with magnetic resonance imaging, the reduction in GNG flux was correlated (r = 0.65; P < 0.02) with the reduction in visceral fat area.


CONCLUSIONS
RSG increases peripheral tissue insulin sensitivity and decreases endogenous glucose release via an inhibition of gluconeogenesis.
Gastaldelli
Amalia
A
Metabolism Unit, National Research Center, Institute of Clinical Physiology, Via Moruzzi 1, 56100 Pisa, Italy. amalia@ifc.cnr.it.
Miyazaki
Yoshinori
Y
Pettiti
Maura
M
Santini
Eleonora
E
Ciociaro
Demetrio
D
Defronzo
Ralph A
RA
Ferrannini
Ele
E
D001786:Blood Glucose / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000188:drug therapy* / Q000378:metabolism; D005260:Female; D005943:Gluconeogenesis / Q000187:drug effects*; D006801:Humans; D007004:Hypoglycemic Agents / Q000627:therapeutic use*; D007328:Insulin / Q000097:blood; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D010919:Placebos; D000077154:Rosiglitazone; D045162:Thiazolidinediones / Q000627:therapeutic use*
D001786:Blood Glucose; D007004:Hypoglycemic Agents; D007328:Insulin; D010919:Placebos; D045162:Thiazolidinediones; D000077154:Rosiglitazone