Effect of pioglitazone on the metabolic and hormonal response to a mixed meal in type II diabetes.
We explored the mechanisms by which a 4-month, placebo-controlled pioglitazone treatment (45 mg/day) improves glycemic control in type II diabetic patients (T2D, n=27) using physiological testing (6-h mixed meal) and a triple tracer technique ([6,6-(2)H(2)]glucose infusion, (2)H(2)O and [6-(3)H]glucose ingestion) to measure endogenous glucose production (EGP), gluconeogenesis (GNG), insulin-mediated glucose clearance and beta-cell glucose sensitivity (by c-peptide modeling). Compared to sex/age/weight-matched non-diabetic controls, T2D patients showed inappropriately (for prevailing insulinemia) raised glucose production (1.05[0.53] vs 0.71[0.36]mmol min(-1) kg(ffm)(-1) pM, P=0.03) because of enhanced GNG (73.1+/-2.4 vs 59.5+/-3.6%, P<0.01) persisting throughout the meal, reduced insulin-mediated glucose clearance (6[5] vs 12[13]ml min(-1) kg(ffm)(-1) nM(-1), P<0.005), and impaired beta-cell glucose-sensitivity (27[38] vs 71[37]pmol min(-1) m(-2) mM(-1), P=0.002). Compared to placebo, pioglitazone improved glucose overproduction (P=0.0001), GNG and glucose underutilization (P=0.05) despite lower insulinemia. GNG improvement was quantitatively related to raised adiponectin. beta-cell glucose sensitivity was unchanged. In mild-to-moderate T2D, pioglitazone monotherapy decreased fasting and post-prandial glycemia, principally via inhibition of gluconeogenesis, improved hepatic and peripheral insulin resistance.
Gastaldelli
A
A
Metabolism Unit, CNR Institute of Clinical Physiology, University of Pisa School of Medicine, Pisa, Italy. amalia@ifc.cnr.it
Casolaro
A
A
Pettiti
M
M
Nannipieri
M
M
Ciociaro
D
D
Frascerra
S
S
Buzzigoli
E
E
Baldi
S
S
Mari
A
A
Ferrannini
E
E
D052242:Adiponectin / Q000097:blood; D001786:Blood Glucose / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000188:drug therapy*; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D005215:Fasting / Q000097:blood; D005230:Fatty Acids, Nonesterified / Q000037:antagonists & inhibitors / Q000378:metabolism; D005260:Female; D005934:Glucagon / Q000097:blood; D005943:Gluconeogenesis / Q000187:drug effects; D005951:Glucose Tolerance Test; D006442:Glycated Hemoglobin / Q000378:metabolism; D006019:Glycolysis / Q000187:drug effects; D006801:Humans; D006943:Hyperglycemia / Q000097:blood; D007004:Hypoglycemic Agents / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D007328:Insulin / Q000097:blood / Q000378:metabolism; D007333:Insulin Resistance; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000187:drug effects / Q000378:metabolism; D007773:Lactates / Q000097:blood; D008297:Male; D008875:Middle Aged; D000077205:Pioglitazone; D045162:Thiazolidinediones / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*
D052242:Adiponectin; D001786:Blood Glucose; D005230:Fatty Acids, Nonesterified; D005934:Glucagon; D006442:Glycated Hemoglobin; D007004:Hypoglycemic Agents; D007328:Insulin; D007773:Lactates; D000077205:Pioglitazone; D045162:Thiazolidinediones