| Abstract | 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. |
| Authors | A Gastaldelli, A Casolaro, M Pettiti, M Nannipieri, D Ciociaro, S Frascerra, E Buzzigoli, S Baldi, A Mari, E Ferrannini
(Affiliation: Metabolism Unit, CNR Institute of Clinical Physiology, University of Pisa School of Medicine, Pisa, Italy. amalia at ifc.cnr.it)
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| Journal | Clinical pharmacology and therapeutics
(Clin Pharmacol Ther)
Vol. 81
Issue 2
Pg. 205-12
(Feb 2007)
ISSN: 0009-9236 United States |
| PMID | 17259945
(Publication Type: Comparative Study, Journal Article, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)
|
| Chemical References |
- Adiponectin
- Blood Glucose
- Fatty Acids, Nonesterified
- Hemoglobin A, Glycosylated
- Hypoglycemic Agents
- Lactates
- Thiazolidinediones
- Insulin
- pioglitazone
- Glucagon
|
| Topics |
- Adiponectin
(blood)
- Blood Glucose
(metabolism)
- Diabetes Mellitus, Type 2
(blood, drug therapy)
- Double-Blind Method
- Drug Administration Schedule
- Fasting
(blood)
- Fatty Acids, Nonesterified
(antagonists & inhibitors, metabolism)
- Female
- Glucagon
(blood)
- Gluconeogenesis
(drug effects)
- Glucose Tolerance Test
- Glycolysis
(drug effects)
- Hemoglobin A, Glycosylated
(metabolism)
- Humans
- Hyperglycemia
(blood)
- Hypoglycemic Agents
(administration & dosage, pharmacology, therapeutic use)
- Insulin
(blood, secretion)
- Insulin Resistance
- Insulin-Secreting Cells
(drug effects, metabolism)
- Lactates
(blood)
- Male
- Middle Aged
- Thiazolidinediones
(administration & dosage, pharmacology, therapeutic use)
|
