Comparison of the effects of pioglitazone and metformin on hepatic and extra-hepatic insulin action in people with type 2 diabetes.
OBJECTIVE
To determine mechanisms by which pioglitazone and metformin effect hepatic and extra-hepatic insulin action.


METHODS
Thirty-one subjects with type 2 diabetes were randomly assigned to pioglitazone (45 mg) or metformin (2,000 mg) for 4 months.


RESULTS
Glucose was clamped before and after therapy at approximately 5 mmol/l, insulin raised to approximately 180 pmol/l, C-peptide suppressed with somatostatin, glucagon replaced at approximately 75 pg/ml, and glycerol maintained at approximately 200 mmol/l to ensure comparable and equal portal concentrations on all occasions. Insulin-induced stimulation of glucose disappearance did not differ before and after treatment with either pioglitazone (23 +/- 3 vs. 24 +/- 2 micromol x kg(-1) x min(-1)) or metformin (22 +/- 2 vs. 24 +/- 3 micromol x kg(-1) x min(-1)). In contrast, pioglitazone enhanced (P < 0.01) insulin-induced suppression of both glucose production (6.0 +/- 1.0 vs. 0.2 +/- 1.6 micromol x kg(-1) x min(-1)) and gluconeogenesis (n = 11; 4.5 +/- 0.9 vs. 0.8 +/- 1.2 micromol x kg(-1) x min(-1)). Metformin did not alter either suppression of glucose production (5.8 +/- 1.0 vs. 5.0 +/- 0.8 micromol x kg(-1) x min(-1)) or gluconeogenesis (n = 9; 3.7 +/- 0.8 vs. 2.6 +/- 0.7 micromol x kg(-1) x min(-1)). Insulin-induced suppression of free fatty acids was greater (P < 0.05) after treatment with pioglitazone (0.14 +/- 0.03 vs. 0.06 +/- 0.01 mmol/l) but unchanged with metformin (0.12 +/- 0.03 vs. 0.15 +/- 0.07 mmol/l).


CONCLUSIONS
Thus, relative to metformin, pioglitazone improves hepatic insulin action in people with type 2 diabetes, partly by enhancing insulin-induced suppression of gluconeogenesis. On the other hand, both drugs have comparable effects on insulin-induced stimulation of glucose uptake.
Basu
Rita
R
Division of Endocrinology, Diabetes, Metabolism, and Nutrition, Mayo Clinic, 200 1st St. SW, Room 5-194 Joseph, Rochester, MN 55905, USA.
Shah
Pankaj
P
Basu
Ananda
A
Norby
Barbara
B
Dicke
Betty
B
Chandramouli
Visvanathan
V
Cohen
Ohad
O
Landau
Bernard R
BR
Rizza
Robert A
RA
D001786:Blood Glucose / Q000187:drug effects / Q000378:metabolism*; D015992:Body Mass Index; D002096:C-Peptide / Q000097:blood; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy* / Q000503:physiopathology*; D003927:Diet, Diabetic; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D005230:Fatty Acids, Nonesterified / Q000097:blood; D005260:Female; D005934:Glucagon / Q000097:blood; D005943:Gluconeogenesis / Q000187:drug effects; D015309:Glucose Clamp Technique; D005990:Glycerol / Q000097:blood; D050261:Glycogenolysis; D006801:Humans; D007004:Hypoglycemic Agents / Q000627:therapeutic use; D007262:Infusions, Intravenous; D007328:Insulin / Q000009:adverse effects / Q000097:blood / Q000494:pharmacology*; D007700:Kinetics; D008099:Liver / Q000187:drug effects / Q000503:physiopathology*; D008297:Male; D008687:Metformin / Q000627:therapeutic use*; D008875:Middle Aged; D000077205:Pioglitazone; D010919:Placebos; D045162:Thiazolidinediones / Q000627:therapeutic use*
D001786:Blood Glucose; D002096:C-Peptide; D005230:Fatty Acids, Nonesterified; D007004:Hypoglycemic Agents; D007328:Insulin; D010919:Placebos; D045162:Thiazolidinediones; D005934:Glucagon; D008687:Metformin; D005990:Glycerol; D000077205:Pioglitazone