Addition of pioglitazone and ramipril to intensive insulin therapy in type 2 diabetic patients improves vascular dysfunction by different mechanisms.
OBJECTIVE
We examined the relationship between glycemic control, vascular reactivity, and inflammation in type 2 diabetic subjects.


METHODS
Thirty subjects with type 2 diabetes were initiated on intensive insulin therapy (continuous subcutaneous insulin infusion [n = 12] or multiple daily injections [n = 18]) and then randomized to either pioglitazone (PIO group;45 mg/day), ramipril (RAM group; 10 mg/day), or placebo (PLC group) for 36 weeks. Euglycemic-hyperinsulinemic clamp was used to quantify insulin resistance, and plethysmography was used to assess changes in forearm blood flow (FBF) after 1) 5 min of reactive hyperemia and 2) brachial artery infusion of acetylcholine (7.5, 15, and 30 microg/min) and sodium nitroprusside (3 and 10 microg/min).


RESULTS
The decreases in A1C (approximately 9.0-7.0%) and fasting plasma glucose (approximately 190-128 mg/dl) were equal in all groups. In the PIO group, glucose disposal increased from 3.1 to 4.7 mg x kg(-1) x min(-1), and there was a greater decrease in plasma triglycerides ( approximately 148 vs. 123 mg/dl) and free fatty acids (approximately 838 vs. 595 mEq/l) compared with the RAM or PLC groups (P < 0.05). Plasma adiponectin doubled with pioglitazone treatment (6.2 +/- 0.7 to 13.1 +/- 1.8 microg/ml), while endothelin-1 decreased only with ramipril treatment (2.5 +/- 0.2 to 1.1 +/- 0.2 pg/ml) (P < 001). The increase in FBF during reactive hyperemia (215%) and acetylcholine (from 132 to 205%, 216 to 262%, and 222 to 323%) was greater in the PIO versus RAM or PLC groups. In contrast, FBF during sodium nitroprusside treatment was greater in the RAM group (141-221% and 218-336%) compared with the PIO or PLC groups (all P < 0.05).


CONCLUSIONS
Addition of pioglitazone or ramipril to intensive insulin therapy in type 2 diabetes further improves vascular dysfunction. Pioglitazone enhances endothelial-mediated vasodilation, whereas ACE inhibition enhances endothelial-independent vasodilation. These different vascular effects, combined with the observation that pioglitazone decreases free fatty acids and triglycerides and increases adiponectin, while ramipril reduces endothelin-1, suggest that different mechanisms underlie the vascular responses.
Fernandez
Marianella
M
Texas Diabetes Institute, San Antonio, Texas, USA.
Triplitt
Curtis
C
Wajcberg
Estela
E
Sriwijilkamol
Apiradee A
AA
Musi
Nicholas
N
Cusi
Kenneth
K
DeFronzo
Ralph
R
Cersosimo
Eugenio
E
D000959:Antihypertensive Agents / Q000627:therapeutic use*; D001783:Blood Flow Velocity / Q000187:drug effects; D001786:Blood Glucose / Q000187:drug effects / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy* / Q000503:physiopathology*; D003925:Diabetic Angiopathies / Q000517:prevention & control*; D004359:Drug Therapy, Combination; D005542:Forearm; D015309:Glucose Clamp Technique; D006442:Glycated Hemoglobin / Q000378:metabolism; D006630:Hispanic or Latino; D006801:Humans; D007004:Hypoglycemic Agents / Q000627:therapeutic use*; D007249:Inflammation / Q000517:prevention & control; D007328:Insulin / Q000008:administration & dosage / Q000627:therapeutic use*; D007332:Insulin Infusion Systems; D000077205:Pioglitazone; D010919:Placebos; D017257:Ramipril / Q000627:therapeutic use*; D045162:Thiazolidinediones / Q000627:therapeutic use*
D000959:Antihypertensive Agents; D001786:Blood Glucose; D006442:Glycated Hemoglobin; D007004:Hypoglycemic Agents; D007328:Insulin; D000077205:Pioglitazone; D010919:Placebos; D017257:Ramipril; D045162:Thiazolidinediones