Low-dose oral glyburide reduces glucose production rates in patients with impaired fasting glucose.

Impaired fasting glucose (IFG) is commonly seen in the US population. Approximately 20% of patients with IFG can progress to develop type 2 diabetes mellitus (DM-2) within 1 year. In the recent diabetes prevention study, lifestyle changes reduced the progression to only 8% per year, and metformin reduced the progression from IFG to DM-2 from 20% to 11% per year. Sulfonylurea therapy in DM-2 increases beta-cell function and fails to accelerate the 4% loss in function observed per year. Low-dose sulfonylurea therapy for IFG may be an effective treatment to delay the onset of type 2 diabetes if the treatment does not cause hypoglycemia. A very low dose of glyburide (20 microg/kg body weight) was given orally to 15 nondiabetic volunteers in an attempt to describe its effects on glucose production rates (GPR), blood glucose concentrations, and conterregulatory hormone profile. Six of the volunteers had IFG (mean +/- SEM, 115 +/- 1.8 mg/dL), and 9 had a normal fasting glucose (NFG) (94 +/- 2.3 mg/dL). Fasting blood glucose (FBG) decreased more in IFG after glyburide when compared with the NFG group (29% +/- 2.4% v 17% +/- 3.5%, P <.05). Patients with IFG had a larger insulin response to glyburide than those with NFG (17.7 +/-3 v 10.7 +/- 2.9 microU/mL; P <.05). The IFG patients also had a greater decrease in GPR (19% +/- 4%) than seen with the normals (12% +/- 3%, P <.05). The steeper decrease in GPR may have been due to a greater insulin response to oral glyburide in those with IFG. Low-dose glyburide increases insulin's effect on the liver.

Peroxisome proliferator-activated receptor-gamma agonist increases both low-density lipoprotein cholesterol particle size and small high-density lipoprotein cholesterol in patients with type 2 diabetes independent of diabetic control.

OBJECTIVE: To ascertain whether troglitazone, independent of control of diabetes, increases low-density lipoprotein (LDL) particle size. METHODS: We administered 600 mg of troglitazone (a peroxisome proliferator-activated receptor-gamma agonist) daily for 8 weeks to 10 patients with type 2 diabetes (8 of whom completed the study). Then troglitazone therapy was discontinued, and alternative medication for diabetic control was used for another 4 weeks. The LDL, very-low-density lipoprotein (VLDL), and high-density lipoprotein (HDL) concentrations and subpopulations, as well as blood glucose and hemoglobin A1c (HbA1c), were determined at weeks 0, 4, 8, and 12 and analyzed statistically. RESULTS: Small, dense LDL cholesterol is commonly seen in patients with diabetes and is thought to be associated with an increased risk for coronary artery disease. After both 4 and 8 weeks of troglitazone therapy, control of diabetes was significantly improved (mean HbA1c values at baseline, week 4, and week 8 were 8.0 +/- 0.7%, 7.4 +/- 0.5%, and 7.0 +/- 0.7%, respectively; P<0.05). HbA1c (6.5 +/- 0.6% at 12 weeks) and blood glucose levels (126 +/- 19 mg/dL at 8 weeks versus 145 +/- 9 mg/dL at 12 weeks) were not significantly different 4 weeks after troglitazone therapy was discontinued. Troglitazone treatment increased the large LDL particle at 4 and 8 weeks, a change that significantly (P<0.05) enlarged the LDL particle size (20.5 +/- 0.3 nm, 21.2 +/- 0.3 nm, and 21.3 +/- 0.2 nm at baseline, week 4, and week 8, respectively). After 8 weeks of troglitazone therapy, VLDL triglycerides were reduced (195 +/- 37 mg/dL versus 136 +/- 28 mg/dL; P<0.05) and HDL was increased (31.6 +/- 2.4 mg/dL versus 35.5 +/- 2.9 mg/dL; P<0.05). This greater HDL value was due to an increase in the small HDL particles. A decrease in the larger VLDL particles (V5 and V6) resulted in a reduction in the mean VLDL particle size (59 +/- 3 nm versus 46 +/- 2 nm; P<0.05). Despite the fact that control of diabetes remained significantly improved after troglitazone therapy was discontinued, the LDL particle size decreased to the baseline value. This change was due to a reduction in the large LDL cholesterol particle (L3). CONCLUSION: This study shows that troglitazone therapy increases LDL particle size, reduces VLDL particle size, and increases small HDL particles. These changes may lower the risk for coronary artery disease.