This randomized controlled study investigated metformin and fenofibrate, compared with metformin alone, for the treatment of peripheral insulin resistance in patients with simple obesity with hyperinsulinaemia but not diabetes. Participants were randomized to receive metformin (500 mg orally three times daily) plus either fenofibrate (200 mg orally once daily; n = 44) or placebo (n = 43) for 6 months. Blood pressure, free fatty acids (FFA), body mass index (BMI), lipid and insulin levels were recorded pre- and post-treatment. β-Cell function and insulin resistance were measured by the homeostasis model assessment for insulin resistance (HOMA-IR) index. Both groups showed significant decreases in blood pressure, FFA, BMI and HOMA-IR relative to baseline. In addition, combined metformin and fenofibrate therapy showed significantly decreased fasting and postmeal insulin levels relative to baseline and relative to the placebo group. Both treatments were well tolerated. Metformin and fenofibrate can increase insulin sensitivity and recover β-cell function in patients with simple obesity accompanied by insulin resistance.
WatsonKEHorowitzBNMatsonG: Lipid abnormalities in insulin resistant states. Rev Cardiovasc Med2003; 4: 228–236.
3.
PoitoutVRobertsonRP: Minireview: secondary β-cell failure in type 2 diabetes—a convergence of glucotoxicity and lipotoxicity. Endocrinology2002; 143: 339–342.
KahnSE: The relative contributions of insulin resistance and beta-cell dysfunction to the pathophysiology of type 2 diabetes. Diabetologia2003; 46: 3–19.
6.
KayJPAlemzadehRLangleyG: Beneficial effects of metformin in normoglycemic morbidly obese adolescents. Metabolism2001; 50: 1457–1461.
7.
FreemarkMBurseyD: The effects of metformin on body mass index and glucose tolerance in obese adolescents with fasting hyperinsulinemia and a family history of type 2 diabetes. Pediatrics2001; 107: E55.
8.
LandinKTengbornLSmithU: Effects of metformin and metoprolol CR on hormones and fibrinolytic variables during a hyperinsulinemic euglycemic clamp in man. Thromb Haemost1994; 71: 783–787.
9.
FendriSRousselBLormeauB: Insulin sensitivity, insulin action and fibrinolysis activity in non-diabetic and diabetic obese subjects. Metabolism1998; 47: 1372–1375.
10.
Chinese Ministry of Health Disease Control Division: Chinese Prevention and Control Guidelines for Overweight and Obese Adults (Trial). Beijing: Chinese Ministry of Health, 2003; pp 3–5 [in Chinese].
11.
WilligSH: Good Manufacturing Practice Guidelines for Pharmaceuticals. Abingdon: Taylor and Francis, 2005.
12.
TrinderP: Determination of blood glucose using an oxidase-peroxidase system with a non-carcinogenic chromogen. J Clin Pathol1969; 22: 158–161.
13.
TuanC-YAbbasiFLamendolaC: Usefulness of plasma glucose and insulin concentrations in identifying patients with insulin resistance. Am J Cardiol2003; 92: 606–610.
14.
MatthewsDRHoskerJPRudenskiAS: Homeostasis model assessment: insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia1985; 28: 412–419.
15.
PuttmannMKrugHvon OchsensteinE: Fast HPLC determination of serum free fatty acids in the picomole range. Clin Chem1993; 39: 825–832.
16.
SwislockiALChenYDGolayA: Insulin suppression of plasma-free fatty acid concentration in normal individuals and patients with type 2 (non-insulin-dependent) diabetes. Diabetologia1987; 30: 622–626.
17.
MakowskiLHotamisligilGS: The role of fatty acid binding proteins in metabolic syndrome and atherosclerosis. Curr Opin Lipidol2005; 16: 543–548.
18.
MaedaKCaoHKonoK: Adipocyte/macrophage fatty acid binding proteins control integrated metabolic responses in obesity and diabetes. Cell Metab2005; 1: 107–119.
19.
SteinbergHOChakerHLeamingR: Obesity/insulin resistance is associated with endothelial dysfunction. Implications for the syndrome of insulin resistance. J Clin Invest1996; 97: 2601–2610.
20.
RizzoMKotur-StevuljevicJBerneisK: Atherogenic dyslipidemia and oxidative stress: A new look. Transl Res2009; 153: 217–223.
21.
KirpichnikovDMcFarlaneSISowersJR: Metformin: an update. Ann Intern Med2002137: 25–33.
22.
KliewerSAXuHELambertMH: Peroxisome proliferator-activated receptors: from genes to physiology. Recent Prog Horm Res2001; 56: 239–263.
23.
GrundySMVegaGL: Fibric acids: effects on lipids and lipoprotein metabolism. Am J Med1987; 83: 9–20.
24.
Effect of fenofibrate on progression of coronary-artery disease in type 2 diabetes: Diabetes Atherosclerosis Intervention Study, a randomised study. Lancet2001; 357: 905–910.
25.
AnderlováKDolezalováRHousováJ: Influence of PPAR-α agonist fenofibrate on insulin sensitivity and selected adipose tissue-derived hormones in obese women with type 2 diabetes. Physiol Res2007; 56: 579–586.
26.
PoliKAToflerGHLarsonMG: Association of blood pressure with fibrinolytic potential in the Framingham offspring population. Circulation2000; 101: 264–269.
27.
WesterbackaJVehkavaaraSBergholmR: Marked resistance of the ability of insulin to decrease arterial stiffness characterizes human obesity. Diabetes1999; 48: 821–827.
ShimabukuroMZhouYTLeviM: Fatty acid-induced β-cell apoptosis: A link between obesity and diabetes. Proc Natl Acad Sci U S A1998; 95: 2498–2502.
30.
DomanskiMJJablonskiKA: Obesity and cardiovascular events in patients with established coronary disease. Eur Heart J2006; 27: 1416–1422.
31.
BoothGLKapralMKFungK: Relation between age and cardiovascular disease in men and women with diabetes compared with non-diabetic people: A population-based retrospective cohort study. Lancet2006; 368: 29–36.
