OBJECTIVE -To evaluate the effects of metformin on glucagon-like peptide 1 (GLP-1) and leptin levels. RESEARCH DESIGN AND METHODS-A total of 10 obese nondiabetic male patients were studied before and after a 14-day treatment with 2,550 mg/day metformin and were compared with 10 untreated obese control subjects. On days 0 and 15, leptin and GLP-1(7-36)amide/(7-37) levels were assessed before and after an oral glucose load during a euglycemic hyperinsulinemic clamp to avoid the interference of variations of insulinemia and glycemia on GLP-1 and leptin secretion. The effects of metformin on GLP-1(7-36)amide degradation in human plasma and in a buffer solution containing dipeptidyl peptidase IV (DPP-IV) were also studied.RESULTS -Leptin levels were not affected by the oral glucose load, and they were not modified after metformin treatment. Metformin induced a significant (P Ͻ 0.05) increase of GLP-1(7-36)amide/(7-37) at 30 and 60 min after the oral glucose load (63.8 Ϯ 29.0 vs. 50.3 Ϯ 15.6 pmol/l and 75.8 Ϯ 35.4 vs. 46.9 Ϯ 20.0 pmol/l, respectively), without affecting baseline GLP-1 levels. No variations of GLP-1 levels were observed in the control group. In pooled human plasma, metformin (0.1-0.5 g/ml) significantly inhibited degradation of GLP-1(7-36)amide after a 30-min incubation at 37°C; similar results were obtained in a buffer solution containing DPP-IV.CONCLUSIONS -Metformin significantly increases GLP-1 levels after an oral glucose load in obese nondiabetic subjects; this effect could be due to an inhibition of GLP-1 degradation. Diabetes Care 24:489 -494, 2001

Aims/hypotheses: Chronic hyperglycaemia in-

■ AbstractPatients with diabetes frequently exhibit the combined occurrence of hyperglycemia and dyslipidemia. Published data on their coexistence are often controversial. Some studies provide evidence for suboptimal lifestyle and exogenous hyperinsulinism at "mild insulin resistance" in adult diabetic patients as main pathogenic factors. In contrast, other studies confirm that visceral adiposity and insulin resistance are the basic features of dyslipidemia in type 2 diabetes (T2D). The consequence is an excess of free fatty acids, which causes hepatic gluconeogenesis to increase, metabolism in muscles to shift from glucose to lipid, beta-cell lipotoxicity, and an appearance of the classical "lipid triad", without real hypercholesterolemia. Recently, it has been proposed that cholesterol homeostasis is important for an adequate insulin secretory performance of beta-cells. The accumulation of cholesterol in beta-cells, caused by defective high-density lipoprotein (HDL) cholesterol with reduced cholesterol efflux, induces hyperglycemia, impaired insulin secretion, and beta-cell apoptosis. Data from animal models and humans, including humans with Tangier disease, who are characterized by very low HDL cholesterol levels, are frequently associated with hyperglycemia and T2D. Thus, there is a reciprocal influence of dyslipidemia on beta-cell function and inversely of beta-cell dysfunction on lipid metabolism and micro-and macrovascular complications. It remains to be clarified how these different but mutually influencing adverse effects act in together to define measures for a more effective prevention and treatment of micro-and macrovascular complications in diabetes patients. While the control of circulating low-density lipoprotein (LDL) cholesterol and the level of HDL cholesterol are determinant targets for the reduction of cardiovascular risk, based on recent data, these targets should also be considered for the prevention of betacell dysfunction and the development of type 2 diabetes. In this review, we analyze consolidated data and recent advances on the relationship between lipid metabolism and diabetes mellitus, with particular attention to the reciprocal effects of the two features of the disease and the development of vascular complications.

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Leptin concentrations are not significantly modified in obese Type 2 diabetic patients. GLP-1(7-36)amide baseline concentrations are reduced in Type 2 diabetes; moreover, diabetic subjects show an impaired response of GLP-1 to oral glucose in euglycaemic, isoinsulinaemic conditions. This impairment, which is not the result of differences in glycaemia or insulinaemia during assessment, could contribute to the pathogenesis of hyperglycaemia in Type 2 diabetes mellitus.

The use of fasting plasma glucose (FPG) only has been proposed for the screening and diagnosis of diabetes, but its sensitivity has been reported to be unsatisfactory. The use of HbA1C, alone or combined with FPG, has been suggested for the screening of diabetes and impaired glucose tolerance (IGT). In a sample of 1215 adult subjects without previously known diabetes, we assessed the sensitivity and specificity of FPG and HbA1C in diagnosing diabetes and IGT, determined by oral glucose tolerance test (OGTT). All lean diabetic patients, and 85% of overweight and obese diabetic individuals, had FPG > or =7 mmol/l. FPG >6.1 mmol/l had a sensitivity of 98.8% and a specificity of 32.9%; HbA1C had a lower specificity and sensitivity for the screening of diabetes. A screening strategy for diabetes based on FPG, with OGTT in all overweight subjects with FPG >6.1 mmol/l, is suggested. Neither FPG nor HbA1C is effective in the screening of IGT; although combined FPG and HbA1C could be useful for case finding, screening for IGT with OGTT is advisable in all subjects at high risk.

OBJECTIVETo assess the association of 1-h plasma glucose (1hPG) and inflammation with normal glucose tolerance (NGT) and pre-diabetes.RESEARCH DESIGN AND METHODSA cohort of 1,062 subjects was enrolled. After oral glucose load (oral glucose tolerance test), we compared subjects with NGT and pre-diabetes above and below the 1hPG cut point (155 mg/dl). Fibrinogen and leukocytes count (white blood cells [WBCs]) for subclinical inflammation, lipid ratios, insulin sensitivity (Matsuda index) were determined.RESULTSPatients with NGT and pre-diabetes (1hPG >155 mg/dl) showed a significant increase of inflammatory markers and lipid ratios (for all, P < 0.05). In age-, sex-, and BMI-adjusted analysis, 1hPG was associated with a significantly higher WBC count and fibrinogen (P < 0.05). Patients with elevated 1hPG showed a highly significant lower insulin sensitivity than subjects <1hPG (P < 0.01).CONCLUSIONSElevated 1hPG in subjects with NGT and pre-diabetes is associated with subclinical inflammation, high lipid ratios, and insulin resistance. Therefore, 1hPG >155 mg/dl could be considered a new “marker” for cardiovascular risk.