Nicolas Wiernsperger

Antiatherogenic properties of metformin: the experimental evidence

Cardiovascular disease (CVD) is the major determining factor of morbidity and mortality in type 2 diabetic patients. The established relationship between type 2 diabetes and atherosclerosis has fueled suggestions that anti-diabetic drugs with beneficial effects on CV risk factors may help attenuate the atherosclerotic process in diabetic patients. Metformin is a hypoglycaemic agent widely used in the management of type 2 diabetes. In addition to its insulin-sensitising action, this drug has favourable effects on various CV risk factors and reduces macrovascular complications in obese type 2 diabetic patients. This review summarises in vivo and in vitro experimental evidence on the antiatherogenic properties of metformin.

Microcirculation in insulin resistance and diabetes: more than just a complication

The microvascular bed is an anatomical entity which is governed by specific, highly regulated mechanisms which are closely adapted to the specific function of each vascular segment. Among those, small arteriolar vasomotion and capacity of small vessels to constrict in response to physical and humoral stimuli play a major role. Other processes of importance for the adequacy of nutritive perfusion are haemorheological properties of whole blood and red cells, adhesiveness of leukocytes and capillary permeability. This review provides some description of these phenomena, how they impact on organ function and how they appear in diabetes. Metformin, as a unique example among the drug arsenal, exerts various effects preferentially at the level of smallest vessels (arterioles, capillaries, venules). This review summarises our actual knowledge and includes several new data showing its high potential for reducing microvascular dysfunction. Most of these unique properties have also been demonstrated in non-diabetic animals or humans, suggesting they are intrinsic to the drug and not secondary to diabetic metabolic improvement. A particular focus is put on the relevance of metformins capacity to stimulate slow wave arteriolar vasomotion and improve functional capillary density, whereby nutritive flow can be re-established. Finally, the implication of microcirculation in other aspects of insulin resistance and diabetes, such as macroangiopathy and metabolic control, is discussed and strengthens the concept of a broad involvement of microvascular dysfunction in these diseases as well as the potential interest of introducing adapted treatment early in the history of a patients diabetes.

Metformin inhibits monocyte adhesion to endothelial cells and foam cell formation

The United Kingdom Prospective Diabetes Study (UKPDS) found that metformin reduces macrovascular complications in type 2 diabetic patients. To investigate the mechanisms involved we examined the effect of metformin on monocyte adhesion to human endothelial cells (ECs) induced by advanced glycation end-products (AGE), and on monocyte differentiation into macrophages and foam cell formation. Treatment of human ECs with AGEs (100 µg/ml) for up to 12 hours significantly increased human monocyte adhesion. Pre-treatment of the cells with metformin (0.1—2.5 µg/ml) inhibited AGE-induced monocyte adhesion and expression of endothelial cell adhesion molecules. In culture, human monocytes spontaneously differentiated into macrophages, as indicated by phenotypic changes, and increased expression of lectin-like oxidised low-density lipoprotein (LDL) receptor and scavenger receptor type A. Incubation of these cells in the presence of metformin decreased expression of all of these parameters. Metformin also inhibited fo...

Impaired glucose tolerance and metformin: clinical and mechanistic aspects

The Diabetes Prevention Program (DPP) showed that metformin reduced the incidence of diabetes in subjects with impaired glucose tolerance (IGT) who were at high risk of progression to type 2 diabetes. Metformin was not as efficient as intensive life style intervention, but had a clinically significant effect in obese individuals and in those with impaired fasting glucose (IFG). This review discusses the clinical implications and the mechanistic aspects of the effect of metformin in IGT and IFG. Acute actions of metformin on postprandial metabolism to improve hepatic glucose handling and improve the lipid profile could contribute to the lower incidence of diabetes. Longer term improvements in haemodynamic parameters and reduced oxidative stress are also implicated. Metformin offers a potential alternative or complement to lifestyle intervention for IGT, and deserves further evaluation in this respect.

Effects of chronic treatment with glibenclamide and/or metformin on the resistance to ischaemia of isolated hearts from Zucker Diabetic Fatty rats (ZDF/GMI-fa/fa)

The study was carried out to determine whether metformin (M) had any deleterious effect on the tolerance to ischaemia of the isolated diabetic rat when administered chronically in combination with glibenclamide (G). The male Zucker Diabetic Fatty (ZDF) rat served as a model of type 2 diabetes that resembles the human syndrome. Three groups of rats were treated for one month with M (100 mg/kg) or G (2 mg/kg) or G + M in their daily food. One group was untreated (C). Aortically perfused hearts were subjected to a 25-minute global low-flow ischaemia and a 30-minute reperfusion. Heart rate (HR), left ventricular developed pressure (LVDP), rate pressure product (RPP) and coronary flow (CF) were monitored. When compared to C hearts, the hearts from G + M rats showed improvements in HR, LVDP and RPP at the end of reperfusion. Hearts from G and M rats exhibited no difference. Myocardial glycogen stores at the end of reperfusion were higher in hearts from G + M rats than in the three other groups. The study did not reveal any deleterious effect of the chronic G + M therapy on the functional recovery of the isolated diabetic heart submitted to ischaemia and reperfusion: indeed, an increase in residual contractile capacity was found. Br J Diabetes Vasc Dis 2003;3:375‐80