Insulin resistance in the control of body fat distribution: a new hypothesis.

Obesity causes insulin resistance, which is a prime etiological factor for type 2 diabetes, dyslipidemia, and cardiovascular disease. However, insulin resistance may be a normal physiological response to obesity that limits further fat deposition and which only has pathological effects at high levels. The current hypothesis suggests that in obesity the initial deposition of triglycerides occurs in subcutaneous adipose tissue and as this increases in size insulin resistance will rise and limit further subcutaneous lipid accumulation. Triglycerides will then be diverted to the visceral fat depot as well as to ectopic sites. This leads to a substantial rise in insulin resistance and the prevalence of its associated disorders. Evidence supporting this hypothesis includes studies showing that in lean subjects the prime determinant of insulin resistance is BMI, that is, subcutaneous fat whilst in overweight and obese subjects it is waist circumference and visceral adiposity. It has also been shown that the metabolic syndrome suddenly increases in prevalence at high levels of insulin resistance and we suggest that this is due to the diversion of lipids from the subcutaneous to the visceral depot. This system may have functioned in our evolutionary past to limit excessive adiposity by causing lipid deposition to occur at a site that has maximal effects on insulin resistance but involves minimal weight gain.

The relationship between insulin sensitivity and serum adiponectin levels in three population groups.

Reduced plasma adiponectin levels are associated with insulin resistance. Black South Africans, like African Americans, are more insulin-resistant than BMI-matched white subjects, as are Asian Indians. We investigated whether this interethnic variation in insulin resistance is due to differences in plasma adiponectin levels. Blood and anthropometric measurements were taken from black, white and Asian-Indian subjects. Serum adiponectin, lipids, glucose and insulin were measured; insulin sensitivity was calculated using HOMA. Black (HOMA = 2.62 +/- 0.99) and Asian-Indian subjects (HOMA = 3.41 +/- 2.85) were more insulin-resistant than BMI-matched white (HOMA = 1.76 +/- 0.63) subjects (p = 0.0001). Furthermore, the white subjects had higher adiponectin levels (8.11 +/- 4.39 microg/ml) compared to black (5.71 +/- 2.50 microg/ml) and Asian Indian (5.86 +/- 2.50 microg/ml) subjects (p = 0.003). When all ethnic groups were combined, multiple regression analysis demonstrated that serum adiponectin levels corrected for BMI and ethnicity did not correlate with HOMA, but did explain 10.0 % of the variance in HDL-cholesterol levels. Within each ethnic group, adiponectin only correlated inversely with HOMA in white subjects. Adiponectin may play a role in determining serum HDL-cholesterol levels, but ethnic variation in insulin sensitivity is not dependent on serum levels of this adipokine. The relationship between adiponectin and insulin resistance varies across ethnic groups.

Cell adhesion molecules - can they be used to predict coronary artery disease in patients with familial hypercholesterolaemia?

Adhesion of leukocytes to endothelial cells via cell adhesion molecules (CAMS) is thought to be pivotal in the initiation of atherosclerosis. As patients with familial hypercholesterolaemia (FH) are known to develop severe, premature coronary artery disease (CAD), we investigated the usefulness of soluble forms of CAMS namely vascular cellular adhesion molecule-1 (VCAM), intercellular cell adhesion molecule-1 (ICAM) and E-selectin as predictive markers of the presence and severity of atherosclerosis in this patient group. Twenty heterozygous FH patients without CAD; 24 heterozygous FH patients with CAD; 17 homozygous FH patients without documented CAD; nine homozygous FH patients with overt CAD; and 50 healthy controls were studied. Carotid artery intima media thickness (IMT) was also measured in the homozygous patients. Levels of the adhesion molecules VCAM, ICAM and E-selectin were not significantly elevated in homozygous FH patients and heterozygous FH patients, both with and without CAD, compared to the normal control subjects. In addition the range of results was so wide and the overlap of values with normal controls so great, that the use of an individual level of either VCAM, ICAM or E-selectin was not predictive of either the presence or degree of atherosclerosis in the FH subjects.

Plasma fatty acid levels in South African interethnic male high school pupils at different ultimate risks of coronary heart disease.

While coronary heart disease (CHD) is responsible for about a quarter of deaths in South African white, coloured and Indian populations, the rate is very low in the black population. Dietary risk factors for CHD include high intakes of saturated fatty acids and cholesterol, with low intakes of mono and polyunsaturated fatty acids. In a characterization study, plasma fatty acid profiles have been determined in seven groups of high school pupils aged 16-18 years, namely, white, rural black, urban black and middle-class and lower socio-economic class coloureds and Indians. Plasma fatty acids were measured by gas liquid chromatography in 20 subjects from each group. Contrary to expectation, urban and rural black pupils had the highest mean molar composition of saturated fatty acids, largely myristic (14:0) and palmitic (16:0) acids. Rural blacks and middle-class coloureds had the highest molar percentage composition of monounsaturated fatty acids, primarily oleic acid (18:1). Again unexpectedly, white, coloured and Indian groups had the highest level of polyunsaturated fatty acids, due entirely to linoleic acid (18:2). As the findings are unrelated to proneness to CHD mortality in the particular communities studied, plasma fatty acid levels are not predictive of the disease. Epidemiologically, there are many examples of lack of correlation in serum lipid levels and proneness to CHD.

The in vitro effect of ridogrel on platelet function in normocholesterolaemic and familial hypercholesterolaemic type IIa subjects.

Platelets from familial hypercholesterolaemia type IIa patients are hyperreactive and produce increased amounts of thromboxane A2. These modifications of platelet function may play an important role in the occurrence of premature atherosclerosis. One approach to the prevention of the thromboembolic complications of atherosclerosis is the use of antiplatelet agents which depress platelet function. Ridogrel, a combined thromboxane synthase inhibitor and thromboxane A2/prostaglandin endoperoxide receptor blocker inhibits platelet aggregation. This study was designed to investigate the in vitro effect of ridogrel on platelet function in normocholesterolaemic and familial hypercholesterolaemia type IIa subjects. In citrated platelet rich plasma ridogrel significantly inhibited platelet aggregation and thromboxane A2 production in response to collagen, ADP and arachidonic acid stimulation. In washed platelets ridogrel significantly decreased aggregation and serotonin release. Ridogrel significantly increased cAMP levels in response to thrombin stimulation. In conclusion, ridogrel at low concentrations significantly inhibited the in vitro function of platelets in a dose dependant manner in both normocholesterolaemic subjects and familial hypercholesterolaemia IIa subjects.

Platelet hyperreactivity in hyperlipidaemia with specific reference to platelet lipids and fatty acid composition.

Platelet function after thrombin stimulation, the fatty acid composition of individual phospholipids, and levels of lipid components (cholesterol, cholesterol ester, phospholipids and triglycerides) were determined in total membranes of platelets from hyperlipidaemic (HL) and control subjects. Platelet aggregation, thromboxane (TX) B2 production and serotonin release was significantly greater in HL patients than in controls. Levels of platelet cholesterol, total phospholipids, cholesterol ester and triglycerides, were significantly higher in the HL patients. Small differences between the two groups were observed for the phospholipid fatty acid patterns. However, levels of arachidonic acid (AA) were significantly higher in phosphatidylinositol (PI) of HL patients (40.01 +/- 6.59 mol%) as compared to the controls (31.52 +/- 9.91 mol%) (P = 0.002). The higher levels of AA in PI, which is considered a donor pool for eicosanoid synthesis, may be an additional mechanism for the well documented platelet hyperfunction and greater TXB2 production in hyperlipidaemic subjects.