Identifying the causative relationship between the fatty acid composition of cell membranes and type 2 diabetes mellitus fundamentally contributes to the understanding of the basic pathophysiological mechanisms of the disease. Important outcomes of the reviewed studies appear to support the hypotheses that the flexibility of a membrane determined by the ratio of (poly)unsaturated to saturated fatty acyl chains of its phospholipids influences the effectiveness of glucose transport by insulin-independent glucose transporters (GLUTs) and the insulin-dependent GLUT4, and from the prediabetic stage on a shift from unsaturated towards saturated fatty acyl chains of membrane phospholipids directly induces a decrease in glucose effectiveness and insulin sensitivity. In addition, it has become evident that a concomitant increase in stiffness of both plasma and erythrocyte membranes may decrease the microcirculatory flow, leading ultimately to tissue hypoxia, insufficient tissue nutrition, and diabetes-specific microvascular pathology. As to the etiology of type 2 diabetes mellitus, a revised hypothesis that attempts to accommodate the reviewed findings is presented.

The objective of this study was to investigate whether reduction in hypertriglyceridaemia is associated with a slower rate of progression of microalbuminuria in patients with non-insulin-dependent diabetes mellitus (NIDDM). Fifteen normotensive NIDDM patients with hypertriglyceridaemia (> 2.5 mmol L-1) and microalbuminuria were randomly selected to receive either placebo (eight patients) or gemfibrozil 600 mg b.i.d. (seven patients). Progression of microalbuminuria was assessed during a 12-month follow-up period with measurements, consisting of blood tests and triplicate 24-h urine collections, at 1, 3, 6, 9 and 12 months. All but one patient in the treatment group showed a favourable response (> or = 20% reduction) of hypertriglyceridaemia to gemfibrozil. One patient in the placebo group showed a spontaneous reduction in triglyceride levels. Progression of microalbuminuria was lower, although not statistically significantly so, in the treatment group (36%) than in the placebo group (65%). In the group with > or = 20% reduction in triglyceride levels, progression of MA was significantly lower than in the group with stable or increasing triglyceride levels (+1%, range -56% to +49% vs. +97%, range -35% to +202% respectively) (P = 0.03). Continued follow-up data of patients switching from placebo to gemfibrozil after the trial further support the role of serum triglyceride reduction in stabilizing albumin excretion. In conclusion, the results indicate that, in microalbuminuric NIDDM patients, effective treatment of dyslipidaemia could be associated with stabilization of urinary albumin excretion.

The rate of progression of microalbuminuria in NIDDM differs considerably between subjects. Diabetic dyslipidemia (high serum triglyceride and low HDL cholesterol) is a predictor of more rapid progression of microalbuminuria in patients with well-controlled blood pressure.

OBJECTIVE -The purpose of this study was to identify independent determinants of mild gestational hyperglycemia (MGH) and gestational diabetes mellitus (GDM) and to assess the correlation between fasting glucose and C-peptide levels among control, MGH, and GDM women.RESEARCH DESIGN AND METHODS -A total of 1,022 consecutive women were evaluated with a 1-h 50-g glucose challenge test (GCT) at between 16 and 33 weeks of gestation. Women with a capillary whole-blood glucose Ն7.8 mmol/l in the GCT underwent a 3-h 100-g oral glucose tolerance test (OGTT). On the basis of a positive GCT, the women with a positive OGTT were classified as GDM, whereas the women with a negative OGTT were classified as MGH. The following data were collected for all women: age, prepregnancy BMI, ethnicity, clinical and obstetric history, pregnancy outcome, and C-peptide level.RESULTS -A total of 813 women (79.6%) were normal, 138 (13.5%) had MGH, and 71 (6.9%) had GDM. There was a stepwise significant increase in mean fasting glucose (3.6 Ϯ 0.4, 3.9 Ϯ 0.4, and 4.7 Ϯ 0.7 mmol/l, respectively) and C-peptide level (0.60 [0.1-2.4], 0.86 [0.3-2.0], and 1.00 [0.5-1.6] nmol/l, respectively) among the three diagnostic groups. Maternal age, non-Caucasian ethnicity, and prepregnancy BMI were associated with GDM, whereas only maternal age and prepregnancy BMI were associated with MGH. A positive correlation between levels of fasting glucose and C-peptide was found in control women (r ϭ 0.39 [95% CI 0.31-0.46]). A similar result was seen in MGH women (r ϭ 0.38 [95% CI 0.23-0.52]), whereas the correlation between fasting glucose and C-peptide was nearly lost in GDM women (r ϭ 0.14 [CI Ϫ0.09 to 0.36]). The fasting C-peptide-to-glucose ratio was reduced by 60% in GDM patients versus control subjects and MGH patients (0.41 Ϯ 0.25 vs. 0.70 Ϯ 0.20 and 0.73 Ϯ 0.23, P Ͻ 0.001).CONCLUSIONS -Of the well-known independent determinants of GDM, only maternal age and prepregnancy BMI were associated with MGH. It appears that additional factors promoting loss of ␤-cell function distinguish MGH from GDM. One of these factors appears to be ethnicity. Diabetes Care 25:72-77, 2002

Free fatty acids released from human adipose tissue contain a limited amount of non-esterified poly-cis-unsaturated fatty acids. In cases of elevated plasma free fatty acids, this condition ultimately leads to a shift from unsaturated to saturated fatty-acyl chains in membrane phospholipids. Because this shift promotes the physical attractive van der Waals interactions between phospholipid acyl chains, it increases stiffness of both erythrocyte and endothelial membranes, which causes a reduction in both insulin-independent and insulin-dependent Class 1 glucose transporters, a reduction in cell membrane functionality, and a decreased microcirculatory blood flow which results in tissue hypoxia. Against the background of these processes, we review recently published experimental phospholipid data obtained from Drosophila melanogaster and from human erythrocytes of controls and patients with type 2 diabetes, with and without retinopathy, along the way free fatty acids interfere with eye and kidney function in patients with type 2 diabetes and give rise to endoplasmic reticulum stress, reduced insulin sensitivity, and ischemia.