HDL associates with insulin resistance and beta-cell dysfunction in South Asian families at risk of type 2 diabetes

Objective: Dyslipidemia precedes type 2 diabetes (T2D) and worsens with increasing glucose intolerance. First degree relatives of T2D patients have an increased risk to develop dyslipidemia and glucose intolerance. The aim of the present study was to assess the relation between the development of dyslipidemia and glucose intolerance in first-degree relatives of T2D patients. Research design and methods: Fasting lipoprotein profiles were determined by density gradient ultracentrifugation in T2D patients and their first-degree relatives (42 Caucasians and 33 South Asians), and in 29 normoglycemic controls from non-T2D families. Glucose tolerance, insulin sensitivity index (ISI) and insulin disposition index (DI) were assessed by an extended, frequently sampled oral glucose tolerance test (OGTT), and fractional insulin synthesis rate (FSR) was measured by C-13-leucine enrichment in urinary C-peptide during the OGTT. Results: Of the first-degree relatives, 40, 16 and 19 had NGT, prediabetes and T2D, respectively. NGT family members had lower plasma HDL-cholesterol (HDL-C) (1.34 +/- 0.07 vs 1.58 +/- 0.06 mmol/L; p = 0.015), HDL2-C (0.41 +/- 0.05 vs 0.57 +/- 0.05 mmol/L; p = 0.021) and HDL3-C (0.62 +/- 0.03 vs 0.72 +/- 0.02 mmol/L; p = 0.043) than controls. HDL2-C levels tended to decrease with increasing glucose intolerance state. In South Asians, buoyant LDL-C levels decreased with increasing glucose intolerance state (p = 0.006). In South Asian families, HDL-C correlated with both ISI and DI (beta 0.42; p = 0.04 and beta 0.53; p = 0.01, respectively), whereas HDL2-C and HDL3-C levels correlated with DI (beta 0.64; p = 0.002 and beta 0.57; p = 0.005, respectively). HDL2-C and plasma triglyceride correlated with FSR (beta 0.48; p = 0.033 and beta 0.50; p = 0.029, respectively). Conclusions: Low HDL2-C and HDL3-C levels are present in NGT first-degree relatives of T2D patients, and HDL2-C tend to decrease further with increasing glucose intolerance. In South Asian families HDL2-C and HDL3-C levels linked predominantly to deteriorating beta cell function.