High-Density Lipoprotein Modulates Glucose Metabolism in Patients With Type 2 Diabetes Mellitus

Abstract

Background-Low plasma high-density lipoprotein (HDL) is associated with elevated cardiovascular risk and aspects of the metabolic syndrome. We hypothesized that HDL modulates glucose metabolism via elevation of plasma insulin and through activation of the key metabolic regulatory enzyme, AMP-activated protein kinase, in skeletal muscle. Methods and Results-Thirteen patients with type 2 diabetes mellitus received both intravenous reconstituted HDL (rHDL: 80 mg/kg over 4 hours) and placebo on separate days in a double-blind, placebo-controlled crossover study. A greater fall in plasma glucose from baseline occurred during rHDL than during placebo (at 4 hours rHDLϭϪ2.6Ϯ0.4; placeboϭϪ2.1Ϯ0.3mmol/L; Pϭ0.018). rHDL increased plasma insulin (at 4 hours rHDLϭ3.4Ϯ10.0; placeboϭ Ϫ19.2Ϯ7.4 pmol/L; Pϭ0.034) and also the homeostasis model assessment ␤-cell function index (at 4 hours rHDLϭ18.9Ϯ5.9; placeboϭ8.6Ϯ4.4%; Pϭ0.025). Acetyl-CoA carboxylase ␤ phosphorylation in skeletal muscle biopsies was increased by 1.7Ϯ0.3-fold after rHDL, indicating activation of the AMP-activated protein kinase pathway. Both HDL and apolipoprotein AI increased glucose uptake (by 177Ϯ12% and 144Ϯ18%, respectively; PϽ0.05 for both) in primary human skeletal muscle cell cultures established from patients with type 2 diabetes mellitus (nϭ5). The mechanism is demonstrated to include stimulation of the ATP-binding cassette transporter A1 with subsequent activation of the calcium/calmodulin-dependent protein kinase kinase and the AMP-activated protein kinase pathway. Conclusions-rHDL reduced plasma glucose in patients with type 2 diabetes mellitus by increasing plasma insulin and activating AMP-activated protein kinase in skeletal muscle. These findings suggest a role for HDL-raising therapies beyond atherosclerosis to address type 2 diabetes mellitus. Key Words: glucose Ⅲ insulin Ⅲ lipoproteins Ⅲ metabolism Ⅲ muscles H igh-density lipoprotein (HDL) is associated with protection from adverse cardiovascular outcomes in large epidemiological trials. 1 Type 2 diabetes mellitus and the cluster of pathologies including glucose intolerance/insulin resistance, obesity, and high plasma triglycerides that constitute the metabolic syndrome are associated with low and dysfunctional HDL. 2,3 In contrast, aerobically trained individuals have high HDL and display enhanced glucose tolerance. 4 Although the mechanisms linking low HDL to atherosclerosis are well characterized, the links between low HDL and disordered energy metabolism remain relatively unexplored. Given the high and escalating prevalence of type 2 diabetes mellitus, obesity, and the metabolic syndrome and the associated marked elevation in cardiovascular morbidity and mortality, this is an important area of investigation. Clinical Perspective p 2111Recent cell-based studies suggest that HDL may modulate plasma glucose through both insulin-dependent 5,6 and -independent mechanisms. 7 The ATP-binding cassette transporter A1 (ABCA1) has been shown to modulate insulin secretion, 6 and HDL can reverse ...

CETP expression reverses the reconstituted HDL-induced increase in VLDL

“…Expression of CETP thus clearly prevents the adverse effects of rHDL on VLDL levels. These data are in line with various human studies in which infusion of rHDL was used as an experimental treatment of CVD ( 12 ), diabetes ( 25 ), and infl ammation ( 26 ). In these clinical studies, no specifi c adverse VLDL-increasing effects were reported, which is in line with our data that human CETP may protect against rHDL-induced elevation of VLDL.…”

Dyslipidemia and Diabetes: Reciprocal Impact of Impaired Lipid Metabolism and Beta-Cell Dysfunction on Micro- and Macrovascular Complications

“…These data demonstrated that a better functionality of HDL particles may contribute to the maintenance of a healthy beta-cell function in subjects with well-controlled T2D. In an in vivo study, intravenous recombinant HDL in T2D patients has quickly allowed to reduce blood glucose levels, with a simultaneous increase in insulin concentrations and beta-cell function and a significant improvement of insulin sensitivity [63].…”

Low Levels of High-Density Lipoprotein Cholesterol Do Not Predict the Incidence of Type 2 Diabetes in an Iranian High-Risk Population: The Isfahan Diabetes Prevention Study

“…Epidemiological studies of the association between low HDLC level and risk of type 2 diabetes (T2D) have provided inconsistent results [11][12][13][14][15][16][17][18][19][20]; the reported associations have been positive [11][12][13][14][15][16][17][18][19], null [20], positive only in men [21,22], positive only in women [13,23], or even inverse [24]. Although increasing plasma HDLC levels have been suggested to reduce the risk of T2D [25], a recent trial showed that treatment with niacin, which raised HDLC, also raised blood glucose and T2D risk [26]. In another trial, treatment with torcetrapib, a plasma lipid transfer protein inhibitor which also raised HDLC concentrations, improved glycemic control [27], but the role of HDLC in reducing the risk of T2D remains poorly defined.…”