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 ...

OBJECTIVE-Excessive production of reactive oxygen species (ROS) via NADPH oxidase has been implicated in the pathogenesis of diabetic nephropathy. Since NADPH oxidase activation is closely linked to other putative pathways, its interaction with changes in protein kinase C (PKC) and increased advanced glycation was examined.RESEARCH DESIGN AND METHODS-Streptozotocin-induced diabetic or nondiabetic Sprague Dawley rats were followed for 32 weeks, with groups randomized to no treatment or the NADPH oxidase assembly inhibitor apocynin (15 mg ⅐ kg Ϫ1 ⅐ day Ϫ1 ; weeks 16 -32). Complementary in vitro studies were performed in which primary rat mesangial cells, in the presence and absence of advanced glycation end products (AGEs)-BSA, were treated with either apocynin or the PKC-␣ inhibitor Ro-32-0432.RESULTS-Apocynin attenuated diabetes-associated increases in albuminuria and glomerulosclerosis. Circulating, renal cytosolic, and skin collagen-associated AGE levels in diabetic rats were not reduced by apocynin. Diabetes-induced translocation of PKC, specifically PKC-␣ to renal membranes, was associated with increased NADPH-dependent superoxide production and elevated renal, serum, and urinary vascular endothelial growth factor (VEGF) concentrations. In both diabetic rodents and in AGE-treated mesangial cells, blockade of NADPH oxidase or PKC-␣ attenuated cytosolic superoxide and PKC activation and increased VEGF. Finally, renal extracellular matrix accumulation of fibronectin and collagen IV was decreased by apocynin.CONCLUSIONS-In the context of these and previous findings by our group, we conclude that activation of NADPH oxidase via phosphorylation of PKC-␣ is downstream of the AGE-receptor for AGE interaction in diabetic renal disease and may provide a novel therapeutic target for diabetic nephropathy. Diabetes 57: 460-469, 2008

OBJECTIVEExcess accumulation of advanced glycation end products (AGEs) contributes to aging and chronic diseases. We aimed to obtain evidence that exposure to AGEs plays a role in the development of type 1 diabetes (T1D).RESEARCH DESIGN AND METHODSThe effect of AGEs was examined on insulin secretion by MIN6N8 cells and mouse islets and in vivo in three separate rodent models: AGE-injected or high AGE–fed Sprague-Dawley rats and nonobese diabetic (NODLt) mice. Rodents were also treated with the AGE-lowering agent alagebrium.RESULTSβ-Cells exposed to AGEs displayed acute glucose-stimulated insulin secretory defects, mitochondrial abnormalities including excess superoxide generation, a decline in ATP content, loss of MnSOD activity, reduced calcium flux, and increased glucose uptake, all of which were improved with alagebrium treatment or with MnSOD adenoviral overexpression. Isolated mouse islets exposed to AGEs had decreased glucose-stimulated insulin secretion, increased mitochondrial superoxide production, and depletion of ATP content, which were improved with alagebrium or with MnTBAP, an SOD mimetic. In rats, transient or chronic exposure to AGEs caused progressive insulin secretory defects, superoxide generation, and β-cell death, ameliorated with alagebrium. NODLt mice had increased circulating AGEs in association with an increase in islet mitochondrial superoxide generation, which was prevented by alagebrium, which also reduced the incidence of autoimmune diabetes. Finally, at-risk children who progressed to T1D had higher AGE concentrations than matched nonprogressors.CONCLUSIONSThese findings demonstrate that AGEs directly cause insulin secretory defects, most likely by impairing mitochondrial function, which may contribute to the development of T1D.

Previous cellular, animal, and human studies suggest that increasing plasma HDL cholesterol may modulate insulin secretion. 5,[20][21][22] Cholesteryl ester transfer protein (CETP) inhibition increases plasma HDL cholesterol via a reduction in the transfer of neutral lipids (triglycerides and cholesteryl esters) between HDL and triglyceride-rich lipoprotein particles. The efficacy of this strategy to improve cardiovascular outcomes has not yet been determined, and there is controversy regarding whether CETP inhibition might produce a dysfunctional form of HDL cholesterol, which is less efficient at promoting reverse cholesterol transport than native HDL. 23 This controversy has arisen, in part, because of the early termination of 2 CETP inhibitor trials resulting from adverse events in the case of torcetrapib 24