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Mesangial expansion is a key feature in the pathogenesis of numerous renal diseases involving the glomerulus. Studies indicate that mutations in apolipoprotein E (apoE) might independently contribute to kidney dysfunction. Although the role of apoE as an atheroprotective molecule is well established, its role in kidney is unclear. In this study, we sought to explore whether apoE has a protective function in kidney. Northern blotting and reverse transcriptase-polymerase chain reaction showed apoE expression in kidney, and mesangial cell is a major source of apoE in kidney. In the kidneys of 14 -16-month-old apoE-null mice, hematoxylin-eosin (HE) staining revealed increased mesangial cell proliferation and matrix formation compared with wild type mice or apoB-overexpressing mice, which have elevated plasma cholesterol and triglycerides. These data suggest that lack of apoE, rather than hyperlipidemia, contributes to increased mesangial expansion. We isolated mesangial cells from mouse kidney and determined the effect of apoE on cell growth. ApoE (E3, 10 g/ml) completely inhibited serum, platelet-derived growth factor (10 ng/ml), as well as low density lipoprotein-induced mesangial cell proliferation. Among the three isoforms, E3 was found to be most effective in inhibiting mesangial cell proliferation. ApoE did not show any cytotoxic effect, and moreover, inhibited mesangial cell apoptosis induced by oxidized low density lipoprotein. These data suggest that apoE regulates growth as well as survival of mesangial cells. We previously showed that apoE induces matrix heparan sulfate proteoglycan (HSPG) in vascular cells, which has an antiproliferative effect. Similarly, apoE induced the mesangial matrix HSPG. Perlecan is the major HSPG of mesangial matrix and subendothelial space, and consistent with this, blockade of perlecan reversed the antiproliferative effect of apoE. Immunohistochemistry revealed reduced staining of perlecan in kidney from apoE-null mice. Because the loss of anionic HSPG in the basement membrane and mesangial matrix is associated with disruption of filtration barrier, these data suggest a novel role for kidney apoE in preserving the filtration barrier. In summary, apoE has a protective function in kidney as an autocrine regulator of mesangial expansion and kidney function.

OBJECTIVEAfter intensive insulin treatment, many obese African American patients with new-onset diabetic ketoacidosis (DKA) and severe hyperglycemia are able to achieve near-normoglycemia remission. The optimal treatment to prevent hyperglycemic relapses after remission is not known.RESEARCH DESIGN AND METHODSThis prospective, 4-year, placebo-controlled study randomly assigned 48 African American subjects with DKA and severe hyperglycemia to metformin 1,000 mg daily (n = 17), sitagliptin 100 mg daily (n = 16), or placebo (n = 15) after normoglycemia remission. Hyperglycemic relapse was defined as fasting glucose >130 mg/dL (7.2 mmol/L) and HbA1c >7.0% (53 mmol/mol). Oral glucose tolerance tests were conducted at randomization and at 3 months and then every 6 months for a median of 331 days. Oral minimal model and incremental area under the curve for insulin (AUCi) were used to calculate insulin sensitivity (Si) and β-cell function, respectively. Disposition index (DI) was calculated as a product of Si and incremental AUCi.RESULTSRelapse-free survival was higher in sitagliptin and metformin (P = 0.015) compared with placebo, and mean time to relapse was significantly prolonged in the metformin and sitagliptin groups compared with the placebo group (480 vs. 305 days, P = 0.004). The probability of relapse was significantly lower for metformin (hazard ratio 0.28 [95% CI 0.10–0.81]) and sitagliptin (0.31 [0.10–0.98]) than for placebo. Subjects who remained in remission had a higher DI (P = 0.02) and incremental AUCi (P < 0.001) than those with hyperglycemia relapse without significant changes in Si.CONCLUSIONSThis study shows that near-normoglycemia remission was similarly prolonged by treatment with sitagliptin and metformin. The prolongation of remission was due to improvement in β-cell function.

Accelerated atherosclerosis is one of the major vascular complications of diabetes. Factors including hyperglycemia and hyperinsulinemia may contribute to accelerated vascular disease. Among the several mechanisms proposed to explain the link between hyperglycemia and vascular dysfunction is the hexosamine pathway, where glucose is converted to glucosamine. Although some animal experiments suggest that glucosamine may mediate insulin resistance, it is not clear whether glucosamine is the mediator of vascular complications associated with hyperglycemia. Several processes may contribute to diabetic atherosclerosis including decreased vascular heparin sulfate proteoglycans (HSPG), increased endothelial permeability and increased smooth muscle cell (SMC) proliferation. In this study, we determined the effects of glucose and glucosamine on endothelial cells and SMCs in vitro and on atherosclerosis in apoE null mice. Incubation of endothelial cells with glucosamine, but not glucose, significantly increased matrix HSPG (perlecan) containing heparin-like sequences. Increased HSPG in endothelial cells was associated with decreased protein transport across endothelial cell monolayers and decreased monocyte binding to subendothelial matrix. Glucose increased SMC proliferation, whereas glucosamine significantly inhibited SMC growth. The antiproliferative effect of glucosamine was mediated via induction of perlecan HSPG. We tested if glucosamine affects atherosclerosis development in apoE-null mice. Glucosamine significantly reduced the atherosclerotic lesion in aortic root. (P < 0.05) These data suggest that macrovascular disease associated with hyperglycemia is unlikely due to glucosamine. In fact, glucosamine by increasing HSPG showed atheroprotective effects.