Renal accumulation of biglycan and lipid retention accelerates diabetic nephropathy.

Hyperlipidemia worsens diabetic nephropathy, although the mechanism by which renal lipids accumulate is unknown. We previously demonstrated that renal proteoglycans have high low-density lipoprotein (LDL) binding affinity, suggesting that proteoglycan-mediated LDL retention may contribute to renal lipid accumulation. The aim of this study was to determine the relative effect of diabetes and hyperlipidemia on renal proteoglycan content. Diabetic and non-diabetic LDL receptor-deficient mice were fed diets containing 0% or 0.12% cholesterol for 26 weeks, and then kidneys were analyzed for renal lipid and proteoglycan content. Diabetic mice on the high-cholesterol diet had accelerated development of diabetic nephropathy with elevations in urine albumin excretion, glomerular and renal hypertrophy, and mesangial matrix expansion. Renal lipid accumulation was significantly increased by consumption of the 0.12% cholesterol diet, diabetes, and especially by both. The renal proteoglycans biglycan and decorin were detectable in glomeruli, with a significant increase in renal biglycan content in diabetic mice on the high-cholesterol diet. Renal biglycan and renal apolipoprotein B were colocalized, and regression analyses showed a significant relation between renal biglycan and renal apolipoprotein B content. The increased renal biglycan content in diabetic nephropathy probably contributes to renal lipid accumulation and the development of diabetic nephropathy.

Reversibility of renal injury with cholesterol lowering in hyperlipidemic diabetic mice.

Hyperlipidemia is a risk factor for development and progression of diabetic nephropathy. However, it is not known if reduction of hyperlipidemia is protective against progression of disease. The goal of this study was to determine if reduction of hypercholesterolemia could limit progression of diabetic nephropathy. Diabetic and nondiabetic LDL receptor deficient (LDLR(-/-)) mice were fed diets containing either no cholesterol (0%) or high cholesterol (0.12%) for 36 weeks. One group each of diabetic and nondiabetic mice were fed the high-cholesterol diet for 26 weeks then changed to the 0% cholesterol diet for the last 10 weeks. Consumption of the high-cholesterol diet exacerbated the development of diabetic nephropathy with elevations in urine albumin excretion, glomerular and renal hypertrophy, and mesangial matrix expansion. Increased glomerular lipid and apolipoprotein B accumulation was found in diabetic mice that consumed the 0.12% cholesterol diet compared with other groups. However, diabetic mice that changed from the high-cholesterol diet to the 0% cholesterol diet for the last 10 weeks had lower urine albumin excretion and mesangial matrix expansion compared with mice that consumed the 0.12% cholesterol diet throughout. This suggests that hyperlipidemia causes continuous renal injury, and that lowering cholesterol levels by dietary means can improve renal function in diabetic LDLR(-/-) mice.

Managing highly insulin-resistant diabetes mellitus: weight loss approaches and medical management.

The prevalence of obesity and diabetes is epidemic. Severe insulin resistance (defined as the need for > or = 200 units of insulin per day to achieve glycemic control) is commonly seen with obesity and can complicate diabetes management. The management of patients with diabetes who have severe insulin resistance is difficult, and at times frustrating, and requires a multifaceted approach. Weight loss is the best treatment option, which can be a challenging task for patients to achieve and maintain. Medications that decrease insulin needs like metformin, thiazolidinediones, or pramlintide may help, but some patients also need high doses of insulin. This article reviews these different treatment options and provides practical advice on weight loss, use of insulin sensitizers, and use of U-500 insulin.

Clinical efficacy and patient satisfaction with U-500 insulin use.

AIMS: The prevalence of highly insulin-resistant diabetes is increasing and treatment requires the use of very high doses of insulin. This study was performed to analyze efficacy and patient satisfaction with use of U-500 concentrated insulin. METHODS: The medical records of 40 patients using U-500 insulin for at least 3 months were reviewed. A quality of life questionnaire was administered 6 or more months after U-500 was initiated. Effects of U-500 use on HbA1c, weight, total daily insulin use, hypoglycemia, and patient satisfaction were measured. RESULTS: Patients had uncontrolled diabetes for 3 years prior to U-500 initiation despite insulin titration. Subjects required continued insulin titration to attain glycemic control even after U-500 initiation, but HbA1c decreased by 1.5% within 3 months. Subjects gained weight with insulin titration. Hypoglycemic symptoms increased early after transition to U-500 insulin, but patients reported fewer hypoglycemic episodes on the quality of life questionnaire. Patient satisfaction with diabetes care and control was significantly improved following transition to U-500 insulin. CONCLUSIONS: Use of U-500 insulin assists with attaining glycemic control in highly insulin-resistant subjects, but at the cost of weight gain and increased insulin doses. However, patient satisfaction is improved with U-500 insulin use.