Thus, we examined the effects of preventional and interventional Cr(pic)3 on glycemic control and the kidney of the db/db mouse which is one of the best characterized and most intensively studied animal models of human type 2 diabetic nephropathy the db/db mouse lacks the leptin receptor due to an autosomal recessive mutation of the diabetic (db) gene. Given that nephropathy is a major complication of type 2 diabetes, it is possible that chronic Cr(pic)3 use could be of potential detrimental consequences to the kidney (i.e., with possibility to cause functional dysregulation and/or altered structure) because of its accumulation within this organ. The kidney is also a principal route of elimination for chromium. Ĭhronic Cr(pic)3 supplementation results in distribution of chromium into a variety of tissues including the kidney. Hydroxyl free radicals can cause severe DNA damage through a large and complex set of reactions ranging from oxidation of deoxyribose and base moieties to strand breaks. Accordingly, it has been suggested that reduction of Cr(pic)3 by ascorbate produces -, which is susceptible to oxidation thereby generating hydroxyl free radicals. Of particular concern has been the potential genotoxicity of Cr(pic)3. While the beneficial metabolic effects of Cr(pic)3 have been the focus of a number of investigations, others have raised concerns regarding its safety and toxicity. Improvement in glucose homeostasis per se, in turn, ameliorates oxidative stress, which is a major sequela of chronic hyperglycemia that contributes importantly to the pathogenesis of diabetic complications including nephropathy. The interest in trivalent chromium stems from studies which indicate that chromodulin is capable of binding to the insulin receptor thereby resulting in amplification of insulin signaling chromodulin is a low molecular weight chromium binding substance or a likely product of its metabolism known as the glucose tolerance factor. High-dose Cr(pic)3 treatment mildly improves glycemic control and it causes moderate reduction in albuminuria, without affecting histopathological appearance of the kidney and increasing the risk for DNA damage.Ĭhromium picolinate (Cr(pic)3) is suggested to improve glycemic control in type 2 diabetes. In conclusion, the severely hyperglycemic db/db mouse displays renal structural and functional abnormalities in association with DNA damage. The results generally revealed similar effects to those of the 100 mg/kg diet of the preventional protocol. In interventional protocol, effects of diets containing 0, 100 and 250 mg/kg supplemental chromium, from 12 to 24 weeks of age, were examined in db/db mice. Treatment with Cr(pic)3 did not increase DNA damage despite marked renal accumulation of chromium. High Cr(pic)3 intake (i.e., 100 mg/kg diet) mildly improved glycemic status and albuminuria without affecting blood pressure or creatinine clearance. Creatinine clearance was lower while blood pressure was similar between untreated db/db mice and their db/m controls. Untreated db/db mice displayed increased plasma glucose and insulin, hemoglobin A1c, renal tissue advanced glycation end (AGE) products, albuminuria, glomerular mesangial expansion, urinary 8-hydroxydeoxyguanosine (8-OHdG, an index of oxidative DNA damage) and renal tissue immunostaining for γH2AX (a marker of double-strand DNA breaks) compared to db/m controls. In preventional protocol, male obese diabetic db/db mice were fed diets either lacking or containing 5, 10 or 100 mg/kg chromium as Cr(pic)3 from 6 to 24 weeks of age male lean nondiabetic db/m mice served as controls. This study examined renal and glycemic effects of chromium picolinate (Cr(pic)3) supplementation in the context of its purported potential for DNA damage.
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