Effects of Chromium Picolinate on Glycemic Control and Kidney of the Obese Zucker Rat

Mahmood S Mozaffari; Rafik AbdelSayed; Jun Yao Liu; Hereward Wimborne; Azza El-Remessy; Ahmed El-Marakby

Disclosures

Nutr Metab. 2009;6:51 

In This Article

Abstract and Introduction

Abstract

Background Chromium picolinate (Cr(pic)3) is advocated as adjuvant therapy for impaired glycemic control, despite concerns for DNA damage. Potential toxicity of Cr(pic)3 should be greater for the kidney that accumulates chromium. Therefore, we tested the hypothesis that Cr(pic)3 treatment of obese Zucker rats (OZR) exacerbates renal abnormalities associated with dysglycemia.
Methods Male OZR were treated with diets lacking or containing 5 and 10 mg/kg of chromium, as Cr(pic)3, for 20 weeks; lean Zucker rats (LZR) served as controls. Glycemic and renal effects of Cr(pic)3 were determined in the context of indices of oxidative stress and inflammation.
Results The OZR displayed increased fasting plasma glucose and insulin in association with enlarged pancreatic islets exhibiting collagen and periodic acid Schiff-positive deposits compared to LZR; Cr(pic)3 treatment did not affect these parameters. The OZR, irrespective of Cr(pic)3, excreted more albumin than LZR. Also, other indices of renal function or histopathology were not affected by Cr(pic)3 treatment. Urinary excretion of 8-hydroxydeoxyguanosine (8-OHdG), an index of oxidative DNA damage, was greater in the OZR than LZR; dietary Cr(pic)3 treatment attenuated 8-OHdG excretion. However, immunostaining of kidney for 8-OHdG revealed similar staining pattern and intensity, despite significant renal accumulation of chromium in Cr(pic)3-treated groups. Finally, increased renal nitrotyrosine and cyclooxygenase-2 levels and urinary excretion of monocyte chemoattractant protein-1 of OZR were partially reversed by Cr(pic)3 treatment.
Conclusion Dietary Cr(pic)3 treatment of OZR does not beneficially influence glycemic status or increase the risk for oxidative DNA damage; rather, the treatment attenuates indices of oxidative stress and inflammation.

Introduction

The worldwide epidemic of obesity is a major predisposing factor for the ever increasing prevalence and incidence of glucose intolerance and type 2 diabetes.[1,2] In turn, obesity and impaired glucose tolerance/type 2 diabetes markedly increase the risk for development of renal and cardiovascular complications.[3,4] Further, obesity is known as a pro-inflammatory state thereby contributing importantly to eventual target organ manifestations and associated morbidity and mortality.[5,6]

Of various animal models of obesity and type 2 diabetes mellitus, the obese Zucker rats (OZR) have been used extensively for studies focused on consequences of the disease and the contributing mechanisms. The OZR have an autosomal recessive mutation of the fa gene encoding the leptin receptor. The OZR display marked obesity, dyslipidemia, severe insulin resistance, increased oxidative stress and a proinflammatory state compared to the lean Zucker rats (LZR).[7–9] Thus, the OZR can serve as a useful animal model for determination of potential influences of therapies aimed at prevention or attenuation of obesity/type 2 diabetes-related abnormalities.

The nutritional supplement, chromium picolinate (Cr(pic)3), contains trivalent chromium which is chelated to three picolinic acid molecules to increase its bioavailability compared to non-chelated forms (e.g., chromium chloride). It is widely used because of claims that it exerts antidiabetic and weight-reduction effects.[10–12] Improvement in glycemic status, in turn, should reduce oxidative stress and the proinflammatory conditions associated with obesity/type 2 diabetes thereby ameliorating target organ complications such as nephropathy. On the other hand, other studies have raised concerns regarding the safety of Cr(pic)3 as they indicate that the formulation increases the risk for DNA damage.[13–16] If indeed the formulation exerts adverse effects in vivo, its potential toxicity would be expected to be more prominent for the kidney which serves not only as its major route of elimination but also accumulates chromium.[17–19] Thus, long-term effects of the formulation need to be established utilizing animal models of the disease for which its use is advocated. Therefore, we tested the hypothesis that, despite improvement in glycemic status, chronic treatment of OZR with Cr(pic)3 causes significant renal accumulation of chromium with adverse consequences for kidney function and structure. Accordingly, renal effects of the chromium formulation were determined in the context of indices of oxidative stress (e.g., tissue nitrotyrosine), inflammation (e.g., urinary excretion of monocyte chemoattractant protein-1 (MCP-1), renal expression of cyclooxygenase-2 and tissue CD68 positive histiocytes) and oxidative DNA damage (e.g., urinary excretion and tissue 8-hydroxydeoxyguanosine (8-OHdG)).

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