Biotin and chromium histidinate improve glucose metabolism and proteins expression levels of IRS-1, PPAR-γ, and NF-κB in exercise-trained rats

To the best of our knowledge, this is the first study to evaluate the effects of dietary chromium histidinate (CrHis) and biotin supplementation on liver transaminases, serum glucose and lipid levels, and proteins expression levels of IRS-1, PPAR-γ, and NF-κB in liver and muscle of exercised rats. We observed that CrHis/biotin supplementation significantly decrease glucose, cholesterol, triglyceride, and NF-κB levels, but increase serum HDL cholesterol, IRS-1 and PPAR-γ expression in the liver and muscle of exercise-trained rats. Interestingly, the beneficial effects of CrHis and biotin on all metabolic parameters were more pronounced when they were administered together.

Exercise is considered a very important tool in the prevention and treatment of various diseases [3, 4, 42]. Numerous studies show that exercise decreases blood glucose level, improves insulin sensitivity, increases the rate of fat oxidation and ameliorates postprandial triglyceride response [1, 43, 44]. However, in the current study, exercised animals exhibited a significant decrease in glucose, total cholesterol and triglyceride levels, but an increase in HDL cholesterol compared to the sedentary control group. Leon et al. [16] have shown that a 12-week exercise decreased cholesterol and TG concentrations and increased HDL cholesterol levels in rats. In another similar work, Leon and Sanchez [45] reported that exercise-induced a decrease in LDL and TG levels, but had no effect on blood total cholesterol concentration. The beneficial effect of exercise on the risk of metabolic diseases may be due to the improvement in glucose and insulin sensitivities, inflammatory markers and blood lipids level [46, 47]. Exercise combined with micronutrient supplementation such as CrHis and biotin are efficient in preventing or treating various metabolic diseases [48, 49]. Chromium (Cr) is an essential trace element particularly involved in carbohydrate, fat, and protein metabolism [27, 50]. Previous works have shown that chromium picolinate (CrPic) supplementation modulated insulin, glucose and lipid metabolism in type 2 diabetic rats [31]. Moreover, Grant et al. [51] reported that exercise training combined with Cr supplementation is more beneficial than exercise training alone in improving various metabolic parameters. Biotin, a water-soluble vitamin, is an integral component of carboxylation reactions involved in glucose and insulin metabolism. Fernandez-Mejia [32] and Osada et al. [52] have reported that biotin deficiency induced fatigue in mice. In addition, Cr and biotin supplementation have been shown to modulate various metabolic pathways such as insulin signalling pathway in patients who are deficient [31, 32]. It was reported that CrPic and biotin supplementation improves glycemic control [25, 34, 53] and modulates lipid pathways [33] in people with type 2 diabetes. Also, some clinical studies indicated that a combination of CrPic and biotin was more efficient in modulating glucose and lipid metabolism in diabetic patients [25, 53, 54]. Similarly, we reported in our previous studies that the combination of CrPic and biotin was efficient in lowering the blood glucose level in heat-stressed quail [5557]. In the present study, we found that CrHis and biotin supplementation led to a significant decrease in glucose and triglyceride levels, but an increase in HDL cholesterol compared with the exercise group. The lowest concentrations of triglycerides and glucose, as well as the highest level of HDL cholesterol, were found in exercise-trained rats treated with both CrHis and biotin. In parallel, previous studies reported that the combination of Cr and biotin is more efficient in modulating insulin, glucose and lipid metabolism in type 2 diabetes patients [25, 53, 54]. Because transaminases levels in the liver are considered a key factor when evaluating the cytotoxicity of a drug, the non- significant change in AST and ALT levels in all groups indicates no harmful effects on hepatocyte cells.

Peroxisome proliferator-activated receptor gamma (PPAR-γ), insulin receptor substrate-1 (IRS-1) and nuclear transcription factor kappa B (NF-κB) are important biomarkers involved in numerous metabolic processes. PPAR-γ plays a key role in regulating lipid, carbohydrate, glucose and insulin metabolisms [58]. It has been shown that exercise induced an increase in PPAR-γ expression in liver [59, 60] and skeletal muscle tissues [61]. In the current study, PPAR-γ expression levels in the liver and muscle tissues were significantly elevated compared to the control group. Remarkably, CrHis and biotin supplementation significantly increased PPAR-γ expression levels in sedentary and exercised rats. The efficacy of CrHis and biotin was more pronounced when used simultaneously, thus indicating a synergetic effect. Our previous findings demonstrated that CrPic and biotin, as well as their combination, increased PPAR-γ expression in adipose tissue and improved insulin resistance in type 2 diabetes rats [62].

Insulin receptor substrate-1 (IRS-1) is involved in metabolic and mitogenic effects of insulin [63, 64]. Numerous studies have reported that exercise increased IRS-1 expression in human skeletal muscle [22, 65]. Similarly, we observed in the present study that exercise rats exhibited an increase in IRS-1 expression in the muscle and liver tissues compared to the sedentary control group. Moreover, in sedentary and exercised rats, CrHis and biotin treatment induced a significant increase in IRS-1 expression in the muscle and liver tissues, compared to their respective control groups. These findings may suggest that the beneficial effect of CrHis and biotin on lipid and glucose metabolism was probably associated with the improvement of insulin signal transduction in target tissues. These results corroborate previous works published by Jain et al. [66] who reported that IRS-1 expression in the liver tissues of type 2 diabetic rats increased after treatment with chromium dinicocysteinate. In other similar studies, CrPic supplementation improved glucose disposal rates and significant increased IRS-1 expression and phosphatidylinositol-3 kinase activity in skeletal muscles in obese rats [35].

Nuclear transcription factor kappa B (NF-κB) is a transcriptional factor particularly involved in the inflammatory process. In the current study, the decrease in NF-κB expression in untreated exercised rats is similar to the previous study, who reported that treadmill training reduced the overexpression of NF-κB in rat brain tissue [67]. Moreover, CrHis and biotin, as well as their combination, induced a significant decrease in NF-κB level in the muscle and liver tissues, compared with the exercise or control group. However, the capacity of these micronutrients in lowering NF-κB expression was more pronounced when CrHis and biotin were administered together. In parallel with the results of the current study, we recently reported a greater reduction in NF-κB expression in diabetic rats supplemented with CrHis [68]. On the contrary, Kuhad et al. [69] reported that NF-κB subunit was significantly elevated in the kidneys of diabetic rats after treatment with CrPic. Because NF-κB level is an indicator of the inflammatory response [70], decreased NF-κB expression in the muscles of rats supplemented with CrHis and biotin may indicate an anti-inflammatory property.