Research articleEffects of biotin supplementation in the diet on insulin secretion, islet gene expression, glucose homeostasis and beta-cell proportion☆
Introduction
Increasingly, vitamins are being recognized as mediators of gene expression [1], [2], illuminating the connection between nutritional signals and biological functions. Vitamin research has identified important transcription factors [3] and has led to the development of new therapeutic agents for different diseases [4], [5], [6] including diabetes [7], [8]. Although less is known about water-soluble vitamins as genetic modulators, evidence of their effects on gene expression is increasing.
Biotin is a water-soluble vitamin that acts as a covalently bound coenzyme of carboxylases. Unrelated to this role, pharmacological concentrations of biotin modify gene expression (reviewed in Ref. [9]) and have a wide repertoire of effects on systemic processes (reviewed in Ref. [10]). DNA microarray studies and high-throughput immunoblotting studies have aided in the identification of thousands of genes whose expression is modified by biotin at both the transcriptional and the posttranscriptional levels [11], [12]. Critical genes for glucose homeostasis, such as hepatic glucokinase [13] and insulin receptor [14], increase their expression in response to biotin supplementation, while the expression of several gluconeogenic genes in diabetic rats is decreased by pharmacological concentrations of biotin [15], [16].
Studies in vitro by others [17], [18] and our group [19], [20] have consistently found that acute exposure to pharmacological doses of biotin enhances glucose-stimulated insulin secretion. Treatment of cultured islets with 1 to 10 μmol/l biotin for 30 min to 24 h increase insulin secretion both at basal (5.5 mmol/l) and stimulatory (16 mmol/l) glucose concentrations [17], [19], [20]. The impact of biotin on insulin secretion is dose dependent [18] and unique among the B vitamins [17].
Pharmacological concentrations of biotin in vitro increase the expression of genes that are critical for maintaining the differentiated phenotype of the beta cell, preserving beta-cell mass (proportion of beta cells) and glucose-stimulated insulin secretion [19], [20], [21], [22]. Culturing isolated rat islets with biotin increases the expression of pancreatic and duodenal homeobox 1 (Pdx-1) [22], a critical transcription factor for the expression of insulin and for several genes involved in insulin synthesis and secretion (reviewed in Ref. [23]). Studies by others using the RIN1046-38 insulinoma cell line [21] and by our group using isolated islets from rats [19], [20] have found that pharmacological concentrations of biotin augment the expression of beta-cell glucokinase, the rate-limiting enzyme in glucose-stimulated insulin secretion [24] and a determinant factor in beta-cell regeneration [25]. We have also found that the mechanism by which biotin increases the expression of Glucokinase involves enhancing insulin secretion through the cyclic guanylate monophosphate (cGMP)/protein kinase G (PKG) signaling pathway, which increases ATP levels and, thus, beta-cell membrane depolarization. Insulin secretion, in turn, increases beta-cell Glucokinase messenger RNA (mRNA) expression via autocrine stimulation of Phospho-inositol-3-kinase (PI3K)/Akt signaling [19].
In line with these effects of biotin on glucose metabolism and insulin secretion, pharmacological doses of biotin lowered hyperglycemia and ameliorated diabetes in some [26], [27], [28] but not all [29] studies done in humans. In a group of patients with type 1 diabetes, supplementation with 16 mg/day of biotin with removal of insulin treatment for 1 week considerably decreased hyperglycemia [26]. In Japanese patients with type 2 diabetes [27] and in patients undergoing hemodialysis [28], pharmacological doses of biotin improved glucose tolerance.
Biotin supplementation also ameliorated hyperglycemia in animal models of diabetes. In KK mice, a genetically diabetic model of moderate hyperglycemia and insulin resistance, biotin administration for 10 weeks lowered postprandial glucose levels and improved both glucose tolerance and insulin sensitivity [30]. In spontaneously type-2 diabetic Otsuka Long-Evams Fatty (OLETF) rats, dietary biotin supplementation also improved glucose tolerance [31].
The evidence that biotin has favorable effects on glucose metabolism has led to the development of commercially available diabetes medications [8], [32], containing pharmacological amounts of biotin 40- to 166-fold increase compared with the reference dietary intake of 30 μg/day [33]. However, in spite of the importance of the pancreatic islet in maintaining normal glucose homeostasis, no studies have addressed the effect of in vivo biotin supplementation on the pancreatic beta cell. Since beta-cell compensation is critical to prevent diabetes development [34], in the present study, we investigated the effects of biotin supplementation on beta-cell function, gene expression and beta-cell proportion.
Section snippets
Animal model and experimental design
Three-week old male BALB/cAnN Hsd mice from the animal facility at the Biomedical Research Institute of the National Autonomous University of Mexico were maintained in barrier conditions under 12-h light/dark cycles, and allowed free access to water and food throughout the experiments, except during fasting. The mice were handled according to the principles of laboratory animal care (National Institutes of Health publication no. 85-23, revised 1985, //grants1.nih.gov/grants/olaw/references/phspol.htm
Effects of biotin supplementation on body weight, food intake and biotin levels
Over 8 weeks of biotin supplementation, the average food intake was 0.12±0.015 and 0.12±0.003 g of food (g of body weight)− 1 day− 1 in the control and supplemented groups, respectively. Thus, during this period, the daily ingestion of biotin was 0.84±0.1 and 48.16±1.1 μmol of biotin (kg body weight)− 1 day− 1 in the control and supplemented groups, respectively. Serum biotin in biotin-supplemented mice was significantly increased compared with control mice (590.6±6.5 nmol/l for biotin supplemented
Discussion
Robust beta-cell function and mass are essential for preventing the development of diabetes [34]. Strategies toward enhancing these attributes will aid in the fight against this disease. Several studies in vitro have shown that pharmacological concentrations of biotin increase insulin secretion [17], [18], [19], [20] and the expression of Glucokinase [19], [20] and Pdx1 [22], proteins that favor function and preservation of beta cells [23], [24], [25]. In the current study, we examined whether
Acknowledgments
The authors are grateful to German's Lab staff, Alberto Rojas-Ochoa, Lilian Esparza-Rosales and Maura Flores-Aguilar for technical assistance; Drs Gerold Grodsky and Martha Pérez-Armendariz for valuable discussions throughout these studies; and Silvestre Frenk for critical reading of the manuscript.
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2021, Toxicology and Applied PharmacologyCitation Excerpt :Toxicology tests, such as whole life-cycle and multi-generation tests that would detect changes in reproductive outcomes and reproductive organ pathology have not yet been evaluated. Our present studies showing the effects of biotin supplementation on cell cycle molecules, in the same experimental model in which we observed favorable effects on glucose and lipid homeostasis (Aguilera-Méndez and Fernández-Mejía, 2012; Larrieta et al., 2010; Lazo de la Vega-Monroy et al., 2013), and no changes on toxicity markers (Riverón-Negrete et al., 2016) raises concern regarding the effects of pharmacological concentrations of biotin on male health, since several studies have found that the majority of male germ cell tumors overexpress cell cycle activators, such as Cyclin A2, and Cdk2 (Liao et al., 2004), whose transcripts were found to be increased by biotin supplementation in the present study. Furthermore, these results, along with our recent finding (Pastén-Hidalgo et al., 2020) that biotin-supplementation impairs testis morphology and has negative effects on spermatozoa structure and motility, strongly caution against the use of supplements with high concentrations of biotin, which are commercially available without regulation and whose cosmetic uses have escalated considerably in recent years (John and Lipner, 2019), despite the lack of sufficient clinical evidence supporting its efficacy (Soleymani et al., 2017).
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Grants and fellowships: Maria-Luisa Lazo de la Vega-Monroy is a Ph.D. student from the Doctorado en Ciencias Biomédicas at Universidad Nacional Autónoma de México and has a scholarship from Consejo Nacional de Ciencia y Tecnología (CVU/scholar no.: 217876/207055). Elena Larrieta was a postdoctoral fellow from the Dirección General de Asuntos del Personal Académico, Universidad Nacional Autónoma de México and from consejo Nacional de Ciencia y Tecnología 44266M. This work was supported by funds from Consejo Nacional de Ciencia y Tecnología (44266M), Dirección General de Asuntos del Personal Académico (IN220908 and 29 214811) and UC-MEXUS (CNO7-87 and EBC/433/CFM).
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Present address: Unidad de Biología Molecular y Medicina Genómica, INCMSZ, Mexico City, México.