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Therapeutic Evaluation of the Effect of Biotin on Hyperglycemia in Patients with Non-Insulin Dependent Diabetes Mellitus
Abstract
The therapeutic efficacy of biotin was evaluated in 43 patients with non-insulin dependent diabetes mellitus. The serum biotin concentration in the patients was significantly lower than that in the 64 healthy control subjects and inversely correlated with the fasting blood glucose level. The oral administration of biotin, 9mg daily, corrected the hyperglycemia in the patients with no change in their serum insulin level. The serum levels of pyruvate and lactate decreased to their normal ranges after the administration. These observations suggest that the biotin administration ameliorates abnormal glucose metabolism in diabetic patients, presumably by enhancing the activity of the biotin-dependent enzyme, pyruvate carboxylase, with a subsequent promotion of glucose utilization for the entry into the tricarboxylic acid cycle. The administration also enhanced the response to glibenclamide in patients who had been resistant to the agent, suggesting a significant increase in the potency of the endogenous insulin action. The result demonstrates that biotin administration is effective for the treatment of the patients. Neither a relapse of clinical symptoms nor an occurrence of undesirable side effects has been observed.
... On the other hand, excessive biotin intake may also ameliorate diabetic status. A study conducted in 43 Japanese T2DM patients demonstrated a decrease of approximately 45% of FBG concentration after one month of oral supplementation of 9 mg of biotin per day (15,27). Similar effects were also observed in type 1 diabetic patients whose FBG levels decreased up to 50% after daily administration of 16 mg biotin for one week (28). ...
... All of the trials were placebo controlled parallel RCTs and the intervention period varied from 4 weeks to 3 months, while 284 patients were in the experiment group and 161 were in the placebo group. One trial (27) did not report the gender of participants, while the male and female participants . ...
... The results of the quality assessment for the included studies are presented in Figure 2. Three trials had a rigorous experimental design and were considered to be at low risk. Two trials (27,39) were considered to be at a moderate risk due to either unclear or lack of reporting on various potential biases. ...
Background
Biotin is a water-soluble vitamin acting as a covalently bound coenzyme in regulating energy production. Previous studies have reported that biotin supplementation may influence blood glucose and lipid level in patients with type 2 diabetes mellitus (T2DM).Methods
We searched Pubmed, Embase, and Cochrane library databases up to 8th August 2022 for studies examining the effects of biotin supplementation in T2DM patients. Pooled effects were measured by weighted mean differences (WMDs) with 95% confidence intervals (CI) using random effects models. Inter-study heterogeneity was assessed and quantified.ResultsA total of five random controlled trials (RCT), involving 445 participants were included. It was suggested that biotin supplementation for 28 to 90 days significantly decreased the level of fasting blood glucose (FBG) (MD: −1.21 mmol/L, 95% CI: −2.73 to 0.31), total cholesterol (TC) (MD: −0.22 mmol/L, 95% CI: −0.25 to −0.19) and triglycerides (TG) (MD: −0.59 mmol/L, 95% CI: −1.21 to 0.03). No significant beneficial effects were observed on insulin (MD: 1.88 pmol/L 95% CI: −13.44 to 17.21). Evidence for the impact of biotin supplementation on the levels of glycated hemoglobin (HbA1c), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C) and very low-density lipoprotein cholesterol (VLDL-C) was limited to draw conclusion.Conclusions
Biotin supplementation may decrease FBG, TC and TG levels. However, its influence on insulin is not significant and further studies on the effects of biotin on HbA1c, LDL-C, HDL-C and VLDL-C are expected.
... The findings that biotin has stimulatory effects on the transcription of genes whose action favors glycemia reduction and decreases the transcription of gluconeogenic genes support other observations that indicate that pharmacological doses of biotin decrease hyperglycemia [26][27][28][29][30]. In genetically diabetic KK mice and in OLETF rats, biotin treatment lowered postprandial glucose concentration and improved tolerance to glucose [26,27]. ...
... In genetically diabetic KK mice and in OLETF rats, biotin treatment lowered postprandial glucose concentration and improved tolerance to glucose [26,27]. Hyperglycemia reduction was also observed in both type 1 and type 2 diabetics treated with biotin [28,29]. In hemodialysis patients, pharmacological doses of biotin improved their oral glucose tolerance tests [30]. ...
... Several studies have demonstrated that biotin deficiency affects glucose metabolism [18,19,22,24,25], indicating that biotin dietary intake is required to maintain glucose homeostasis. On the other hand, pharmacological doses of biotin (milligrams) favor glucose homeostasis [26][27][28][29][30] and are currently used in the treatment of diabetes [31,32]. Pharmacologic supplementation of biotin of 40× the RDI (i.e., 1.2 mg/day) for 14 days reaches serum concentrations in a range of 9.4-47.7 nmol/L [60]. ...
... Biotin status has also been found to be altered in diabetic patients. Maebashi et al (4) found that serum biotin concentrations in type 2 diabetic patients were significantly lower than those in control subjects. An inverse correlation between serum biotin and fasting blood glucose concentrations has also been observed (4,5). ...
... Maebashi et al (4) found that serum biotin concentrations in type 2 diabetic patients were significantly lower than those in control subjects. An inverse correlation between serum biotin and fasting blood glucose concentrations has also been observed (4,5). Furthermore, biotin deficiency has been linked to impaired oral-glucose-tolerance tests and decreased utilization of glucose in rats (6,7). ...
... In addition, the diabetic state appears to be ameliorated by biotin treatment. Hyperglycemia reduction was observed in both type 1 and type 2 diabetic subjects treated with biotin (4,5). In hemodialysis patients, pharmacologic doses of biotin improve their oral-glucose-tolerance tests (8). ...
... In reference to the latter, the vitamin has been shown to increases the expression of pancre-atic and duodenal homeobox 1 (Pdx-1) (44), a critical transcription factor for the expression of insulin, and several genes involved in its synthesis and secretion by pancreatic beta cells (2). In pancreatic beta cells, biotin appears to increase the expression of insulin receptor (7) and glucokinase (3,30,39), a rate-limiting enzyme in glucose-stimulated insulin secretion (20). It also decreases the expression of several gluconeogenic genes (6,36). ...
... It also decreases the expression of several gluconeogenic genes (6,36). Finally, biotin supplementation appears to have the ability to reduce hyperglycemia and improve glucose tolerance in humans (5,15,20), as well as in animal models of diabetes (26,46). ...
... The pancreas was isolated, minced, and digested with collagenase IV (1 mg/ml) containing DNase I (0.1 mg/ml) for 30 min with occasional shaking at 37°C. After digestion, pancreatic tissues were filtered through nylon mesh and the filtrate was subjected to discontinuous Ficoll gradient (25,23,20, and 11%, respectively) for isolation of islets. Islets were collected from the interface of 20 and 11% of Ficoll, subsequently washed three times, and used for uptake studies as described before (23). ...
Biotin is essential for the normal function of pancreatic beta cells. These cells obtain biotin from their surroundings via transport across their cell membrane. Little is known about the uptake mechanism involved, how it is regulated, and how it is affected by internal and external factors. We addressed these issues using the mouse-derived pancreatic beta-TC-6 cells and freshly isolated mouse and human primary pancreatic beta cells as models. The results showed biotin uptake by pancreatic beta-TC-6 cells occurs via a Na(+) - dependent, carrier-mediated process, that is sensitive to desthiobiotin, as well as to pantothenic acid, and lipoate; the process is also saturable as a function of concentration (apparent Km = 22.24 ± 5.5 µM). These cells express the sodium-dependent multivitamin transporter (SMVT), whose knockdown (with doxycycline - inducible shRNA) led to a sever inhibition in biotin uptake. Similarly, uptake of biotin by mouse and human primary pancreatic islets is Na(+)-dependent and carrier-mediated, and both cell types express SMVT. Biotin uptake by pancreatic beta-TC-6 cells is also adaptively regulated (via transcriptional mechanism) by extracellular substrate level. Chronic treatment of pancreatic beta-TC-6 cells with bacterial lipopolysaccharides (LPS) leads to inhibition in biotin uptake. This inhibition is mediated via a Toll-Like receptor 4 -mediated process, and involves a decrease in membrane expression of SMVT. These findings show, for the first time, that pancreatic beta cells/islets take up biotin via a specific and regulated carrier-mediated process, and that the process is sensitive to the effect of LPS.
... Pharmacological doses of biotin have hypolipidemic [4][5][6][7][8] and hypoglycemic effects [7,[9][10][11][12] and reduce diabetes complications [11][12][13] in both animal models and humans. These effects are associated with changes in gene and protein expression [12,[14][15][16][17][18] in key metabolic organs, such as the liver and the pancreatic islets. ...
... In humans, no adverse effects were found with administration of 0.25 to 100 mg biotin. A lack of adverse effects has been reported in patients with inborn errors of biotin metabolism [46], normal individuals [24], diabetic patients [10,13], and patients undergoing hemodialysis [11]. Rats fed diets containing up to 1,000 mg/kg diet did not show liver damage [21]. ...
Pharmacological concentrations of biotin have pleiotropic effects. Several reports have documented that biotin supplementation decreases hyperglycemia. We have shown that a biotin-supplemented diet increased insulin secretion and the mRNA abundance of proteins regulating insulin transcription and secretion. We also found enlarged pancreatic islets and modified islet morphology. Other studies have shown that pharmacological concentrations of biotin modify tissue structure. Although biotin administration is considered safe, little attention has been given to its effect on tissue structure. In this study, we investigated the effect of biotin supplementation on hepatic morphology and liver toxicity markers. Male BALB/cAnN Hsd mice were fed a control or a biotin-supplemented diet for 8 weeks. Versus the control mice, biotin-supplemented mice had an altered portal triad with dilated sinusoids, increased vascularity, and bile conducts. Furthermore, we observed an increased proportion of nucleomegaly and binucleated hepatocytes. In spite of the liver morphological changes, no differences were observed in the serum liver damage indicators, oxidative stress markers, or antioxidant enzymes. Our data demonstrate for the first time that biotin supplementation affects liver morphology in normal mice, and that these modifications are not paralleled with damage markers.
... Biotin (vitamin B 7 ) serves as a cofactor for carboxylase enzymes in fatty acid synthetic pathways, the citric acid cycle, and amino acid metabolism (Fernandez-Mejia, 2005). Type 2 diabetics have demonstrated lower circulating levels of biotin compared to healthy controls and an inverse relationship between biotin levels and fasting plasma glucose (Coggeshall, Heggers, Robson, & Baker, 1985;Maebashi et al., 1993). ...
... Diabetic patients treated for 28 days with 15 mg of biotin supplements had improvements in fasting glucose and insulin levels (Fernandez-Mejia, 2005; Fernandez-Mejia, Zendejas-Ruiz, Revilla-Monsalve, & Islas-Andrede, 2003). One study showed that patients with type 2 diabetes have reduced serum concentrations of biotin and that a 30-day supplementation improved fasting glucose (Maebashi et al., 1993). The clinical utility of B-group vitamins like nicotinamide and biotin still needs to be established as they may play an important role in glycemic control for type 2 diabetics. ...
Cited By (since 1996):1, Export Date: 18 October 2014
... Biotin (vitamin B 7 ) serves as a cofactor for carboxylase enzymes in fatty acid synthetic pathways, the citric acid cycle, and amino acid metabolism (Fernandez-Mejia, 2005). Type 2 diabetics have demonstrated lower circulating levels of biotin compared to healthy controls and an inverse relationship between biotin levels and fasting plasma glucose (Coggeshall, Heggers, Robson, & Baker, 1985;Maebashi et al., 1993). ...
... Diabetic patients treated for 28 days with 15 mg of biotin supplements had improvements in fasting glucose and insulin levels (Fernandez-Mejia, 2005; Fernandez-Mejia, Zendejas-Ruiz, Revilla-Monsalve, & Islas-Andrede, 2003). One study showed that patients with type 2 diabetes have reduced serum concentrations of biotin and that a 30-day supplementation improved fasting glucose (Maebashi et al., 1993). The clinical utility of B-group vitamins like nicotinamide and biotin still needs to be established as they may play an important role in glycemic control for type 2 diabetics. ...
With global aging population, age-related cognitive decline becomes epidemic. Lifestyle-related factor is one of the key preventative measures. Dietary pattern analysis which considers dietary complexity has recently used to examine the linkage between nutrition and cognitive function. A priori approach defines dietary pattern based on existing knowledge. Results of several dietary pattern scores were summarized. The heterogeneity of assessment methods and outcome measurements lead to inconsistent results. Posteriori approach derives a dietary pattern independently of the existing nutrition-disease knowledge. It showed a dietary pattern abundant with plant-based food, oily fish, lower consumption of processed food, saturated fat, and simple sugar which appears to be beneficial to cognitive health. Despite inconclusive evidence from both approaches, diet and exercise, beneficial for other diseases, remains to be the two key modifiable factors for cognitive function. Large-scale prospective studies in multiethics population are required to provide stronger evidence in the future.
... Biotin levels were found to be lower in individuals with type 2 diabetes and administration of biotin was shown to lower blood glucose level in these individuals without altering the insulin levels [24]. A recent systematic review and meta-analysis on biotin showed that biotin can reduce fasting blood glucose, total cholesterol and triglyceride levels in individuals with type 2 diabetes mellitus [25]. ...
Aim:
The incidence of gestational diabetes mellitus is increasing worldwide. Biotin is shown to improve glycemic status in diabetes mellitus. We wanted to study whether there is a difference in biotin levels between mothers with and without gestational diabetes mellitus (GDM), association of biotin with blood glucose, and with the outcome of GDM.
Methods:
We recruited 27 pregnant mothers with GDM and 27 pregnant mothers without GDM. We measured the biotin levels using enzyme linked immunosorbent assay (ELISA). We measured the blood glucose during OGTT and fasting insulin levels in the study participants.
Results:
We found that biotin levels were slightly decreased in mothers with GDM [271 (250,335)] as compared to control mothers [309 (261,419)], though it was not statistically significant (p = 0.14). Blood glucose levels were found to be significantly higher in GDM mothers as compared to control mothers during fasting, 1 h and 2 h plasma sample obtained during OGTT. Biotin was not significantly associated with blood glucose in pregnant mothers. Logistic regression analysis showed that biotin (OR = 0.99, 95 % CI = 0.99-1.00) has no association with the outcome of GDM.
Conclusion:
Ours is the first study to compare the biotin levels in GDM mothers and control mothers. We found that the biotin levels were not significantly altered in GDM mothers as compared to control mothers and biotin levels have no association with the outcome of GDM.
... These might stand for the discrepancies in these results. Despite the confirmation of biotin deficiency in T2D [73] and the beneficial effects of biotin supplementation on glucose metabolism [74][75][76], further research concerning the role of gut bacteria in biotin metabolism and its association with metabolic disorders and obesity is necessary to search for markers of these disorders and therapeutic possibilities. Also, purine metabolism was found to be positively associated with visceral fat. ...
Abstract Background Microbiota and its metabolites are known to regulate host metabolism. In cross-sectional study conducted in postmenopausal women we aimed to assess whether the microbiota, its metabolites and gut barrier integrity marker are correlated with cardiometabolic risk factors and if microbiota is different between obese and non-obese subjects. Methods We analysed the faecal microbiota of 56 obese, postmenopausal women by means of 16S rRNA analysis. Stool short chain fatty acids, calprotectin and anthropometric, physiological and biochemical parameters were correlates to microbiome analyses. Results Alpha-diversity was inversely correlated with lipopolysaccharide (Rho = − 0.43, FDR P (Q) = 0.004). Bray–Curtis distance based RDA revealed that visceral fat and waist circumference had a significant impact on metabolic potential (P = 0.003). Plasma glucose was positively correlated with the Coriobacteriaceae (Rho = 0.48, Q = 0.004) and its higher taxonomic ranks, up to phylum (Actinobacteria, Rho = 0.46, Q = 0.004). At the metabolic level, the strongest correlation was observed for the visceral fat (Q
... In light of this, biotin deficiency correlates to impaired oral glucose tolerance tests and decreased utilization of glucose in rats 123,125 . Clinical studies revealed that diabetic patients exhibited lower serum levels of biotin than controls with an inverse correlation between serum biotin and fasting blood glucose concentration 126,127 . Concomitantly, pharmacological doses of biotin improved diabetic state and they also decreased plasma lipid concentrations, influencing lipid metabolism. ...
Objective:
The occurrence of side effects related to the use of combined oral contraceptives (COCs) - or even the fear of them - often affects patients' compliance and their quality of life. Such adverse effects include both physical and psychological alterations. Therapies based on COCs are related to lower levels of vitamins and minerals, including vitamins B, C and E, zinc, magnesium, and selenium. This review gathers scientific evidence about the effectiveness of the administration of specific micronutrients to address nutritional needs and recover adverse conditions.
Materials and methods:
We reviewed literature searching through different databases (MEDLINE, Scopus, Google Scholar). We used different keywords, including micronutrients, COCs, side effects, B vitamins, vitamin C, vitamin E, vitamin D, zinc, magnesium, selenium and Centella Asiatica. We narrowed the search down to English literature, including both preclinical and clinical studies. The outcome of database search was to highlight beneficial effects of specific micronutrients on the evaluated side reactions.
Results:
Based on the collected evidence, dietary supplementations of specific micronutrients, whose depletion occurs during COC treatments, have significant beneficial effects. By acting on different aspects and pathways, such supplementation prevents and counteracts discomforts and side effects related to COC treatments.
Conclusions:
Considering the wide use of OCs, taking appropriate dietary supplements could be an effective approach in clinical practice, tailoring therapies and improving both safety and tolerability.
... Biotin, a nutraceutical agent, has been demonstrated through animal and clinical studies to have the capability of assisting in glycemic control in diabetic individuals if taken at a high dose of 9-15 mg per day (Zhang et al., 1996;Zhang et al., 1997;Maebashi et al., 1993). Various animal studies and few clinical studies established the effect of supplementary magnesium on the preservation of adipocyte insulin sensitivity (McCarty, 2005). ...
Background and Objective: Diabetes is an insidious as well as a debilitating metabolic disease with variety of causes that could lead to severe complications in multiple organs within the body system. There has been no documented scientific evidence as regards total cure of this complex chronic disease; therefore, it demands a lifelong management. This has necessitated the recent evaluation of several plant derived foods as costeffective alternatives in the management of diabetes and its associated complication. Materials and Methods: This review is based on integration of information from multi-databases after a comprehensive literature search on the various plant derived foods that have been reported to have shown a certain degree of amelioration in the management of diabetes and diabetic complications. Result and Discussion: Published reports suggest that oxidative stress primarily mediated by uncontrolled hyperglycemia play a pivotal role in the pathogenesis of diabetes and its associated complications. Therefore, various plant-derived foods are believed to delay, prevent or manage diabetes and its associated complications using different mechanisms which could be established through their potential to increase insulin sensitivity, free radicals scavenging abilities, hypolipidemic, hypoglycaemic, hypocholesterolemic, antioxidative, anti-inflammatory and inhibition of α-amylase and α-glucosidase activities. Conclusion: Based on the evidence presented in this review, plant-derived foods possess bioactive constituents believed to be rich in antioxidants and proteins which may be responsible for their mode of actions; we propose that Cucuma longa (curcumin), Garcinia kola (kolaviron), Telfairia occidentalis and Parkia biglobosa be explored in the management of diabetes and its associated complications due to their outstanding beneficial effects.
... These two significant pathways are biotin metabolism (map 00780) and vascular smooth muscle contraction (map 04270) (Xie et al., 2006;Hashimoto et al., 2020). For biotin metabolism, several studies have shown that plasma triacylglycerol, low-density lipoprotein cholesterol (LDL), and fasting glucose are reduced in patients with T2D who take biotin supplementation (Maebashi et al., 1993;Revilla-Monsalve et al., 2006). Furthermore, biotin intake has been reported to be effective in improving glycaemic control through diabetic animal models (Reddi et al., 1988;Zhang et al., 1997). ...
Integrative multi-omics analysis has become a useful tool to understand molecular mechanisms and drug discovery for treatment. Especially, the couplings of genetics to metabolomics have been performed to identify the associations between SNP and metabolite. However, while the importance of integrative pathway analysis is increasing, there are few approaches to utilize pathway information to analyze phenotypes using SNP and metabolite. We propose an integrative pathway analysis of SNP and metabolite data using a hierarchical structural component model considering the structural relationships of SNPs, metabolites, pathways, and phenotypes. The proposed method utilizes genome-wide association studies on metabolites and constructs the genetic risk scores for metabolites referred to as genetic metabolomic scores. It is based on the hierarchical model using the genetic metabolomic scores and pathways. Furthermore, this method adopts a ridge penalty to consider the correlations between genetic metabolomic scores and between pathways. We apply our method to the SNP and metabolite data from the Korean population to identify pathways associated with type 2 diabetes (T2D). Through this application, we identified well-known pathways associated with T2D, demonstrating that this method adds biological insights into disease-related pathways using genetic predispositions of metabolites.
... 19 Another B vitamin, vitamin B7 (biotin), has been shown to be decreased in subjects with moderate obesity 21 and type 2 diabetes. 22 Yet this vitamin has been neglected in the con- In addition to those metabolic observations regarding vitamin D, many studies also reported strong links of this vitamin with adipose tissue in terms of vitamin D storage but also modulation of adipocyte differentiation or even energy metabolism and inflammation by this vitamin. ...
There are numerous factors involved in obesity progression and maintenance including systemic low‐grade inflammation, adipose tissue dysfunction, or gut microbiota dysbiosis. Recently, a growing interest has arisen for vitamins' role in obesity and related disorders, both at the host and gut bacterial level. Indeed, vitamins are provided mostly by food, but some, from the B and K groups in particular, can be synthesized by the gut bacterial ecosystem and absorbed in the colon. Knowing that vitamin deficiency can alter many important cellular functions and lead to serious health issues, it is important to carefully monitor the vitamin status of patients with obesity and potentially already existing comorbidities as well as to examine the dysbiotic gut microbiota and thus potentially altered bacterial metabolism of vitamins. In this review, we examined both murine and human studies, to assess the prevalence of sub‐optimal levels of several vitamins in obesity and metabolic alterations. This review also examines the relationship between vitamins and the gut microbiota in terms of vitamin production and the modulation of the gut bacterial ecosystem in conditions of vitamin shortage or supplementation. Furthermore, some strategies to improve vitamin status of patients with severe obesity are proposed within this review.
... After the meal, even the glycemic action type of a body can be affected by its gut microbiota composition (Zeevi et al., 2015;Mendes-Soares et al., 2019). Some studies show that biotin deficiency may be associated with T2D (Maebashi et al., 1993;Wu et al., 2020) and biotin supplementation may help glucose regulation (Fernandez-Mejia, 2005;Albarracin et al., 2008;Lazo de la Vega-Monroy et al., 2013). ...
Human gut microbiota is a complex community of organisms including trillions of bacteria. While these microorganisms are considered as essential regulators of our immune system, some of them can cause several diseases. In recent years, next-generation sequencing technologies accelerated the discovery of human gut microbiota. In this respect, the use of machine learning techniques became popular to analyze disease-associated metagenomics datasets. Type 2 diabetes (T2D) is a chronic disease and affects millions of people around the world. Since the early diagnosis in T2D is important for effective treatment, there is an utmost need to develop a classification technique that can accelerate T2D diagnosis. In this study, using T2D-associated metagenomics data, we aim to develop a classification model to facilitate T2D diagnosis and to discover T2D-associated biomarkers. The sequencing data of T2D patients and healthy individuals were taken from a metagenome-wide association study and categorized into disease states. The sequencing reads were assigned to taxa, and the identified species are used to train and test our model. To deal with the high dimensionality of features, we applied robust feature selection algorithms such as Conditional Mutual Information Maximization, Maximum Relevance and Minimum Redundancy, Correlation Based Feature Selection, and select K best approach. To test the performance of the classification based on the features that are selected by different methods, we used random forest classifier with 100-fold Monte Carlo cross-validation. In our experiments, we observed that 15 commonly selected features have a considerable effect in terms of minimizing the microbiota used for the diagnosis of T2D and thus reducing the time and cost. When we perform biological validation of these identified species, we found that some of them are known as related to T2D development mechanisms and we identified additional species as potential biomarkers. Additionally, we attempted to find the subgroups of T2D patients using k-means clustering. In summary, this study utilizes several supervised and unsupervised machine learning algorithms to increase the diagnostic accuracy of T2D, investigates potential biomarkers of T2D, and finds out which subset of microbiota is more informative than other taxa by applying state-of-the art feature selection methods.
... In humans, biotin is needed for normal development, growth, and health. Studies have shown that it may help treat or prevent specific disorders such as alopecia, biotin-responsive basal ganglia disease, congenital anomalies, multiple sclerosis, onychorrhexis (brittle fingernails), photoaging, and Type 2 diabetes (Alfadhel et al., 2013;Chessa et al., 2019;Famenini and Goh, 2014;Komorowski et al., 2019a,b;Maebashi et al., 1993;Mock, 2009;Sedel et al., 2015Sedel et al., , 2016. Furthermore, a number of genetic disorders associated with secondary biotin deficiency including biotinidase deficiency, holocarboxylase synthetase deficiency, and biotin transport deficiency are treated with supplemental biotin (Wolf, 2012;Elrefai and Wolf, 2015;Mardach et al., 2002). ...
A novel, highly soluble biotin salt, magnesium biotinate (MgB), was assessed for general and genetic toxicity using several toxicologic tests. This battery of tests included in vitro bacterial reverse mutation test, in vitro mammalian micronucleus assay, and oral acute, 14-day, and 90-day repeat-dose toxicity in Sprague-Dawley (SD) rats. The results of the in vitro studies indicate that MgB is not mutagenic, clastogenic, or aneugenic. The acute oral toxicity study established an LD50 ≥ 5000 mg MgB/kg. In the 14-day oral toxicity study, doses of MgB up to 2500 mg MgB/kg/day produced no clinical signs or mortality. In the 90-day oral toxicity study, administration of 600 mg MgB/kg/day resulted in no clinical signs and was determined to be the no-observed-adverse-effect-level (NOAEL), which equates to 39 g biotin/day for a 70 kg human. Since MgB is composed of 93% biotin, the 600 mg NOAEL equates to approximately 1.3 million times the current recommended daily allowance of 30 μg biotin/day and 3,900 times supplement levels of 10 mg biotin/day. Based on the toxicologic profile and lack of findings in various in vitro and in vivo studies, MgB may be considered safe for long-term human use.
... Biotin supplementation modifies the expression of critical genes that are involved in the regulation of carbohydrate and lipid metabolism [8][9][10][11][12][13][14]. In agreement with these findings, several observations have indicated that biotin supplementation improves glucose and triglyceride homeostasis [15][16][17][18][19], which has led to the development of commercially available medications containing pharmacologically relevant amounts of biotin (2 mg/day) in combination with chromium picolinate [20,21]. ...
Studies have found that biotin favors glucose and lipid metabolism, and medications containing biotin have been developed. Despite the use of biotin as a pharmacological agent, few studies have addressed toxicity aspects including the possible interaction with cytochrome P450 enzyme family. This study analyzed the effects of pharmacological doses of biotin on the expression and activity of the cytochrome P4501A subfamily involved in the metabolism of xenobiotics. Wistar rats were treated daily with biotin (2 mg/kg, i.p.), while the control groups were treated with saline. All of the rats were sacrificed by cervical dislocation after 1, 3, 5, or 7 days of treatment. CYP1A1 and CYP1A2 mRNAs were modified by biotin while enzyme activity and protein concentration were not affected. The lack of an effect of biotin on CYP1A activity was confirmed using other experimental strategies, including (i) cotreatment of the animals with biotin and a known CYP1A inducer; (ii) the addition of biotin to the reaction mixtures for the measurement of CYP1A1 and CYP1A2 activities; and (iii) the use of an S9 mixture that was prepared from control and biotin-treated rats to analyze the activation of benzo[a]pyrene (BaP) into mutagenic metabolites using the Ames test. The results suggest that biotin does not influence the CYP1A-mediated metabolism of xenobiotics.
... [12][13][14][15][16] Additionally, supplementation with high-dose biotin could be beneficial in the treatment of dermatitis, diabetes mellitus, and depression. [17][18][19][20][21][22] In pregnancy, supplementation of up to 300 lg biotin per day might be required, which should not interfere with current immunoassays. 17,22 Biotin is also very popular as a self-medication to reduce hair loss or to improve the condition of skin and nails in supraphysiological doses of up to 30 mg daily, and supplements containing as much as 100 mg of biotin are available overthe-counter. ...
Context.—
Immunoassays using the interaction between streptavidin and biotin are used for clinical chemical analytes on platforms by many different manufacturers. The design can be susceptible to interference from high-dose biotin intake in patients, which remains an often-overlooked confounder despite recently increased awareness.
Objective.—
To evaluate an easily implementable method of in vitro biotin depletion for the removal of biotin interference in immunoassays for potentially time-critical analytes.
Design.—
A biotin stock solution was made and de-identified patient samples were spiked to reach a biotin concentration of 1.126 × 10 ⁶ pg/mL, the maximum reported biotin concentration 1 to 2 hours after a single oral dose of 300 mg biotin. Then, the resulting interference in Elecsys immunoassays for cortisol, cyclosporine A, tacrolimus, digitoxin, thyroid-stimulating hormone, free triiodothyronine, free thyroxine, C-peptide, insulin, N-terminal pro-B–type natriuretic peptide, troponin T high sensitive, human immunodeficiency virus, procalcitonin, β human chorionic gonadotropin, toxoplasma immunoglobulin M, and toxoplasma immunoglobulin G was evaluated before and after biotin depletion using streptavidin particles.
Results.—
All tested immunoassays, with the exception of toxoplasma immunoglobulin M and toxoplasma immunoglobulin G, suffered from significant biotin interference. The depletion protocol removed assay interference due to biotin and produced results that were close or identical to initial prespike measurements.
Conclusions.—
Despite an increase in turnaround times, biotin adsorption is a feasible countermeasure for biotin interference in Elecsys immunoassays. Until test kits with an increased resistance to the interference from high-dose biotin intake are distributed, the evaluated protocol can provide results properly reflecting the patient's clinical condition.
... When administered at doses of 300 mg/day, one clinical trial showed clinical improvement in 13 out of 103 patients with multiple sclerosis, versus none in the placebo control arm [12]. More modest levels of biotin supplementation have been shown to significantly reduce fasting glucose levels in patients with type 2 diabetes mellitus, as well as triglyceride levels in those with and without type 2 diabetes mellitus [13][14][15]. However, some of the results from these data are conflicting. ...
A 67-year-old female with a past medical history of multiple endocrine issues presented for follow-up subsequent to abnormal routine blood testing results. These included low thyroid stimulating hormone (TSH), low parathyroid hormone (PTH), and mildly elevated calcium levels. The presence of hypercalcemia and accompanying low PTH raised the concern for malignancy, while the depressed TSH indicated hyperthyroidism. Review of the patient's medications revealed daily supplementation with 5 mg of vitamin B7 (biotin). The biotin was discontinued after suspecting the supplement was interfering with the patient's lab values. The labs were repeated one month later. The results showed normalized TSH, PTH, and calcium levels. The increasingly wide-spread use of biotin supplementation and the use of biotin as a component in many of the most common clinical assays has led to a trend of lab errors due to biotin interference. While some physicians are aware of the possibility of skewed results, steps need to be taken to prevent misdiagnosis. This includes ensuring that information about this issue is more widely disseminated, accurately accounting for a patient's supplement use, reconciling proper clinical correlation with lab results, and promptly reporting when biotin is determined to be the cause of otherwise unexplained lab errors.
... [120][121][122][123][124][125] Moreover, it has been reported to aid glycaemic control both in animal models of diabetes and in diabetic patients, although favourable impacts on hepatocyte function also contribute in this regard. 126 ...
... 166 While there have been suggestions that biotin supplementation (even with chromium picolinate) may be beneficial in diabetes especially with hypertriglyceridemia, there is no strong indication for recommendation. [167][168][169][170][171] Profound biotinidase deficiency (PBD) is an autosomal recessively inherited disorder that can create optic neuropathy. [172][173] Biotin is obviously critical in the body but it appears to be provided for in the diet in most developed countries. ...
Cross-Talk for Health Care Providers: Part Two/Nutrition and Behavior as it Applies to Systemic and Ocular Disease
... Although data are lacking on the incidence of biotin deficiency in patients with obesity or diabetes, it has been demonstrated that patients with type 2 diabetes have lower biotin levels compared with healthy controls and that these low plasma levels are associated with hyperglycaemia [8,146,147]. ...
Overweight and obesity are highly prevalent throughout the world and can adversely affect the nutritional status of individuals. Studies have shown that many people with obesity have inadequate intake of iron, calcium, magnesium, zinc, copper, folate and vitamins A and B12, likely as a result of poor diet quality. Nutritional inadequacies or deficiencies may also occur due to altered pharmacokinetics in the individual with obesity and due to interactions in those with overweight or obesity with various pharmaceuticals. However, it has been demonstrated that the adult population in the United States as a whole is deficient in certain micronutrients as a result of the availability and overconsumption of high-calorie, low-nutrient processed foods. Poor nutrition may contribute to the development of certain chronic conditions, such as type 2 diabetes, which is already more prevalent in those with obesity. Clinicians need to be aware of these gaps, particularly in those individuals with obesity who are undergoing bariatric surgery or taking pharmaceutical products long term to facilitate weight loss. Patients with overweight or obesity likely struggle to achieve a balanced diet and may benefit from consultation with a dietitian. Along with providing recommendations for healthy eating and exercise, supplementation with specific micronutrients or multivitamins should be considered for individuals at the highest risk for or with established deficiencies. Further research is needed to understand the factors underlying nutritional inadequacies in individuals with overweight or obesity, as well as the outcomes of treatment strategies employed to address them.
... 58,67,[69][70][71] It has also been observed that compared with healthy controls, patients with diabetes have lower plasma concentrations of vitamin C 72 and lower circulating concentrations of biotin, with an inverse correlation between biotin status and fasting plasma glucose. 73,74 Low levels of serum vitamin D have been found to significantly increase cardiometabolic risk (including insulin resistance, metabolic syndrome, and cardiovascular disease risk), 75 and preliminary evidence suggests that vitamin D with or without calcium supplementation may improve glucose metabolism and insulin signaling. [76][77][78][79] Antidiabetic medications can also affect micronutrient status. ...
Objective: Prescription drug use is on the rise, and the use of dietary supplementation remains common. In the United States, more than half of all adults take a dietary supplement in any given month. As a result, drug-nutrient interactions are becoming an important consideration when pharmacists counsel patients about their drug regimens. We reviewed the literature to identify common and/or clinically relevant drug-nutrient interactions that pharmacists may encounter in practice. Data Sources: A MEDLINE search for English-language publications from 1970 through March 2017 was performed using search terms (and variations) related to drugs, medications, micronutrients, and interactions. Study Selection and Data Extraction: Relevant studies, case reports, and reviews describing drug-nutrient interactions were selected for inclusion. Data Synthesis: Some drug-nutrient interactions may result in micronutrient insufficiencies or even frank deficiencies, thereby necessitating augmentation with multivitamin/minerals or individual vitamin/mineral dietary supplements. This most often occurs with long-term therapy for chronic conditions, such as treatment with proton-pump inhibitors and histamine-2 receptor antagonists. In addition, some chronic diseases themselves, such as diabetes, may predispose patients to micronutrient insufficiencies, and dietary supplementation may be advisable. Conclusions: Drug-nutrient interactions can often be resolved through specific dosing strategies to ensure that the full effect of the medication or the dietary supplement is not compromised by the other. In rare cases, the dietary supplement may need to be discontinued or monitored during treatment. Pharmacists are in a key position to identify and discuss these drug-nutrient interactions with patients and the health care team.
... Not much research has been done biotin concentration in the type 2 diabetes patients controls and inversely correlated with the fasting blood glucose level. The oral administration of biotin, 9 mg daily, corrected the hyperglycaemia in patients with no change in their serum insulin level 62 . A study of biotin and chromium picolinate supplementation of type 2 diabetic rats has shown anti-diabetic effects 63 . ...
The present review evaluates the relationship between type 2 diabetes mellitus and vitamins. Oxidative stress has been implicated in the development of type 2 diabetes and its several complications. Antioxidant vitamins A, C and E are found decreased in type 2 diabetes and there is increasing evidence that antioxidants may have role not only in reducing development of diabetes and its complications, but also in improving glycemic control. Several B vitamins e.g. Thiamine, Pyridoxine, Biotin, B12 are also found decreased in type 2 diabetes. Thiamine has beneficial role in diabetic nephropathy while Pyridoxine may have a role in treatment of diabetic retinopathy. Metformin, when used for long term, has been found to cause deficiency of Folate and B12. Vitamin D deficiency is considered a risk factor for the development of type 2 diabetes as well as its complications particularly cardiovascular ones; moreover, vitamin D supplementation has favourable effects on glycaemia. There are no current recommendations of routine supplementation of vitamins above the recommended dietary allowances either to prevent development of type 2 diabetes or to improve outcomes in people with type 2 diabetes unless there is underlying deficiencies. However, patients taking metformin for long time may need folic acid and B12 supplementation.
... High-dose biotin appears to have the potential to rectify this situation to some degree. Presumably as a result of these effects, studies in rodent models of diabetes, as well as some pilot clinical trials in both types of diabetes, report that high-dose biotin can improve glycemic control [220,221,224,[227][228][229]. ...
Oxidative stress, the resulting uncoupling of endothelial nitric oxide synthase (eNOS), and loss of nitric oxide (NO) bioactivity, are key mediators of the vascular and microvascular complications of diabetes. Much of this oxidative stress arises from up-regulated nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activity. Phycocyanobilin (PhyCB), the light-harvesting chromophore in edible cyanobacteria such as spirulina, is a biliverdin derivative that shares the ability of free bilirubin to inhibit certain isoforms of NADPH oxidase. Epidemiological studies reveal that diabetics with relatively elevated serum bilirubin are less likely to develop coronary disease or microvascular complications; this may reflect the ability of bilirubin to ward off these complications via inhibition of NADPH oxidase. Oral PhyCB may likewise have potential in this regard, and has been shown to protect diabetic mice from glomerulosclerosis. With respect to oxidant-mediated uncoupling of eNOS, high-dose folate can help to reverse this by modulating the oxidation status of the eNOS cofactor tetrahydrobiopterin (BH4). Oxidation of BH4 yields dihydrobiopterin (BH2), which competes with BH4 for binding to eNOS and promotes its uncoupling. The reduced intracellular metabolites of folate have versatile oxidant-scavenging activity that can prevent oxidation of BH4; concurrently, these metabolites promote induction of dihydrofolate reductase, which functions to reconvert BH2 to BH4, and hence alleviate the uncoupling of eNOS. The arginine metabolite asymmetric dimethylarginine (ADMA), typically elevated in diabetics, also uncouples eNOS by competitively inhibiting binding of arginine to eNOS; this effect is exacerbated by the increased expression of arginase that accompanies diabetes. These effects can be countered via supplementation with citrulline, which efficiently enhances tissue levels of arginine. With respect to the loss of NO bioactivity that contributes to diabetic complications, high dose biotin has the potential to "pinch hit" for diminished NO by direct activation of soluble guanylate cyclase (sGC). High-dose biotin also may aid glycemic control via modulatory effects on enzyme induction in hepatocytes and pancreatic beta cells. Taurine, which suppresses diabetic complications in rodents, has the potential to reverse the inactivating impact of oxidative stress on sGC by boosting synthesis of hydrogen sulfide. Hence, it is proposed that concurrent administration of PhyCB, citrulline, taurine, and supranutritional doses of folate and biotin may have considerable potential for prevention and control of diabetic complications. Such a regimen could also be complemented with antioxidants such as lipoic acid, N-acetylcysteine, and melatonin-that boost cellular expression of antioxidant enzymes and glutathione-as well as astaxanthin, zinc, and glycine. The development of appropriate functional foods might make it feasible for patients to use complex nutraceutical regimens of the sort suggested here.
... (14) (15) Biotin also has shown beneficial effects in diabetic neuropathy , dyslipidemia associated with Type 2 DM in recent human trials. (16) (17)(18) Patients with Type 2 DM are also prone for nutritional deficiency of biotin manifesting as dermatitis , alopecia. So multiple benefits can be obtained by patients with Type 2 DM. ...
... The recommended daily intake (RDI) of biotin is 30 g per day (1). Biotin doses up to 100 times the RDI are frequently encountered in nutritional supplements promoted for conditions such as type 2 diabetes mellitus (2) and are reported to be beneficial for skin and hair. High-dose biotin (10 000 times RDI) has been documented to improve clinical outcomes and quality of life in patients with secondary progressive multiple sclerosis (MS) (3,4). ...
Context:
Biotin (Vitamin B7) is an essential co-factor for four carboxylases involved in fatty acid metabolism, leucine degradation and gluconeogenesis. The recommended daily intake (RDI) of biotin is approximately 30μ g per day. Low-moderate dose biotin is a common component of multivitamin preparations and high dose biotin (10,000 times RDI) has been reported to improve clinical outcomes and quality of life in patients with progressive multiple sclerosis. Biotin is also a component of immunoassays and supplementation may cause interference in both thyroid and non-thyroid immunoassays.
Objective:
To assess whether biotin ingestion caused abnormal thyroid function tests (TFTs) in a patient through assay interference Design: We report a patient with biotin-associated abnormal TFTs, and a systematic review of the literature Setting: A tertiary endocrine service in Hamilton, New Zealand Results: The patient had markedly abnormal thyroid function tests that did not match the clinical context. Following biotin cessation, TFTs normalised far more rapidly than possible given the half-life of thyroxine, consistent with assay interference by biotin. Multiple other analytes also tested abnormal in the presence of biotin.
Conclusion:
Biotin ingested in moderate to high doses can cause immunoassay interference. Depending on the assay format, biotin interference can result in either falsely high or low values. Interference is not limited to thyroid tests and has the potential to affect a wide range of analytes. It is important for clinicians to be aware of this interaction to prevent misdiagnosis and inappropriate treatment.
... Biotin, a nutraceutical agent, has been demonstrated through animal and clinical studies to have the capability of assisting in glycemic control in diabetic individuals if taken at a high dose of 9-15 mg per day (Zhang et al., 1996;Zhang et al., 1997;Maebashi et al., 1993). Various animal studies and few clinical studies established the effect of supplementary magnesium on the preservation of adipocyte insulin sensitivity (McCarty, 2005). ...
Background and Objective: Diabetes is an insidious as well as a debilitating metabolic disease with variety of causes that could lead to severe complications in multiple organs within the body system. There has been no documented scientific evidence as regards total cure of this complex chronic disease; therefore, it demands a lifelong management. This has necessitated the recent evaluation of several plant derived foods as costeffective alternatives in the management of diabetes and its associated complication.Materials and Methods: This review is based on integration of information from multi databases after a comprehensive literature search on the various plant derived foods that have been reported to have shown a certain degree of amelioration in the management of diabetes and diabetic complications.Result and Discussion: Published reports suggest that oxidative stress primarily mediated by uncontrolled hyperglycemia play a pivotal role in the pathogenesis of diabetes and its associated complications. Therefore, various plant-derived foods are believed to delay, prevent or manage diabetes and its associated complications using different mechanisms which could be established through their potential to increase insulin sensitivity, free radicals scavenging abilities, hypolipidemic, hypoglycaemic, hypocholesterolemic, antioxidative, anti-inflammatory and inhibition of α-amylase and α-glucosidase activities.Conclusion: Based on the evidence presented in this review, plant-derived foods possess bioactive constituents believed to be rich in antioxidants and proteins which may be responsible for their mode of actions; we propose that Cucuma longa (curcumin), Garcinia kola (kolaviron), Telfairia occidentalis and Parkia biglobosa be explored in the management of diabetes and its associated complications due to their outstanding beneficial effects.
... Thus, in vivo biotin supplementation augmented beta cell proportion as well as beta cell function. Conversely, it has been reported that the circulating biotin level is lower in type 2 diabetic patients compared with normoglycemic individuals (Maebashi et al. 1993). Supplementation of biotin plus chromium improved glucose me-tabolism and glycemic control in clinical trials involving type 2 diabetic patients (Singer and Geohas 2006;Albarracin et al. 2008), and also improved atherogenic risk factors and serum lipids in both diabetic and non-diabetic individuals (Albarracin et al. 2007;Geohas et al. 2007;Revilla-Monsalve et al. 2006). ...
Biotin is a B vitamin involved in multiple metabolic pathways. In humans, biotin deficiency is relatively rare but can cause dermatitis, alopecia, and perosis. Low biotin levels occur in individuals with type-2 diabetes, and supplementation with biotin plus chromium may improve blood sugar control. The acute effect on pancreatic gene expression of biotin repletion following chronic deficiency is unclear, therefore we induced biotin deficiency in adult male rats by feeding them a 20% raw egg white diet for 6 weeks. Animals were then randomized into 2 groups: one group received a single biotin supplement and returned to normal chow lacking egg white, while the second group remained on the depletion diet. After 1 week, pancreata were removed from biotin-deficient (BD) and biotin-repleted (BR) animals and RNA was isolated for microarray analysis. Biotin depletion altered gene expression in a manner indicative of inflammation, fibrosis, and defective pancreatic function. Conversely, biotin repletion activated numerous repair and anti-inflammatory pathways, reduced fibrotic gene expression, and induced multiple genes involved in pancreatic endocrine and exocrine function. A subset of the results was confirmed by quantitative real-time PCR analysis, as well as by treatment of pancreatic AR42J cells with biotin. The results indicate that biotin repletion, even after lengthy deficiency, results in the rapid induction of repair processes in the pancreas.
... С целью улучшения функ ционального состояния β-клеток целесообразно его применение с биотином, который является серосодержащим соединением, учас твующим в качестве коэнзима в процессах карбоксилирования. Биотин также повышает экспрессию глюкокиназы в β-клетках, что, естественно, улучшает функциональную активность глицерол-3-дегидрогеназного шунта в β-клетках [26,27]. Не исключено, что применение биотина и СоQ10 в комплексной терапии сахарного диабета 2 типа будет способствовать также и снижению степени выраженности, а может быть и исчезновению так называемой резистентности β-клеток к сульфонилмочевинным препаратам (вторичная резистентность к сульфонилмочевинным препаратам), что часто наблюдается у больных сахарным диабетом 2 типа при длительном их применении. ...
Изучение роли и значимости свободных радикалов в нарушении метаболизма позволило установить, что свободные радикалы кислорода участвуют в патогенезе почти 100 заболеваний, включая сахарный диабет и его сосудистые осложнения. Установлено, что при этих заболеваниях в мембранах и цитозоле клеток различных тканей выявляется повышенное содержание как свободных радикалов, так и продуктов их свободнорадикального окисления (альдегиды, кетоны, эпоксиды, гидроперекиси, диеновые и триеновые конъюгаты). Исследованиями подтверждено, что источниками образования свободных радикалов кислорода являются шесть путей метаболизма глюкозы.
... The role of biotin in improving skeletal muscle insulin sensitivity is not as well established. The majority of pre-clinical studies evaluating the mechanisms of biotin action with regard to lowering glucose have studied its effects on blood glucose, hepatocytes, and pancreatic beta cells (66)(67)(68)(69)(70)(71). However, hypotheses do exist that advocate for the role of biotin as a means to improve glucose uptake in skeletal muscle. ...
Type 2 diabetes is a common metabolic disorder characterized by resistance to the actions of insulin to stimulate skeletal muscle glucose disposal. In light of the staggering financial/human cost of type 2 diabetes, there is considerable need for safe and effective agents that can be used to prevent and/or adjunctively treat the disease. Available evidence suggests that a number of natural supplements, including cinnamon, biotin, fenugreek, ginseng, banaba, and alpha-lipoic acid, have the potential to reduce the risk for type 2 diabetes in the large at-risk population. The evidence also suggests that, when used adjunctively, these natural products are likely to help clinicians achieve optimal glycemic control, improve long-term prognosis, and/or minimize the need for insulin therapy in type 2 diabetics. More research, particularly well-designed, long-term human clinical trials, is certainly needed to accurately define the value and place of these supplements in diabetes prevention and management.
A synthesis of 2-epi-biotin sulfone was accomplished from commercially available l-cysteine. The synthesis features an unprecedented tandem S,N-carbonyl migration/aza-Michael/spirocyclization reaction from an l-cysteine-derived enone with aq. ammonia, in which three new sigma bonds and two rings are formed. In addition, the synthesis includes a highly diastereoselective late-stage Haller-Bauer reaction of sulfone for direct introduction of the carbon side chain.
Bal arıları meyve, sebze ve tohum oluşumu için çok önemli hayvanlardır.
Arılar, çiçekli bitkilerin erkek yapılarındaki polenleri dişi kısımlarına
aktararak bitkilerde meyve ve tohum oluşumunu sağlar. Ayrıca bal
yapmaları nedeniyle de tarih boyunca bu böceklere çok önem verilmiştir.
Biz insanlar her zaman bal arısına hayran olmuşuzdur. Afrika, Avrupa
ve Asya’daki en eski atalarımız, yüz binlerce yıl boyunca, bu arının bal
depolama ve balmumu yapma konusundaki şaşırtıcı endüstrisine, çok
değerli iki maddeye kesinlikle hayran kaldılar. Daha yakın zamanlarda,
son 10.000 yılda, karmaşık arıcılık zanaatını icat ettik ve bal arıları
üzerine bilimsel çalışmalarımıza başladık. Örneğin, bu arının «çiçek
değişmezliği» uygulamasını ilk kez tanımlayan antik filozof Aristotales’ti:
Bir işçi arı, yiyecek toplamanın verimliliğini artırmak için yiyecek
arama gezisi boyunca genellikle bir tür çiçeğe yapışır. Bal arısının
doğal dünyasında nasıl yaşadığını bilmek, geniş bir bilimsel araştırma
yelpazesi gerekmektedir. Bunun nedeni, Apis mellifera’nın biyolojideki,
özellikle davranışla ilgili temel soruları araştırmak için model sistemlerden
biri haline gelmesidir. Bu arıları ister hayvan bilişindeki, ister
davranışsal genetikteki veya sosyal davranışlardaki bazı gizemleri çözmek
için çalışıyor olun, birinin deneysel araştırmalarını tasarlamadan
önce doğal biyolojilerine aşina olmak kritik derecede önemlidir.
Supplements containing pharmacological concentrations of biotin are commercially available. The mechanisms by which biotin at pharmacological concentrations exerts its action have been the subject of multiple investigations, particularly for biotin's medicinal potential and wide use for cosmetic purposes. Several studies have reported that biotin supplementation increases cell proliferation; however, the mechanisms involved in this effect have not yet been characterized. In a previous study, we found that a biotin-supplemented diet increased spermatogonia proliferation. The present study was focused on investigating the molecular mechanisms involved in biotin-induced testis cell proliferation. Male BALB/cAnNHsd mice were fed a control or a biotin-supplemented diet (1.76 or 97.7 mg biotin/kg diet) for eight weeks. Compared with the control group, the biotin-supplemented mice presented augmented protein abundance of the c-kit-receptor and pERK1/2Tyr204 and pAKTSer473, the active forms of ERK/AKT proliferation signaling pathways. No changes were observed in the testis expression of the stem cell factor and in the serum levels of the follicle-stimulating hormone. Analysis of mRNA abundance found an increase in cyclins Ccnd3, Ccne1, Ccna2; Kinases Cdk4, Cdk2; and E2F; and Sp1 & Sp3 transcription factors. Decreased expression of cyclin-dependent kinase inhibitor 1a (p21) was observed but not of Cdkn2a inhibitor (p16). The results of the present study identifies, for the first time, the mechanisms associated with biotin supplementation-induced cell proliferation, which raises concerns about the effects of biotin on male reproductive health because of its capacity to cause hyperplasia, especially because this vitamin is available in large amounts without regulation.
The link between the gut microbiota and type 2 diabetes (T2D) warrants further investigation because of known confounding effects from antidiabetic treatment. Here, we profiled the gut microbiota in a discovery (n = 1,011) and validation (n = 484) cohort comprising Swedish subjects naive for diabetes treatment and grouped by glycemic status. We observed that overall gut microbiota composition was altered in groups with impaired glucose tolerance, combined glucose intolerance and T2D, but not in those with impaired fasting glucose. In addition, the abundance of several butyrate producers and functional potential for butyrate production were decreased both in prediabetes and T2D groups. Multivariate analyses and machine learning microbiome models indicated that insulin resistance was strongly associated with microbial variations. Therefore, our study indicates that the gut microbiota represents an important modifiable factor to consider when developing precision medicine approaches for the prevention and/or delay of T2D.
Tissue-specific metabolism determines their functions that collectively sense and respond to numerous stress cues to achieve systemic homeostasis. Chronic stress skews such metabolic profiles and leads to failure of organs as evidenced by a bias towards lipid synthesis and storage in the aging brain, muscle, and liver under Alzheimer's disease, sarcopenia, and non-alcoholic fatty liver disease, respectively. In contrast, the tissue destined for lipid synthesis and storage such as adipose limits its threshold and develops diabetes mellitus. However, the underlying factors that contribute to this lipogenic shift between organs are unknown. From this perspective, a differential biotin utilization between lipid-rich tissues such as adipose and brain during aging was hypothesized owing to the established role of biotin in lipogenesis. The same was tested using young and aged Wistar rats. We found that adipose-specific biotin content was much higher than the brain irrespective of aging status as well as its associated cues. However, within tissues, the adipose fails to maintain its biotinylation levels during aging whereas the brain seizes more biotin and exhibits lipid accumulation. Furthermore, mimicking the age-related stress cues in vitro such as high glucose and endoplasmic reticulum stress deprive the astroglial biotin content, but not that of adipocytes. Lipid accumulation in the aging brain was also correlated with increased S-adenosylmethionine levels and biotin utilization by astrocytes. In summary, differential biotin utilization between adipose and brain under aging and their respective cell types like adipocytes and astrocytes under age-associated stress cues connects well with the lipogenic shift in rat brain.
One of the most common micronutrient deficiencies with cutaneous findings is the vitamin B, also known as biotin, deficiency. Biotin deficiency may be due to congenital lack of biotinidase, or acquired following some conditions that interfere with its absorption, such as inflammatory bowel disorders, a diet too rich in avidin, magnesium deficiency, smoking habit and treatment with broad-spectrum antibiotics, anticonvulsants and sulfonamides. This review highlights the role of biotin in the most common skin disorders such associated with biotin deficiency and an approach to their treatment. Biotin administration may improve the treatment of hair loss when deficiency is detected on the basis of a careful patient history, clinical examination and the determination of serum biotin levels. The use of biotin is rationale in seborrheic dermatitis as the vitamin intercepts the main metabolic pathways underlying the pathogenesis of the disease. Treatment with biotin could also be useful in comedonal acne characterized by a high rate of seborrhea, and may be helpful for acne treated with topical retinoids, contributing to the control of flaking and irritation. The tolerability of biotin is excellent and there is no risk of hypervitaminosis even in the case of high doses. It is important that administration is controlled by physicians and follows a medical diagnosis and prescription. Correct doses used in dermatological conditions are safe and are not at risk of interference with laboratory tests.
During maturation, pancreatic islets achieve their full capacity to secrete insulin in response to glucose, undergo morphological changes in which alpha-cells decrease and beta-cell mass increases, and they acquire the normal alpha- and beta-cell proportion changes that are important for islet functions later in life. In rodents, the first week of postweaning is critical for islet maturation. Multiple studies have documented the detrimental effects of several conditions on pancreatic maturation; however, few studies have addressed the use of pharmacological agents to enhance islet maturation. Biotin might have a potential action on islet maturation. Pharmacological concentrations of biotin have been found to modify islet morphology and function. In a previous study, we found that mice fed a biotin-supplemented diet for 8 weeks after weaning showed an increase in basal and glucose stimulated insulin secretion, enlarged islet size, and modified islet structure. In the present study, we investigated the effect of biotin on maturation features during the first week postweaning. Female BALB/cAnN Hsd mice were fed a control or a biotin-supplemented diet for 1 week after weaning. Compared with the control, biotin-supplemented mice showed an increase in pancreatic islet number and area in addition to an augmented proportion of beta-cells in the islet. These effects were related to an increase in beta-cell proliferation. No differences were found in insulin secretion, blood glucose concentrations, or serum insulin levels. These results indicate that biotin supplementation is capable of affecting beta-cell proliferation and might be a therapeutic agent for establishing strategies for regenerative medicine.
A recent controlled trial has established that high-dose biotin supplementation – 100 mg, three times daily – has a stabilizing effect on progression of multiple sclerosis (MS). Although this effect has been attributed to an optimization of biotin’s essential cofactor role in the brain, a case can be made that direct stimulation of soluble guanylate cyclase (sGC) by pharmacological concentrations of biotin plays a key role in this regard. The utility of high-dose biotin in MS might reflect an anti-inflammatory effect of cGMP on the cerebral microvasculature, as well on oligodendrocyte differentiation and on Schwann cell production of neurotrophic factors thought to have potential for managing MS. But biotin’s ability to boost cGMP synthesis in the brain may have broader neuroprotective potential. In many types of neurons and neural cells, cGMP exerts neurotrophic-mimetic effects – entailing activation of the PI3K-Akt and Ras-ERK pathways – that promote neuron survival and plasticity. Hippocampal long term potentiation requires nitric oxide synthesis, which in turn promotes an activating phosphorylation of CREB via a pathway involving cGMP and protein kinase G (PKG). In Alzheimer’s disease (AD), amyloid beta suppresses this mechanism by inhibiting sGC activity; agents which exert a countervailing effect by boosting cGMP levels tend to restore effective long-term potentiation in rodent models of AD. Moreover, NO/cGMP suppresses amyloid beta production within the brain by inhibiting expression of amyloid precursor protein and BACE1. In conjunction with cGMP’s ability to oppose neuron apoptosis, these effects suggest that high-dose biotin might have potential for the prevention and management of AD. cGMP also promotes neurogenesis, and may lessen stroke risk by impeding atherogenesis and hypertrophic remodeling in the cerebral vasculature. The neuroprotective potential of high-dose biotin likely could be boosted by concurrent administration of brain-permeable phosphodiesterase-5 inhibitors.
Objective
Despite increasing evidence that pharmacological concentrations of biotin modify glucose metabolism, no studies have addressed the effects of biotin supplementation on glucagon production and secretion, considering glucagon is one of the major hormones in maintaining glucose homeostasis. In the present study, we investigated the effects of dietary biotin supplementation on glucagon expression, secretion, and action.
Research Methods & Procedures
Male BALB/cAnN Hsd mice were fed a control or a biotin-supplemented diet (1.76 or 97.7 mg biotin/kg diet) for eight weeks post-weaning. Glucagon gene mRNA expression was measured by the real-time polymerase chain reaction. Glucagon secretion was assessed in isolated islets and by glucagon concentration in plasma. Glucagon action was evaluated by glucagon tolerance tests, phosphoenolpyruvate carboxykinase (Pck1) mRNA expression, and glycogen degradation.
Results
Compared to the control group, glucagon mRNA and secretion were increased from the islets of the biotin-supplemented group. Fasting plasma glucagon levels were higher, but no differences between the groups were observed in non-fasting glucagon levels. Despite the elevated fasting glucagon levels, no differences were found in fasting blood glucose concentrations, fasting/fasting-refeeding glucagon tolerance tests, glycogen content and degradation, or mRNA expression of the hepatic gluconeogenic rate limiting enzyme, Pck1.
Conclusions
These results demonstrated that dietary biotin supplementation increased glucagon expression and secretion without affecting fasting blood glucose concentrations or glucagon tolerance and provided new insights into the effect of biotin supplementation on glucagon production and action.
Development of a simple electrochemical immunosensor, for the direct detection of biotin, is important for monitoring biotin content. A displacement assay was used in biotin detection, in which surface-bound antibodies were dissociated from the surface of immunosensor in the presence of free biotin. Pre-treatment of samples is not required for biotin detection using this electrochemical immunosensor. Using this electrochemical immunosensor, the recoveries of biotin in the two infant formulas A and B were 93.9% and 91.3%, respectively, of their biotin concentrations as stated on their packaging. The direct detection of biotin, with this electrochemical immunosensor, in supplements X, Y, and Z, showed recoveries as high as 92.9%, 106.5%, and 100.0%, respectively. The accuracy of our electrochemical immunosensor was validated with high pressure liquid chromatography (HPLC). The surface of immunosensor had a strong anti-fouling property and high specificity for actual applications in complex matrices. Additionally, the developed immunosensor shows good stability, reproducibility, and intra- and inter-day precision. This electrochemical immunosensor can directly detect biotin in infant formulas, biotin-containing supplements, and serum.
Two scalable chemical processes for the cinchona alkaloid catalyst recovery were demonstrated. In the first approach, the organocatalyst quinine was removed first as the neutral tartrate from alcohol, one recrystallization giving pure salt. Quinine was then recovered in 95 % yield by basification of its aqueous tartrate salt and could be reused without any further purification. In the second approach, the pure quinine catalyst could be easily obtained in almost quantitative yield and with 99 % chemical purity after a single recrystallization from toluene and its spectral data (1H NMR and the value of specific rotation) were in agreement with those of the literature previously reported. The methods are versatile and applicable for industrial-scale synthesis of biologically relevant substance (+)-biotin.
Background:
Biotin acts as a coenzyme for carboxylases regulating lipid and amino acid metabolism. We investigated alterations of the biotin-dependent functions in obesity and the downstream effects of biotin restriction in adipocytes in vitro.
Subjects:
24 monozygotic twin pairs discordant for BMI. Mean within-pair difference (heavy-lean co-twin, Δ) of BMI was 6.0 kg/m(2) (range 3.1-15.2 kg/m(2)).
Methods:
Adipose tissue (AT) DNA methylation, gene expression of AT and adipocytes, and leucocytes (RT-qPCR), serum biotin, C-reactive protein (CRP) and triglycerides were measured in the twins. Human adipocytes were cultured in low and control biotin concentrations and analyzed for lipid droplet content, mitochondrial morphology and mitochondrial respiration.
Results:
The gene expressions of carboxylases PCCB and MCCC1 were upregulated in the heavier co-twins' leucocytes. ΔPCCB (r=0.91, P=0.0046) and ΔMCCC1 (r=0.79, P=0.036) correlated with ΔCRP within-pairs. Serum biotin levels were lower in the heavier (274 ng/l) than in the lean co-twins (390 ng/l, P=0.034). ΔBiotin correlated negatively with Δtriglycerides (r=-0.56, P=0.045) within-pairs. In AT HLCS and ACACB were hypermethylated and biotin cycle genes HLCS and BTD were downregulated (P<0.05). Biotin-dependent carboxylases were downregulated (ACACA, ACACB, PCCB, MCCC2, and PC, P<0.05) in both AT and adipocytes of the heavier co-twins. Adipocytes cultured in low biotin had decreased lipid accumulation, altered mitochondrial morphology and deficient mitochondrial respiration.
Conclusions:
Biotin-dependent functions are modified by adiposity independent of genetic effects, and correlate with inflammation and hypertriglyceridemia. Biotin restriction decreases lipid accumulation and respiration, and alters mitochondrial morphology in adipocytes.International Journal of Obesity accepted article preview online, 25 November 2015. doi:10.1038/ijo.2015.237.
A cluster of inter-related conditions such as central obesity, dyslipidemia, impaired glucose metabolism, and hypertension is referred to as Metabolic Syndrome, which is a risk factor for the development of type-2 diabetes. The micro- and macro-vascular complications of diabetes contribute to its morbidity and mortality. In addition to its calcitropic effect, vitamin D is a regulator of gene expression as well as cell proliferation and differentiation. Various cross-sectional and longitudinal cohort studies have indicated a beneficial effect from vitamin D supplementation on the development of type-2 diabetes. Binding of retinol-bound retinol-binding protein to a membrane-binding protein suppresses insulin signaling. All-trans retinoic acid, a derivative of vitamin A, reverses these effects, resulting in increased insulin sensitivity, suppression of the phosphoenolpyruvate carboxy kinase (PEPCK) gene, and the induction of the glucokinase gene. Glucokinase and PEPCK are also regulated in opposite directions by the vitamin biotin, acting at the transcriptional level. Biotin also regulates the synthesis of insulin by the islet of Langerhans cells of the pancreas. The increase in advanced glycation end products (AGEs) is implicated in the initiation and progression of diabetes-associated microvascular diseases. Benfotiamine, a derivative of thiamine, and pyridoxamine, a vitamer of vitamin B6, both have anti-AGE properties, making them valuable therapeutic adjuvants in the treatment of diabetic complications. Thus, various vitamins and their derivatives have profound therapeutic potential in the prevention and treatment of type-2 diabetes.
During the last few decades, an increasing number of vitaminmediated effects has been discovered at the level of gene expression in addition to their wellknown roles as substrates and cofactors; the best recognized examples are the lipophilic vitamins A and D. Although little is known about watersoluble vitamins as genetic modulators, there are increasing examples of their effect on gene expression. Biotin is a hydro soluble vitamin that acts as a prosthetic group of carboxylases. Besides its role as carboxylase cofactor, biotin affects several systemic functions such as development, immunity and metabolism. In recent years, significant progress has been made in the identification of genes that are affected by biotin at the transcriptional and posttranscriptional levels as well as in the elucidation of mechanisms that mediate the effects of biotin on the gene expression. These studies bring new insights into biotin mediated gene expression and will lead to a better understanding of biotin roles in the metabolism and in systemic functions.
Zusammenfassung
Biotin-Resorption im Dickdarm des Schweines
In der Untersuchung sollte festgestellt werden, ob und in welcher Höhe Biotin aus dem Dickdarm resorbiert werden kann. Das Biotin wurde sechs männlichen, erwachsenen Göttinger Miniaturschweinen zweimal jeweils 7 Tage lang in einer Dosis von 0,167 bzw. 0,334 μmol × kg−0.75 Körpergewicht × Tag−1 kontinuierlich intracaecal infundiert. Die Tiere waren zuvor für 4 Monate auf eine Biotin-Mangel-Diät gesetzt worden. 50 bzw. 61% des infundierten Biotins wurden im Kot nicht wiedergefunden. Die Infusionen führten zu einem Anstieg der Biotin-konzentration im Plasma von 0,031 auf 0,248 μmol × 1−1 bzw. von 0,084 auf 0,340 μmol × 1−1. Die Biotinausscheidung im Harn erhöhte sich im Mittel von 0,08 auf 0,59 bzw. von 0,15 auf 1,10 μmol je 24 Stunden. Hieraus errechnet sich eine Resorption von mindestens 18% des infundierten Biotins. Aus der im Kot ausgeschiedenen Menge ergibt sich ein Maximum der Resorption von 50 bis 60%. Es wird die Schlußfolgerung gezogen, daß es einen beträchtlichen Transport von Biotin durch die Mucosa des Dickdarms gibt, der zur Deckung des Biotinbe-darfs beitragen könnte, vorausgesetzt, bakterielles Biotin besitzt eine gleich hohe Bioverfüg-barkeit wie die in diesen Versuchen infundierten Mengen.
Glucokinase activity was affected by hormones, dietary state, and dietary sources (e.g., glucose). Therefore, various factors (such as glucose, insulin, and biotin) affecting glucokinase activity in the rat liver were investigated. The activity of glucokinase was low in diabetic, fasting, and/or biotin-deficient rats. In the present study, the denovo synthesis of the glucokinase induced by the insulin and biotin in the intact rat was proposed. The first induction of glucokinase was activated by insulin. The second phase of enzyme activity could be induced by biotin. In addition, supplementation of cGMP with glucose and insulin to biotin deficient rats fully restored the enzyme activity as did biotin, showing that cGMP induction of glucokinase was dependent on the biotin status of the animal.
The influence of a change of colonic availability of biotin on biotin status was studied. This was done by inhibition of biotin absorption by intracaecal avidin infusion. Five adult minipigs with a permanent caecal 'T' cannula were fed on a semi-synthetic, biotin-deficient diet for 4 months. Following an 8-week adaptation period there were nine sequential 1-week infusion periods with or without oral lactulose or antibiotics. Avidin infusion during weeks 2, 5 and 8 amounted to 18 mg/d (13 U/mg). Plasma biotin concentrations were not changed by avidin infusions. There was a significant average 84% rise in faecal biotin excretion during the avidin periods. Urinary biotin output following avidin decreased by 21%. This is taken as evidence that biotin synthesized by colonic bacteria is available for host metabolism. A rough estimate shows that under basal conditions 1.7-17% of the metabolic allowance may be covered by this metabolic route.
Hyperinsulinemia is frequently associated with a variety of insulin-resistant states and has been implicated causally in the development of insulin resistance. This study examines the metabolic consequences of prolonged hyperinsulinemia in humans. Basally and 1 h after cessation of a 20-h infusion of insulin (0.5 mU X kg-1 X min-1, aimed at elevating plasma insulin levels to approximately 30 mU/L) or normal saline, subjects were assessed for glucose turnover with 3-[3H]glucose; insulin sensitivity, as measured by either the euglycemic glucose-clamp technique or the intravenous glucose tolerance test (IVGTT) minimal model method of Bergman; and monocyte insulin-receptor binding. Hepatic glucose production (Ra) was suppressed by greater than 95% during each euglycemic clamp and during the 20-h insulin infusion. After the insulin infusion, Ra and glucose utilization rate returned to the initial basal level within 1 h, as did insulin levels. At that time, insulin sensitivity was significantly decreased, as measured by the "insulin action" parameter during the 40- to 80-min phase of the clamp (0.049 +/- 0.003 vs. 0.035 +/- 0.007 min-1, P less than .05) and during the 80- to 120-min phase (0.047 +/- 0.005 vs. 0.039 +/- 0.007 min-1, .05 less than P less than .1).(ABSTRACT TRUNCATED AT 250 WORDS)
We used the in vivo intestinal loop approach, with short (10-min) and long (3-h) incubations, to examine biotin absorption in proximal jejunum, distal ileum, cecum and proximal colon. In short-term studies, luminal biotin disappearance from rat ileum was about half that observed in the jejunum, whereas absorption by proximal colon was about 12% of that in the jejunum. In 3-h closed-loop studies, the absorption of 1.0 microM biotin varied regionally. Biotin absorption was nearly complete in the small intestine after 3 h; however, only about 15% of the dose had been absorbed in the cecum and 27% in the proximal colon after 3 h. Independent of site of administration, the major fraction of absorbed biotin was recovered in the liver; measurable amounts of radioactive biotin were also present in kidney and plasma. The results support the potential nutritional significance for the rat of biotin synthesized by bacteria in the distal intestine, by demonstrating directly an absorptive capability of mammalian large bowel for this vitamin.
It has been proposed that hyperinsulinaemia may cause or exacerbate insulin resistance. The present studies were undertaken to test this hypothesis in man. Glucose utilization, glucose production, and overall glucose metabolism at submaximally and maximally effective plasma insulin concentrations (approximately 80 and approximately 1700 mU/l), and monocyte and adipocyte insulin binding were measured in normal volunteers on two occasions: once after 40 h of hyperinsulinaemia (25-35 mU/l) produced by infusion of insulin and once after infusion of saline (75 mmol/l; plasma insulin approximately 10 mU/l). After 40 h of hyperinsulinaemia, glucose utilization and overall glucose metabolism at submaximally and maximally effective plasma insulin concentrations were both slightly, but significantly, reduced compared with values observed after the infusion of saline (p less than 0.05), whereas glucose production rates were unaffected. Monocyte and adipocyte binding were also unaffected. These results indicate that hyperinsulinaemia of the magnitude observed in insulin resistant states, such as obesity, can produce insulin resistance in man. Assuming that human insulin sensitive tissues possess spare insulin receptors and that monocyte and adipocyte insulin binding accurately reflect insulin binding in insulin-sensitive tissues, the decreased maximal responses to insulin and the lack of change in insulin binding suggest that this insulin resistance occurred at a post-binding site.
In our earlier study on gluconeogenesis in biotin-deficient rats we showed metabolic blocks at the pyruvate carboxylase and glyceraldehyde-3-P dehydrogenase steps. This resulted in an accumulation of pyruvate and lactate, and in a decrease in the level of malate and citrate in liver. The ratio of was also markedly reduced. The present study was made to ascertain how soon this condition is alleviated after biotin administration. Using 24-hr fasted biotin-deficient rats, the levels of pyruvate, lactate, malate, citrate, glucose, NADH and NAD were determined in rapidly frozen livers at 0, 1, 2, 4, and 8 hr after an injection of biotin. Incorporation of l-alanine-U-14C into blood glucose after biotin administration and the effect of actinomycin D and puromycin on this process was also studied. Within 2–4 hr after biotin administration, a marked increase in malate and citrate, and also in the reducing power, with a concomitant decrease in pyruvate was observed. The overall effect of the restoration of gluconeogenesis could be seen from the increased level of glucose in liver and blood and also from the increased incorporation of labeled alanine into blood glucose. Actinomycin D or puromycin administration prior to biotin injection failed to inhibit this restoration. The results indicate that there was no de novo synthesis of pyruvate apocarboxylase or the holocarboxylase synthetase and imply that (a) the lack of biotin was limiting holopyruvate carboxylase synthesis and (b) the decreased reducing power was limiting optimal glyceraldehyde-3-P dehydrogenase activity.
In biotin deficiency, energy production was impaired in two ways: by decreased utilization of glucose and by decreased oxidative phosphorylation. The decrease in the utilization of glucose was reflected in low glucose tolerance, a decrease in glycogen synthesis, and amino acid incorporation in liver proteins and an increase in the excretion of ketone bodies. Fructose or sorbitol feeding or insulin administration to the deficient animal brought about an improvement in amino acid incorporation. In biotin deficiency the lipid content of mitochondria was significantly decreased.
Biotin and its analog, (+)-biotin-p-nitrophenyl ester enhanced guanylate cyclase activity two- to threefold in rat liver,
kidney, colon, cerebellum, and heart. Dose-response relationships revealed that at concentrations as low as 1 micromolar,
both biotin and its analog caused maximal augmentation of guanylate cyclase activity. These data suggest a role for the activation
of guanylate cyclase in the mechanism of action of this vitamin.
The carboxylase deficiencies have recently received much attention because of their increased recognition by geneticists and physicians, ease of laboratory diagnosis, and potential for treatment by protein restriction and vitamin supplementation. Disorders characterized by deficiencies of the four known human biotin-dependent enzymes have now been described. These enzymes are acetyl CoA carboxylase, a pivotal enzyme in the synthesis of fatty acids; pyruvate carboxylase, which catalyzes the initial committed step in gluconeogenesis; propionyl CoA carboxylase, which catabolizes the branched-chain amino acids valine, isoleucine, methionine, and threonine, as well as the odd-chain fatty acids and the side chain of cholesterol; and β-methylcrotonyl CoA carboxylase, which catalyzes the catabolism of leucine. In addition, a heterogeneous group of multiple carboxylase deficiencies have recently been characterized in which the activities of at least three mitochondrial biotin-dependent carboxylases are diminished. The purpose of this review article is to delineate and compare the clinical, biochemical, and genetic features of these inherited metabolic disorders.
To determine whether hyperinsulinaemia can cause insulin resistance in man and, if so, whether this occurs at a receptor or post-receptor site, nine normal volunteers were infused with insulin for 6 h at a rate (2 mU X kg-1 X min-1) which resulted in steady-state plasma insulin concentrations of 140 +/- 13 mU/l and four subjects were infused with saline (0.45%). Isolated adipocytes and monocytes were used as models for studying insulin binding, while adipocytes were also used to study insulin action in vitro. Adipocyte insulin binding did not decrease following infusion of insulin (4.6 +/- 0.5 versus 4.4 +/- 0.4% per 2 X 10(5) cells, before and after, respectively), whereas monocyte insulin binding did (7.2 +/- 0.6 versus 6.2 +/- 0.6% per 10(7) cells, p less than 0.05). Initial rates of adipocyte 3-0-methyl glucose transport were decreased in the absence of insulin (basal) and at submaximally effective (33.3 pmol/l) but not at maximally effective insulin concentrations. At all insulin concentrations and in the absence of insulin, rates of glucose conversion to lipids were decreased more than 50% (p less than 0.05), whereas rates of glucose oxidation were unaffected. This decrease in the rates of conversion of glucose to lipids could not be accounted for by the decrease in rates of glucose transport. These results suggest that hyperinsulinaemia can cause insulin resistance in man and that, at least initially, this occurs at a post-receptor site. Furthermore, the discordant effect of hyperinsulinaemia on monocyte and adipocyte insulin binding indicates that monocyte insulin binding may not always reflect insulin binding in insulin-sensitive tissues.
The exposure of primary cultures of hepatocytes to insulin. 10(-8) M, for 16 h results in a decrease in high affinity insulin binding with no alterations in lower affinity binding. This is reflected in a decrease in the sensitivity, but normal responsiveness, of cultured hepatocytes to the acute effect of insulin on the uptake of aminoisobutyric acid. The shift in sensitivity, however, can only be partially explained by the decrease in insulin binding. With regard to lipid synthesis, hepatocytes cultured in the presence of insulin, 10(-8) M, are normally sensitive and hyperresponsive to the acute effects of insulin. These data indicate that the insensitivity or resistance of a given tissue to insulin may be specific for the biologic response being evaluated, that postbinding events may be more important than alterations in insulin binding in determining both the sensitivity and responsiveness of a tissue to insulin, and that generalizations concerning the sensitivity or responsiveness of a tissue to insulin based on binding data alone may be unwarranted.
We have examined the effect of in vitro hyperinsulinemia on insulin binding, glucose transport, and insulin degradation in isolated rat adipocytes. When cells were incubated with insulin for 2 or 4 h at 37 degrees C, followed by washing in insulin-free buffer to remove extracellular and receptor-bound insulin, a time and dose-dependent decrease in insulin receptors was observed, which was accompanied by a reduced ability of cells to degrade insulin. Furthermore, the quantitatively predicted rightward shift in the insulin-glucose transport dose-response curve could be demonstrated. In addition to this reduction in insulin sensitivity, a striking decrease in maximal insulin-stimulated glucose transport was observed in the 4-h insulin-treated cells, indicating an abnormality distal to the insulin receptor. Thus, in vitro insulin-induced insulin resistance in adipocytes is caused by both receptor and postreceptor abnormalities. The post-receptor defect is most likely at the level of the glucose transport system per se because the insulinlike agents, spermine and antiinsulin receptor antibodies, also had a markedly reduced ability to stimulate glucose transport in 4-h insulin-treated cells. On the other hand, when cells were incubated with 100 ng/ml insulin for up to 4 h, after which time 2-deoxy glucose uptake was measured without removing buffer insulin or allowing receptor-bound insulin to dissociate, no decrease in maximal insulin-stimulated glucose transport was found. In conclusion, (a) insulin leads to a dose-dependent loss of insulin receptors in freshly isolated adipocytes accompanied by the predicted functional consequence of decreased receptors, i.e., a rightward shift in the insulin-glucose transport dose-response curve, (b) prolonged incubation with insulin causes a marked postreceptor defect in the glucose transport system, (c) maintenance of the activated state of the glucose transport system prevents the expression of the post-receptor defect, (d) the location of the postreceptor abnormality is most likely in the glucose transport system per se, and (e) insulin-induced receptor loss is accompanied by a decrease in insulin degradation.
- K Dakshinamurti
- J Chauhan
Dakshinamurti, K., and Chauhan, J. (1989): Biotin. Vitam. Horm., 45, 337-384.
- A D Deodhar
- S P Mistry
Deodhar, A.D., and Mistry, S.P. (1969): Control of gluconeogenesis in biotin-deficient rat
liver. Arch. Biochem. Biophys., 129, 321-328.