Effects of Biotin Deprivation and Biotin Supplementation
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A number of key carboxylase enzymes involved in metabolism depend upon the vitamin biotin for their structure and function. Humans and animals require biotin to be supplied in the diet. Biotin deficiency is relatively rare in the developed world and typically reflects consumption of egg white-enriched or ketogenic diets, whereas deficiency in underdeveloped countries is more likely to be due to biotin-poor diets. The effects of biotin deficiency are not typically life-threatening, but can lead to developmental delays in children, or hair and skin abnormalities in affected individuals. In contrast, biotin supplementation has been shown to provide salutary benefit in some individuals, such as diabetics. Here we examine the biochemistry of biotin, as well as the effects of biotin deficiency and supplementation, with a focus on human health.
KeywordsBiotin Prosthetic group Carboxylases Multiple carboxylase deficiency Glucose metabolism Cell differentiation and proliferation Pancreatic inflammatory proteins Pharmacological effects
List of Abbreviations
Multiple carboxylase deficiency
Sodium-dependent multivitamin transporter
Biotin is a water-soluble vitamin. Its discovery, elucidation of its structure, and delineation of its role in metabolism involved diverse investigations spanning several decades. Biotin was shown to be cis-hexahydro-2-oxo-1H-thieno [3,4] imidazole-4-valeric acid. The best known and understood role of biotin is as the prosthetic group of the biotin-containing enzymes – propionyl-CoA carboxylase (PCC), pyruvate carboxylase (PC), β-methylcrotonyl-CoA carboxylase (MCC), and acetyl-CoA carboxylase (ACC). The biotin-dependent carboxylase catalyzes an adenosine triphosphate (ATP)-dependent CO2 fixation reaction in which biotin functions as a CO2 carrier on the surface of the enzyme. These enzymes catalyze key reactions in gluconeogenesis, fatty acid biosynthesis, and amino acid catabolism. In addition, biotin has been shown to participate in other cellular events such as transcriptional and translational regulation. This review examines the role of biotin in metabolism, biotin deficiency, biotin dependency, as well as the non-prosthetic group functions of biotin.
Structure and Biosynthesis
Absorption and Transport
Biotin is widely distributed in foodstuffs, although in low concentrations. Egg yolk, liver, nuts, and legumes are rich in biotin. Most of the biotin in foods such as meat and cereals is protein bound. Enzymatic hydrolysis in the gastrointestinal tract releases biocytin (or biotinyl peptides) rather than free biotin. Biotinidase activity is present in pancreatic and intestinal secretions as well as in brush border membranes. The uptake of biotin by human cell lines is saturable (Dakshinamurti and Chalifour 1981; Chalifour and Dakshinamurti 1982). The uptake of biotin and biocytin in rat jejunal segments is biphasic (Dakshinamurti et al. 1987). At concentrations below 50 nM, the saturable uptake mechanism would make enough biotin available to the animal. This saturable component uses a sodium-dependent multivitamin transporter (SMVT) having affinity for pantothenic acid, lipoic acid, as well as biotin. The rarity of primary biotin deficiency in humans is consistent with this. The late-onset type of multiple carboxylase deficiency (MCD) was shown to be due to the lack of a system for absorbing biotin in the nanomolar range, and in turn due to the lack of biotinidase. Biotinidase is the only protein in brush border membranes and the only protein in human serum that binds to biotin (Chauhan and Dakshinamurti 1986, 1988). Based on the above studies, it was suggested that biotinidase in vivo functions in the transport of biotin (Dakshinamurti and Chauhan 1989). It has been shown that in cases of late-onset MCD, patients lack the system for absorbing nanomolar biotin and respond only to pharmacological biotin doses, indicating that only the saturable portion of the biotin transport system is defective (Roth et al. 1982; Roth 1985).
Microbial growth assays using microorganisms such as Lactobacillus plantarum, Lactobacillus casei, Ochromonas danica, or Saccharomyces cerevisiae have traditionally been used to measure biotin content. Avidin-binding assays measure the ability of biotin to compete with radiolabeled (3H or 14C) biotin for binding to avidin (Dakshinamurti et al. 1974; Dakshinamurti and Allan 1979). Avidin-binding assays using electrochemical or bioluminescence detection or a double-antibody technique have been published (Terouanne et al. 1989; Thuy et al. 1991).
There is no reliable estimate of the biotin requirement of various human groups. The Food and Nutrition Board of the National Research Council has prescribed adequate intakes for various age groups (National Research Council, Dietary Reference Intakes Tables, The National Academies, Washington, D.C., 2005).
Biotin as Prosthetic Group of Biotin Enzymes : Role in Metabolism
Biotin-dependent carboxylases function in two steps – biotin carboxylase and carboxyl transferase. The biotin carboxylase component catalyzes the MgATP-dependent carboxylation of the N1 of the biotin cofactor using bicarbonate as the CO2 donor. Biotin is linked covalently through an amide linkage to the ε amino group of a specific lysine in the biotin carboxyl carrier protein by a protein ligase. In the second step, the carboxyl transferase catalyzes CO2 transfer from carboxybiotin to the carboxyl group acceptor. The substrates are coenzyme A esters such as acetyl-CoA, propionyl-CoA, and 3-methylcrotonyl-CoA. Pyruvate serves directly as a substrate (Tong 2013).
ACC catalyzes the ATP-dependent carboxylation of acetyl CoA, leading to the formation of malonyl-CoA. In mammals, there are two isoforms of ACC: ACC1 is expressed in lipogenic tissues such as liver, adipose tissue, and lactating mammary gland. The product malonyl-CoA is the building block to extend the chain length of fatty acids by two carbon increments, catalyzed by fatty acid synthase. Long-chain fatty acids are incorporated into complex lipids such as triglyceride and phospholipid. ACC1 is regulated by hormones and dietary and nutritional state. ACC1 is stimulated by citrate and inhibited by long-chain acyl-CoA and by phosphorylation of the enzyme. Mammals have another isoform – ACC2 – which is associated with the outer mitochondrial membrane and is expressed in the heart, skeletal muscle, and liver. The product of ACC2, malonyl-CoA, is an inhibitor of carnitine palmitoyltransferase-1, involved in the transport of long-chain fatty acyl-CoAs into the mitochondria for β-oxidation. ACC2 knockout mice show elevated fatty acid oxidation and increased energy expenditure (Abu-Elheiga et al. 2001).
In the catabolic pathways of odd-chain fatty acids, PCC is crucial for the catabolism of branched-chain amino acids isoleucine, threonine, and valine as well as methionine. PCC catalyzes the conversion of propionyl-CoA to methylmalonyl-CoA which in turn enters the tricarboxylic acid cycle via succinyl-CoA. Mammalian PCC is a mitochondrial enzyme which is activated by monovalent cations (K+, NH4 +). Inherited deficiency of PCC leads to propionic acidemia (Dakshinamurti and Chauhan 1988).
MCC catalyzes the conversion of 3-methylcrotonyl-CoA to 3-methylglutaconyl-CoA and is involved in the catabolism of leucine and isovalerate. Deficiency in the activity of this enzyme results in 3-methylcrotonyl-glycinuria, an inborn error of metabolism.
PC catalyzes pyruvate conversion to oxaloacetate, with a crucial role in gluconeogenesis in the liver and the kidney where it catalyzes the first step in the synthesis of glucose from pyruvate. It is also present in lipogenic tissues and participates in fatty acid synthesis by transporting acetyl groups via citrate and reducing groups via malate, from the mitochondria to the cytosol. It has an anaplerotic role in the formation of oxaloacetate, replenishing intermediates of the tricarboxylic acid cycle that have been used up for the synthesis of glucose, fatty acids, and amino acids. A rare autosomal recessive metabolic disorder resulting in deficient PC activity has been reported with multiple clinical manifestations.
With the exception of ACC1, the biotin carboxylases are mitochondrial enzymes. Biotin deficiency affects mitochondrial metabolism and function significantly. Oxidative phosphorylation is impaired in biotin-deficient rat liver mitochondria (Dakshinamurti et al. 1970). A role for biotin in maintaining mitochondrial complex IV and heme metabolism has been reported (Atamna et al. 2007).
Biotin deficiency affects the level of tricarboxylic acid cycle intermediates. PC has an anaplerotic role, and its deficiency decreases the production of succinyl-CoA. MCC deficiency leads to methylcrotonyl-CoA accumulation in the mitochondria where it reacts with glycine, depleting its content in the mitochondrial matrix. Succinyl-CoA and glycine are the precursors of heme synthesis. Thus, biotin deficiency, through depletion of these intermediates, leads to a decrease of mitochondrial complex IV, a functional indicator of heme deficiency, decreasing ATP production (Atamna et al. 2007). The significant role of biotin in energy metabolism is indicated by the sparing of the brain and the heart from the effects of general biotin deficiency, thus protecting these organs at the expense of organs such as the liver and kidney (Pacheco-Alvarez et al. 2004; Velazquez-Arellano et al. 2008). Because of the relative insensitivity to biotin deficiency, cardiac tissue is able to maintain ATP synthesis.
Hair thinning with loss of color, periorificial skin rash, hypotonia, lethargy, and developmental delay are the clinical sequelae of pronounced biotin deficiency in human adults and infants. Early reports of these clinical findings were the result of feeding individuals an egg white diet. The egg white protein avidin binds to free biotin, rendering it unavailable for absorption. Diet-induced biotin deficiency, with its unique clinical signs, is rare; however, milder conditions of deficiency can occur.
Measurement of serum biotin and the urinary excretion of biotin and its metabolite bisnorbiotin have been used as measures of the biotin status of individuals, but they are fraught with uncertainty. Indices based on the metabolic function of biotin have been found to be more reliable as indicators of biotin status. Among these are the urinary excretion of metabolites in biotin-mediated steps in metabolism and the activation index of biotin enzymes. Urinary excretion of 3-hydroxyisovaleryl carnitine and 3-hydroxyisovaleric acid is increased in early biotin deficiency due to a decrease in activity of the biotin enzyme MCC (Stratton et al. 2011). PCC activity in peripheral blood lymphocytes has been shown to be an early and more sensitive indicator of marginal biotin deficiency than urinary excretion of 3-hydroxyisovaleric acid. Malnutrition in developing countries is a major cause of multiple vitamin deficiencies. In the developed world, biotin deficiency is related to genetic factors leading to biotin dependency. However, conditions of prolonged parenteral nutrition lacking biotin supplementation, or the use of infant formulas lacking biotin, have been shown to result in biotin deficiency (Sato et al. 2016; Wakabayashi et al. 2016). Long-term treatments with a heterogeneous group of anticonvulsants have been shown to result in biotin deficiency due to impaired biotin absorption and salvage by the kidney (Mock and Dyken 1997). A low-carbohydrate, high-fat “ketogenic” diet is used to treat drug-resistant epilepsy and has been shown to induce a relative biotin deficiency (Yuasa et al. 2013). A marginal deficiency of biotin is common in normal human pregnancy. The frequency of such deficiency during the first trimester is of concern due to the teratogenicity of biotin deficiency.
Single Carboxylase Deficiency
The incidence in infants of organic acidemia has been investigated and characterized as due to the lack of one or more of the biotin carboxylases (Sweetman and Nyhan 1986). Inherited disorders of individual biotin carboxylases have been reported. These patients do not respond to pharmacological biotin doses. PCC deficiency causes elevated concentrations of propionic and lactic acids in blood and increased levels of their secondary metabolites such as 3-hydroxypropionic acid, 2-methylcitrate, and propionyl glycine excreted in the urine.
Multiple Carboxylase Deficiency
In MCD, the patient exhibits deficiencies of all three mitochondrial carboxylases – PC, PCC, and MCC. Two distinct types of MCD are recognized based on the age of onset and the nature of clinical presentation (Sweetman and Nyhan 1986). A deficiency of HCS is generally regarded to be the prime biochemical lesion in the neonatal type of MCD. The beneficial response of the affected infant to large doses of biotin administered prenatally to the mother suggests a defective HCS with a high Km for biotin (Roth et al. 1982). Incidentally, this was the first instance of successful prenatal treatment of this condition. The prenatal treatment followed by postnatal biotin supplementation of the child resulted in the total avoidance of any effects of biotin deficiency in the child.
The late-onset (or juvenile) form of MCD is associated with low serum biotin values and is associated with defective biotin absorption due to biotinidase deficiency. Biotinidase, along with HCS, participates in the cellular biotin cycle (Fig. 3). Biotinidase deficiency is an autosomal recessive inherited metabolic disorder. Untreated individuals develop neurological and cutaneous symptoms as well as myelopathy. These symptoms can be prevented if the biotin treatment is started at birth or before symptoms develop. Newborn biotinidase screening has been instituted in many countries worldwide (Wolf 2011, 2015). A case of biotin dependency due to a defect in biotin transport was reported. In this child, biotin dependency was not the result of biotinidase, holocarboxylase, or biotin deficiency but the result of a genetic defect in a biotin transport protein distinct from the SMVT.
Besides the carboxylases in which biotin is attached covalently to the apocarboxylase, there are a group of proteins which bind biotin non-covalently. Both avidin, the biotin-binding protein of raw hen egg white, and streptavidin, a bacterial protein, have exceedingly high affinities for biotin (Km of 10−15 M). This is the strongest known non-covalent binding between a protein and a small molecular weight ligand. Other biotin-binding proteins include biotinidase, biotin HCS, biotin antibodies, and nuclear biotin-binding protein, with progressively lower affinities for biotin.
Monoclonal antibodies to biotin have been prepared using keyhole limpet hemocyanin (Dakshinamurti et al. 1986; Dakshinamurti and Rector 1990). One of the four clones isolated produced antibody of high affinity that bound both free and haptenic biotin antigen as well as biocytin. The high affinity between biotin and avidin has been utilized in various areas of biological research. Of much significance is the use of avidin-biotin complex for the localization and evaluation of cell surface receptors. The use of monoclonal biotin antibodies facilitates these studies.
Avidin -biotin technology, based upon the strong interaction between avidin or streptavidin and biotin, has been applied in biology, medicine, and technology. Even biotin covalently bound to a protein is available for binding by avidin or streptavidin. The various chemical and enzymatic biotinylation procedures have contributed to the extensive use of the avidin (streptavidin)-biotin technology (Dundas et al. 2013). The monoclonal anti-biotin antibody has been shown to be an excellent substitute for streptavidin-based immunoassay systems.
Non-prosthetic Group Functions
Biotin Requirement for Cultured Cells and for Cell Differentiation
A requirement for biotin was demonstrated for HeLa cells, human fibroblasts, and Rous sarcoma virus-transformed baby hamster kidney cells (Chalifour and Dakshinamurti 1982; Bowers-Komro and McCormick 1985). Mammalian cultured cells under conditions such as serine starvation, when they do not get growth signals, come to a halt in the quiescent, non-growing G0 state. Normal cells in G1 arrest due to serine starvation do not incorporate [3H]-thymidine into DNA, but do so as soon as serine is restored. However, biotin-deficient cells, under similar conditions, do not incorporate [3H]-thymidine even when serine is restored. When biotin is restored to the medium, the biotin-deficient cells, after a lag, start incorporating thymidine into DNA, with a stimulation of protein synthesis during this lag.
The 3T3-L1 mouse fibroblast cell line can differentiate into an adipose cell type. When the cells reach confluence and start to differentiate, they greatly increase the rate of triglyceride synthesis. This parallels the coordinate increase in the activities of the key enzymes of lipogenesis and correlates with the rise in the nuclear run-off transcription rates for the mRNA during differentiation. This process of differentiation can be accelerated by increasing the amount of serum in the culture medium, or by adding insulin or biotin to the culture medium.
Biotin deficiency in mice changes the subpopulation of spleen lymphocytes and decreases their proliferative response to concanavalin A . Under conditions of biotin deficiency, the involution of the thymus is accelerated and thymocyte maturation is arrested, indicating that a specific stage in T cell maturation is sensitive to biotin deficiency.
Development of the Palatal Process
Congenital malformations occur in domestic fowl maintained on a biotin-deficient diet. At mid-gestation, biotin-deficient embryos weighed less than normal embryos and had external malformations such as micrognathia and micromelia . There was a marked decrease in the size of the palatal process due to altered proliferation of the mesenchyme. The development of the palatal process in culture was investigated (Watanabe et al. 1995). After 72 h of organ culture, more than 40% of the explants from normal (biotin-repleted) mouse embryos were in stage 6 of development, which dropped to only 6.5% for embryos cultured in biotin-deficient medium. Administration of biotin to biotin-deficient dams 24 h prior to removal of the embryo resulted in over 50% of explants at stage 6 of development when cultured in a medium containing 10−7 M biotin. There was no detrimental effect on any of the organic acid intermediates or their secondary metabolites on palatal closure of the explants when these compounds were added to the organ culture medium, indicating the continuous requirement for biotin during proliferation of the mesenchyme, perhaps for the synthesis of growth factors during organogenesis. As a marginal deficiency of biotin in normal human pregnancy is quite common, the teratogenic effects of such deficiency are a matter of concern.
Biotin and the Reproductive System
In mammals, spermatogenesis is dependent primarily on testosterone, which is produced in the Leydig cells and acts on the tubular cells of the seminiferous tubules to drive spermatogenesis. Testicular and serum levels of testosterone are decreased in the biotin-deficient rat (Paulose et al. 1989). Biotin deficiency was accompanied by a significant sloughing of the seminiferous tubule epithelium in these rats. Treatment of biotin-deficient rats with gonadotropins or biotin increases the levels of serum testosterone. Even when the testosterone levels are maintained high in biotin-deficient rats by testosterone implants, the increase in serum testosterone does not result in normal spermatogenesis. In contrast, the administration of biotin alone or with testosterone to biotin-deficient rats leads to normal spermatogenesis. This suggests that biotin is involved in the formation of local testicular factors that are required in addition to testosterone and follicle-stimulating hormone, for the normal interaction among Leydig, Sertoli, and peritubular cells.
The effects of diets with varying biotin contents on the estrus cycle, estradiol and progesterone serum levels, ovarian morphology, uterine mRNA abundance of estradiol and progesterone nuclear receptors, as well as estradiol-degrading enzymes in the liver of BALB/cAnNHsd female mice were studied (Baez-Saldana et al. 2009). Biotin deficiency was associated with reduction in ovary weight, arrested estrous cycle, and significant changes in ovarian morphology. Biotin deficiency decreases serum insulin growth factor-1 concentration, which might account for the effects observed in ovarian follicles in biotin-deficient mice.
Immunological and Inflammatory Functions
Cytokines , secreted by immune cells in response to antigen stimulation, bind to target cell receptors to activate intracellular signaling cascades controlling cellular processes such as growth, proliferation, and apoptosis. The expression of genes encoding the cytokine interleukin-2 and its receptor correlates with the biotin status of human lymphoid cells (Wiedmann et al. 2003). The effect of biotin on the metabolism of cytokines might underlie its role in immune function. The activities of various cell signals such as biotinyl-AMP, SP1 and SP3, nuclear factor NF-κB, and receptor tyrosine kinase are biotin dependent. Biotin deficiency upregulates tumor necrosis factor-α production, and biotin excess downregulates it (Kuroishi 2015). As this factor has an important role in the pathogenesis of inflammatory disease, the possibility of treating inflammatory diseases with biotin would be a fruitful area of investigation.
Biotin and Glucose Metabolism
The initial and rate-limiting step in the metabolic utilization of glucose is its phosphorylation by glucokinase , whose activity is influenced by dietary, nutritional, and hormonal states of the animal. Hepatic glucokinase is decreased in biotin-deficient rats fed with either high or low carbohydrate diets, and administration of insulin or biotin restored glucokinase activity to normal levels (Dakshinamurti and Cheah-Tan 1968a, b). Biotin also played a role in the precocious development of glucokinase in young rats (Dakshinamurti and Ho Chong 1970). In all these studies, enzyme activity correlated with protein synthesis. Pharmacologic levels of biotin increased glucokinase activity levels in biotin-repleted animals (Dakshinamurti 2005). Hepatic glucokinase activity in biotin-injected starved rats increased threefold compared with starved rats. The relative amount of glucokinase mRNA in the liver of biotin-injected starved rats increased fourfold over the levels seen in normal-fed rats and about 20-fold of that seen in starved rats not receiving biotin injection. Glucokinase induction was marked and rapid and correlated with increased glucokinase enzyme activity. In “run-on” transcription assays using isolated liver nuclei, biotin administration to the whole animal increased glucokinase gene transcription sevenfold, an effect that was not due to an increase in overall transcription efficiency as the transcription of the β-actin gene was unaffected (Chauhan and Dakshinamurti 1991).
In both fasted and diabetic rats, hepatic phosphoenolpyruvate carboxykinase (PEPCK) activities are markedly increased. Refeeding a high-carbohydrate diet to fasted rats decreased PEPCK mRNA due to repression of PEPCK gene transcription by insulin. Three hours after biotin administration to starved rats, hepatic PEPCK mRNA levels decreased to 15% of the levels seen in non-biotin-injected starved rats. The effect of biotin paralleled the effect of insulin in these animals. In “run-on” transcription experiments using isolated liver nuclei, biotin suppressed hepatic PEPCK mRNA by 55% at 30 min after biotin administration. The inhibition is dominant over other stimulatory effects (Dakshinamurti and Li 1994). There are many similarities between biotin and insulin in their actions on enzymes of glucose metabolism. Both induce a key glycolytic enzyme and repress PEPCK, the key gluconeogenic enzyme. Further experiments indicate that biotin repressed the gluconeogenic genes through a pathway independent of insulin signaling (Sugita et al. 2008).
Biotin stimulated glucokinase activity and mRNA expression after a short-term treatment in cultured pancreatic β cells. Biotin also stimulated glucokinase activity and insulin secretion in rat islets in culture. Islet glucokinase activity and mRNA are reduced by 50% in the biotin-deficient rat. Insulin secretion in response to glucose was also impaired in islets isolated from biotin-deficient rats (Romero-Navarro et al. 1999). Biotin deficiency also affects pancreatic islet morphology. Besides defects in insulin sensitivity, there was disruption of islet architecture with an increase in the number of α cells in the islet core. Biotin deficiency promoted hyperglycemic mechanisms (Larrieta et al. 2012). Administration of pharmacological concentrations of biotin to normal rodents enhanced insulin secretion and the expression of genes and signaling pathways that favor islet function and augmented the proportion of β cells by enlarging islet size (Lazo de la Vega-Monroy et al. 2013).
Biotin starvation reduces glucose consumption and energy production in three different eukaryotes, despite the fact their phylogenetic lines diverged more than a billion years ago. In these biotin-starved organisms – yeast, nematode, and rat – the genomic expression corresponded to scant glucose conditions, pointing to a strongly selected role of biotin in the control of carbon metabolism (Ortega-Cuellar et al. 2010; Velazquez-Arellano et al. 2011). This concept is strengthened by the similarities between biotin and insulin across species. In genetically diabetic kk mice and rats, biotin improved glucose tolerance. Similar results were also observed in humans with type I or type II diabetes (Singer and Geohas 2006). A combination of biotin and chromium picolinate improved glycemic control in poorly controlled diabetics receiving standard antidiabetic therapy (Albarracin et al. 2008).
A significant proportion of radioactive biotin injected into chicks or rats localized to the nuclear fraction of cells (Dakshinamurti and Mistry 1963b). During progressive biotin deficiency, the nuclear biotin content was relatively conserved, whereas there was a marked depletion of cytoplasmic and mitochondrial biotin content. A biotin-binding protein from rat liver nuclei has been isolated (Dakshinamurti and Chauhan 1990). This, along with other evidence on the incorporation of amino acids into protein, indicated that biotin was involved in genetic regulation of protein synthesis (Dakshinamurti and Mistry 1963a). Later it was shown that all five histone classes extracted from human lymphocytes contained biotin (Stanley et al. 2001). HCS was distributed primarily in the nucleus of HeLa, Hep2, and fibroblasts with only a minor component in the cytoplasm (Narang et al. 2004; Gravel and Narang 2005). Thus, a dual role for HCS was established: its traditional role in the biotinylation of apocarboxylases and a novel role in the attachment of biotin to histones. HCS appears to interact with the methyl-CpG-binding domain protein 2 and also histone methyl transferase, thus creating epigenetic synergies between biotinylation and methylation events (Gravel and Narang 2005).
Biotin Induction of Pancreatitis-Associated Proteins
Recently, the effect of biotin repletion on the pancreas using a rat model of chronic biotin depletion was studied (Dakshinamurti et al. 2015). Animals fed with egg white-supplemented chow for 6 weeks were subsequently returned to a normal chow diet and given a single dose of biotin, or remained on the egg white diet for 1 week. Pancreatic gene expression was then analyzed by microarray.
Pancreatitis-associated protein 1 (PapI)/regenerating islet-derived 3 beta
Pancreatitis-associated protein 2 (PapII)/regenerating islet-derived 3 alpha
Osteopontin/secreted phosphoprotein 1
Such changes in Pap expression clearly reflect a potent induction; however, it pales compared to the changes observed in the biotin-repleted pancreas. This may simply reflect in vitro versus in vivo differences, however, as others noted that inflammation itself induces Pap gene expression (Closa et al. 2007). Given the microarray evidence of inflammation in the biotin-depleted pancreas, it is possible that restoration of biotin synergistically activates a Pap-mediated repair program in conjunction with the inflammation-driven mechanism.
Collectively, this data suggests that biotin deficiency results in pancreatic inflammation and fibrosis, possibly impairing its normal endocrine and exocrine functions. These results correlate with earlier reports of low biotin levels in diabetic patients and improved blood sugar control by biotin plus chromium picolinate. Biotin therefore appears to play an important role in normal pancreatic health and function. This data also suggests that much of the damage caused by biotin loss can be relatively rapidly reversed, concomitant with the activation of damage repair pathways, at least during the time period tested in this study (6 weeks). This is encouraging for individuals who may suffer acute or chronic biotin deficiency and furthermore suggests that biotin may be of benefit to diabetics in general, an avenue for further research.
Pharmacologic Effects: Biotin and Biotin-Binding Proteins
Animal studies have shown that biotin deficiency results in impaired glucose tolerance and decreased glucose utilization. Various clinical studies have indicated an inverse correlation between serum biotin levels and fasting blood glucose. The hypoglycemic effect of pharmacological doses of biotin has been reported in both type 1 and type 2 diabetic patients (Albarracin et al. 2008).
A common feature of metabolic syndrome is insulin resistance. It is also associated with hypertension. The pharmacological effect of biotin on hypertension was studied in the stroke-prone spontaneously hypertensive rat strain (Watanabe-Kamiyama et al. 2008). Biotin was beneficial: even a single dose decreased systolic blood pressure, an action that might be related to the effect of biotin as a soluble guanylate cyclase activator (Spence and Koudelka 1984; Singh and Dakshinamurti 1988). Biotin regulates the expression of several genes through activation of this cyclase (De La Vega and Stockert 2000).
ACC1 is a key lipogenic enzyme. In mammalian lipogenic tissues, this enzyme is regulated by dietary, nutritional, and hormonal conditions. Allosteric activation by citrate, feedback inhibition by long-chain fatty acids, reversible phosphorylation, and gene regulation of enzyme synthesis are the mechanisms regulating enzyme activity of ACC1. ACC1 is a cytosolic enzyme. In contrast, ACC2 is expressed mostly in the heart and skeletal muscle mitochondria where its product, malonyl-CoA, potently inhibits fatty acid oxidation. Long-chain fatty acids are converted by carnitine palmitoyltransferase into acyl carnitines for transport into the mitochondria, a process inhibited by ACC2-produced malonyl-CoA (Tong 2005; Tong and Harwood 2006). ACC2 knockout mice showed decreased malonyl-CoA content in skeletal and cardiac muscle, with increased fatty acid oxidation and reductions in total body fat, plasma free fatty acids and glucose, and tissue glycogen. These animals are protected from diet-induced diabetes and obesity (Oh et al. 2005). Because of its unique position in metabolism, the inhibition of ACC1 would inhibit de novo fatty acid production in lipogenic tissues and inhibition of ACC2 would inhibit fatty acid oxidation in the skeletal muscle and heart. This would have a favorable effect on cardiovascular risk factors associated with diabetes, insulin resistance, obesity, and the cluster of conditions referred to as the metabolic syndrome. A specific inhibitor of ACC2 would have therapeutic implications and is an area of intense current research.
One of the most devastating rice pathogens in the world is the fungus Magnaporthe oryzae, which depends on biotin for its growth (Skamnioti and Gurr 2009). Tamavidin1, an avidin-like biotin-binding protein from the mushroom Pleurotus cornucopiae, restricts the growth of M. oryzae. The possibility of reducing the availability of biotin to M. oryzae in rice by expression of the gene that encodes for tamavidin1 was investigated (Takakura et al. 2012). The positive results indicated a role for this strategy to engineer disease-resistant plants through the pathogen’s auxotrophy. Biotin-binding proteins expressed in transgenic plants are insecticidal to a wide variety of insects and, thus, useful in transgenic crop protection. Although their role in the protection of food crops such as rice has been established with some caveats, their use in protection of non-food crops such as fiber, forestry, and biofuel crops is boundless (Christeller et al. 2010).
Policies and Protocols
To our knowledge, policies on the provision of biotin in the diet, either for deficient individuals or as an adjunct to treatment of disease, are currently lacking. Biotin deficiency is not associated with short- or long-term threats to human life and furthermore is relatively rare, although occurrence is more likely in underdeveloped nations. A strong regulatory policy framework is thus unlikely to be needed, such as daily dietary requirements, particularly since such requirements remain poorly defined. Instead, it may be better to promote education of the benefit of biotin. Pregnant women may be biotin deficient and risk developmental delays in their children. In this case, government policies to promote monitoring of biotin status during pregnancy may be warranted. Government policies to promote education of pregnant women on the risks of biotin deficiency may also be useful. Likewise, those on long-term anticonvulsant therapy are likely to be biotin deficient, requiring supplementation.
Emerging evidence that biotin supplementation is beneficial in certain diseases such as diabetes suggests that it may be prudent to consider the development of policies at the point of care establishing the parameters of such supplementation. Further study in this area is strongly recommended, since biotin supplementation may provide a very cost-effective approach to helping manage diabetes and related conditions.
Dictionary of Terms
Avidin – A protein found at high concentration in egg white, as well as other sources, which binds to biotin with high affinity.
Biotin – A water-soluble vitamin that serves as a prosthetic group for multiple carboxylase enzymes. An alternate name for biotin is vitamin H.
Biotinidase – An enzyme that cleaves covalently bound biotin from biotin-containing molecules. Biotinidase is the only known biotin-binding protein in human plasma.
Carboxylase – An enzyme for transferring carboxyl moieties from a donor to an acceptor molecule.
Sodium-dependent multivitamin transporter (SMVT) – A saturable transporter responsible for biotin uptake at the nanomolar level in the gut. SMVT is also able to bind to and transport pantothenic acid and lipoic acid.
Biotin, a water-soluble vitamin, has a crucial role in the metabolism of carbohydrates and amino acids as well as in the synthesis and oxidative metabolism of lipids.
Biotin acts as a prosthetic group for a number of key metabolic carboxylases.
Humans and other animals obtain biotin from the diet, whereas many other organisms are capable of synthesizing biotin endogenously.
While dietary guidelines for biotin in humans have been published, the precise requirement for biotin in the diet remains poorly defined.
Biotin deficiency can cause alopecia, skin rash, lethargy, hypotonia, and, in biotin-deficient infants or children, developmental delays.
Diet-induced biotin deficiency is rare, but can occur in response to excessive consumption of egg whites due to the biotin-binding capacity of avidin, due to chronic consumption of biotin-poor diets, or following long-term consumption of a ketogenic diet.
Normal human pregnancy is associated with a biotin-deficient state; patients who have been on long-term anticonvulsant therapy are also biotin deficient.
In addition to its role as the prosthetic group of the carboxylases, biotin has significant non-prosthetic group functions affecting cell proliferation, differentiation, glucose metabolism, and the inflammatory state.
Pharmacological doses of biotin have profound ameliorative effects on conditions such as diabetes and inflammation.
Biotin repletion studies in biotin-deficient rats suggest that biotin is capable of inducing the expression of reparative factors such as the pancreatitis-associated proteins.
- De La Vega LA, Stockert RJ (2000) Regulation of the insulin and asialoglycoprotein receptors via cGMP-dependent protein kinase. Am J Physiol Cell Physiol 279:C2037–C2042Google Scholar
- Ortega-Cuellar D, Hernandez-Mendoza A, Moreno-Arriola E et al (2010) Biotin starvation with adequate glucose provision causes paradoxical changes in fuel metabolism gene expression similar in rat (Rattus norvegicus), nematode (Caenorhabditis elegans) and yeast (Saccharomyces cerevisiae). J Nutrigenet Nutrigenomics 3:18–30CrossRefPubMedGoogle Scholar
- Wiedmann S, Eudy JD, Zempleni J (2003) Biotin supplementation increases expression of genes encoding interferon-gamma, interleukin-1beta, and 3-methylcrotonyl-CoA carboxylase, and decreases expression of the gene encoding interleukin-4 in human peripheral blood mononuclear cells. J Nutr 133:716–9PubMedGoogle Scholar