Title
Effect of biotin on glucokinase activity, mRNA expression and insulin release in cultured beta-cells.
Author
Borboni P; Magnaterra R; Rabini RA; Staffolani R; Porzio O; Sesti G; Fusco A; Mazzanti L; Lauro R; Marlier LN
Source
Acta Diabetol, 1996 Jul, 33:2, 154-8
Abstract
Biotin is known to influence hepatic glucokinase (GK) expression both at a transcriptional and at a translational level. The aim of the present paper was to investigate the effect of biotin on pancreatic GK. For this purpose, RIN1046-38 cells were cultured in the presence of different biotin concentrations for different times; there-after, GK mRNA expression, GK activity and insulin release were studied. Results demonstrated that biotin has a biphasic effect on GK mRNA expression, being stimulatory after short-term treatment and inhibitory after longterm treatment. GK activity was increased after long-term treatment. Insulin release was not affected by biotin treatment. These data suggest that biotin may influence glucose metabolism also by acting directly at the level of beta-cells.

Title
Structure, function and regulation of pyruvate carboxylase.
Author
Jitrapakdee S; Wallace JC
Source
Biochem J, 1999 May, 340 ( Pt 1):, 1-16
Abstract
Pyruvate carboxylase (PC; EC 6.4.1.1), a member of the biotin-dependent enzyme family, catalyses the ATP-dependent carboxylation of pyruvate to oxaloacetate. PC has been found in a wide variety of prokaryotes and eukaryotes. In mammals, PC plays a crucial role in gluconeogenesis and lipogenesis, in the biosynthesis of neurotransmitter substances, and in glucose-induced insulin secretion by pancreatic islets. The reaction catalysed by PC and the physical properties of the enzyme have been studied extensively. Although no high-resolution three-dimensional structure has yet been determined by X-ray crystallography, structural studies of PC have been conducted by electron microscopy, by limited proteolysis, and by cloning and sequencing of genes and cDNA encoding the enzyme. Most well characterized forms of active PC consist of four identical subunits arranged in a tetrahedron-like structure. Each subunit contains three functional domains: the biotin carboxylation domain, the transcarboxylation domain and the biotin carboxyl carrier domain. Different physiological conditions, including diabetes, hyperthyroidism, genetic obesity and postnatal development, increase the level of PC expression through transcriptional and translational mechanisms, whereas insulin inhibits PC expression. Glucocorticoids, glucagon and catecholamines cause an increase in PC activity or in the rate of pyruvate carboxylation in the short term. Molecular defects of PC in humans have recently been associated with four point mutations within the structural region of the PC gene, namely Val145-->Ala, Arg451-->Cys, Ala610-->Thr and Met743-->Thr.

Title
A high biotin diet improves the impaired glucose tolerance of long-term spontaneously hyperglycemic rats with non-insulin-dependent diabetes mellitus.
Author
Zhang H; Osada K; Maebashi M; Ito M; Komai M; Furukawa Y
Source
J Nutr Sci Vitaminol (Tokyo), 1996 Dec, 42:6, 517-26
Abstract
The Otsuka Long-Evans Tokushima Fatty (OLETF) rat, serving as a spontaneously diabetic model with non-insulin-dependent diabetes mellitus (NIDDM), exhibits impaired glucose tolerance (IGT) at about 16 weeks of age. In this study, we investigated whether or not biotin, a water-soluble vitamin, improved the IGT of OLETF rats. To this end, we administered diets containing one of three levels of biotin, a high-biotin diet (BH), a normal-biotin diet (BN) and a basal-biotin diet (BB), to OLETF rats up to 24 weeks of age. An oral glucose tolerance test (OGTT) was performed four times between 13 and 22 weeks of age. The administration of a BH corrected the IGT of OLETF rats. Upon further investigation, we found that insulin secretion in the OLETF-BH rats was decreased to a significant extent, signaling that the hyperinsulinemia typical to the OLETF-BH rats had clearly improved. Body weights were significantly lower in the OLETF-BH group than in the other OLETF groups, even though the OLETF-BH rats showed a significantly higher average daily food intake. The body weight gain of the OLETF-BH rats followed the same tendency as the control-LETO (Long Evans Tokushima Otsuka) rats (LETO-BB and LETO-BN). These results demonstrate that a high-level biotin diet can improve the glucose handicap in NIDDM rats.

Title
Oral glucose tolerance test after high-dose i.v. biotin administration in normoglucemic hemodialysis patients.
Author
Koutsikos D; Fourtounas C; Kapetanaki A; Agroyannis B; Tzanatos H; Rammos G; Kopelias I; Bosiolis B; Bovoleti O; Darema M; Sallum G
Source
Ren Fail, 1996 Jan, 18:1, 131-7
Abstract
Abnormal glucose metabolism in uremia may result from a complex interplay between decreased insulin secretion and insulin resistance. Recent studies report beneficial effect of biotin administration in glucose metabolism in diabetic animals and in a small number of patients with diabetes mellitus. The aim of the present study was to evaluate the response of oral glucose tolerance test (OGTT) to the i.v. administration of large doses of biotin in hemodialysis patients. Eleven hemodialysis patients aged 56.90 +/- 11.20 (32-76) years on regular hemodialysis thrice a week for 2.72 +/- 1.79 (1-7) years were studied. Fasting venous plasma glucose, glucosylated hemoglobin (%GH), and plasma glucose concentration 2 h after the administration of a 75-g glucose load were measured before, and 2 weeks and 2 months after administration of 50 mg of biotin i.v. postdialysis, and after a 2-month washout period. During the study, dialysis schedule and patients' medication, diet, and dry weight were kept unchanged. OGTT was abnormal in 4 patients before biotin administration and became normal in 3 patients (75%). Our results offer support to the findings of other studies about the beneficial effect of biotin in experimental or clinical diabetes mellitus, and argue for the involvement of biotin in glucose metabolism.

Title
Effects of dietary biotin on enhanced sucrose intake and enhanced gustatory nerve responses to sucrose seen in diabetic OLETF rat.
Author
Tsunoda K; Osada K; Komai M; Zhang H; Morimoto K; Suzuki H; Furukawa Y
Source
J Nutr Sci Vitaminol (Tokyo), 1998 Apr, 44:2, 207-16
Abstract
We used the sucrose preference test and taste nerve recording to investigate the effect of dietary biotin on the abnormal sucrose taste sensitivity and preferences seen during the course of diabetes mellitus. For this, we used Otsuka Long-Evans Tokushima fatty (OLETF) rats. The chorda tympani nerve (CT nerve) response to sucrose (> 1 M) was of greater relative magnitude in OLETF rats than in non-diabetic control (Long-Evans Tokushima Lean, LETO) rats, but the responses to other basic taste stimuli (such as HCl, quinine-HCl and L-glutamic acid) did not differ between the two groups. In behavioral experiments using a two-bottle preference test, solution intake for sucrose (> 50 mM) was higher in OLETF rats than in LETO rats. The neural responses to sucrose (1.5-2 M) in OLETF rats were lower when given a biotin-high diet (BH-OLETF) than when given a biotin-basal diet (BB-OLETF), but this was not true of the other basic tastes. However, there were no significant differences between BH-OLETF and BB-OLETF rats in terms of sucrose solution intake. These findings suggest that the enhanced sugar sensitivity observed in OLETF rats is probably the result of a genetic difference between OLETF and LETO rats, though the discrepancy can be modified by the dietary biotin level.

Title
A high biotin diet improves the impaired glucose tolerance of long-term spontaneously hyperglycemic rats with non-insulin-dependent diabetes mellitus.
Author
Zhang H; Osada K; Maebashi M; Ito M; Komai M; Furukawa Y
Source
J Nutr Sci Vitaminol (Tokyo), 1996 Dec, 42:6, 517-26
Abstract
The Otsuka Long-Evans Tokushima Fatty (OLETF) rat, serving as a spontaneously diabetic model with non-insulin-dependent diabetes mellitus (NIDDM), exhibits impaired glucose tolerance (IGT) at about 16 weeks of age. In this study, we investigated whether or not biotin, a water-soluble vitamin, improved the IGT of OLETF rats. To this end, we administered diets containing one of three levels of biotin, a high-biotin diet (BH), a normal-biotin diet (BN) and a basal-biotin diet (BB), to OLETF rats up to 24 weeks of age. An oral glucose tolerance test (OGTT) was performed four times between 13 and 22 weeks of age. The administration of a BH corrected the IGT of OLETF rats. Upon further investigation, we found that insulin secretion in the OLETF-BH rats was decreased to a significant extent, signaling that the hyperinsulinemia typical to the OLETF-BH rats had clearly improved. Body weights were significantly lower in the OLETF-BH group than in the other OLETF groups, even though the OLETF-BH rats showed a significantly higher average daily food intake. The body weight gain of the OLETF-BH rats followed the same tendency as the control-LETO (Long Evans Tokushima Otsuka) rats (LETO-BB and LETO-BN). These results demonstrate that a high-level biotin diet can improve the glucose handicap in NIDDM rats.

Title
Oral glucose tolerance test after high-dose i.v. biotin administration in normoglucemic hemodialysis patients.
Author
Koutsikos D; Fourtounas C; Kapetanaki A; Agroyannis B; Tzanatos H; Rammos G; Kopelias I; Bosiolis B; Bovoleti O; Darema M; Sallum G
Source
Ren Fail, 1996 Jan, 18:1, 131-7
Abstract
Abnormal glucose metabolism in uremia may result from a complex interplay between decreased insulin secretion and insulin resistance. Recent studies report beneficial effect of biotin administration in glucose metabolism in diabetic animals and in a small number of patients with diabetes mellitus. The aim of the present study was to evaluate the response of oral glucose tolerance test (OGTT) to the i.v. administration of large doses of biotin in hemodialysis patients. Eleven hemodialysis patients aged 56.90 +/- 11.20 (32-76) years on regular hemodialysis thrice a week for 2.72 +/- 1.79 (1-7) years were studied. Fasting venous plasma glucose, glucosylated hemoglobin (%GH), and plasma glucose concentration 2 h after the administration of a 75-g glucose load were measured before, and 2 weeks and 2 months after administration of 50 mg of biotin i.v. postdialysis, and after a 2-month washout period. During the study, dialysis schedule and patients' medication, diet, and dry weight were kept unchanged. OGTT was abnormal in 4 patients before biotin administration and became normal in 3 patients (75%). Our results offer support to the findings of other studies about the beneficial effect of biotin in experimental or clinical diabetes mellitus, and argue for the involvement of biotin in glucose metabolism.

Title
Cerebral metabolic change after treatment in biotinidase deficiency.
Author
Lott IT; Lottenberg S; Nyhan WL; Buchsbaum MJ
Source
J Inherit Metab Dis, 1993, 16:2, 399-407
Abstract
A 13.5-year-old boy with biotinidase deficiency was studied 8 days before and 5 months after biotin treatment by positron emission tomography (PET) and computerized electroencephalographic topography (CET). With biotin treatment there was a marked improvement in the presenting symptom of loss of visual acuity and a more modest recovery in spastic quadraparesis. By PET scanning, the relative metabolic rate for glucose was more than 2 standard deviations lower in the temporal and occipital cortices than in adult or age-matched controls. With biotin treatment, these values rose to normal limits for both control groups. By CET, normalized EEG equivalent to the relative glucose metabolic rate showed asymmetric slowing in the left temporal and frontal regions before treatment, whereas none of the 32 leads exceeded normal limits of delta, theta, alpha or beta after treatment. These results suggest a strong correlation between clinical, metabolic and electrical measures of brain function as related to biotin treatment in biotinidase deficiency.

Title
Influence of glucose on pyruvate carboxylase expression in pancreatic islets.
Author
MacDonald MJ
Source
Arch Biochem Biophys, 1995 May, 319:1, 128-32
Abstract
Pancreatic islets were cultured for 1 day in the presence of 1 to 20 mM glucose and islet proteins were separated on polyacrylamide gels and transferred to nitrocellulose. Pyruvate carboxylase and an unidentified biotin-containing protein were visualized with [125I]streptavidin followed by autoradiography. The amount of pyruvate carboxylase was proportional to the concentration of glucose. Estimates of the amount of the enzyme in islets were made by comparing the density of the islet pyruvate carboxylase band with a standard curve of various amounts of authentic pyruvate carboxylase. This indicated that the enzyme comprised 0.4% of total islet protein. Net synthesis of the enzyme was increased by cAMP and methyl succinate. A nuclear run-on assay showed that glucose caused increases in pyruvate carboxylase and pyruvate dehydrogenase E1 alpha subunit transcripts and decreases in branched chain ketoacid dehydrogenase E1 alpha transcripts in rat insulinoma (RINm5F) cells. Pancreatic islets cultured in the presence of 1 mM glucose for 1 day cannot respond to glucose with insulin release. Previous studies demonstrated that carbon flux into the citric acid cycle intermediates via both carboxylation and decarboxylation is decreased in glucose-incapacitated islets (M. J. MacDonald, 1993, Arch. Biochem. Biophys. 300, 205-214), 1993). The current results support the idea that carboxylation of glucose-derived pyruvate, as well as decarboxylation of pyruvate, is important for glucose-induced insulin secretion.

Title
Biochemical consequences of biotin deficiency in osteogenic disorder shionogi rats.
Author
Furukawa Y; Numazawa T; Fukazawa H; Ikai M; Ohinata K; Maebashi M; Kim DH; Ito M; Komai M; Kimura S
Source
Int J Vitam Nutr Res, 1993, 63:2, 129-34
Abstract
The biological consequences of biotin deficiency in rats were investigated using osteogenic disorder Shionogi rats which have a hereditary defect in ascorbic acid synthesizing ability. Decrease of liver ascorbic acid content and fasting plasma glucose and an increase of plasma non-esterified fatty acid (NEFA) appeared in biotin deficient rats fed a diet containing 200 mg ascorbic acid per 100 g diet, compared with the pair fed control. On the other hand, in the case of rats fed a diet containing 500 mg ascorbic acid, although the clinical features of biotin deficiency developed, the ascorbic acid contents of liver and adrenal gland increased in comparison with those of AsA 200 mg groups, and the alterations of plasma levels of glucose and NEFA were improved partially in glucose and greatly in NEFA, respectively. This suggests that ascorbic acid may be consumed in the improvement of the metabolic impairments induced by biotin deficiency.