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Endocrinology Vol. 140, No. 10 4595-4600
Copyright © 1999 by The Endocrine Society

ARTICLES

Biotin Regulation of Pancreatic Glucokinase and Insulin in Primary Cultured Rat Islets and in Biotin- Deficient Rats1

Guillermo Romero-Navarro, Gabriela Cabrera-Valladares, Michael S. German, Franz M. Matschinsky, Antonio Velazquez, Juehu Wang and Cristina Fernandez-Mejia

From the Nutritional Genetics Unit (G.R.N., G.C.V., A.V., C.F.M.) Biomedical Research Institute, National University of Mexico; Hormone Research Institute (M.S.G., J.W.) University of California San Francisco; and Diabetes Research Center (F.M.M.) University of Pennsylvania, Medical Center

Address all correspondence and requests for reprints to: Cristina Fernandez-Mejia, Unidad de Genetica de la Nutricion, Instituto de Investigaciones Biomedicas Universidad Nacional Autonoma de Mexico (UNAM)/Instituto Nacional de Pediatria (INP), Av. del Iman 1, 4th floor, Mexico City, C.P. 04530, Mexico. E-mail: crisfern{at}servidor.unam.mx


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Biotin has been reported to affect glucose homeostasis; however, its role on pancreatic islets of Langerhans has not been assessed. In this report, we demonstrate that physiologic concentrations of biotin stimulate glucokinase activity in rat islets in culture. Using the branched DNA (bDNA) assay, a sensitive signal amplification technique, we detected relative increases in glucokinase mRNA levels of 41.5 ± 13.% and 81.3 ± 19% at 12 and 24 h respectively in islets treated with [10-6 M] biotin. Because glucokinase activity controls insulin secretion, we also investigated the effect of biotin on insulin release. Treatment with [10-6 M] biotin for 24 h increased insulin secretion. We extended our studies by analyzing the effect of biotin deficiency on pancreatic islet glucokinase expression and activity, as well as insulin secretion. Our results show that 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 the deficient rat. These data show that biotin affects pancreatic islet glucokinase activity and expression and insulin secretion in cultured islets.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
BIOTIN IS A hydrosoluble vitamin that acts as cofactor of gluconeogenic and fatty acid synthesis; however, evidence is growing about the role of this vitamin in development, cell differentiation and gene expression (1). This effect is not totally surprising because other vitamins from the lipophilic family have been widely shown to affect these processes. Biotin has also been demonstrated to affect gene expression of the hepatic asialoglycoprotein receptor (2) and two critical enzymes of glucose metabolism: hepatic glucokinase (3) and hepatic phosphoenolpyruvate carboxykinase (PEPCK) (4). However, biotin did not affect the PEPCK renal isoform (4), suggesting that biotin effects are limited to hepatic metabolism.

Previous observations support the existence of a relationship between biotin status and glucose metabolism: a, Biotin deficiency has been linked to hyperglycemia and decreased utilization of glucose (5, 6). b, Biotin supplementation improves glucose and insulin tolerance in the diabetic KK mice (7). c, High-dose biotin lowers fasting blood glucose in diabetic patients (8, 9). Furthermore in diabetic rats, administration of the vitamin increases hepatic pyruvate kinase and phosphofructokinase activity but not phosphohexose isomerase, suggesting a role of biotin on glycolysis in the liver (10).

The pancreatic islets of Langerhans regulate blood glucose levels through the regulation of insulin secretion, but the effect of biotin on islet tissue has not been assessed. In this study, we investigated the effect of biotin on the regulation of two pancreatic islet genes that play an important role in glucose homeostasis: insulin and glucokinase. ß cell glucokinase regulates insulin secretion in response to changes in blood glucose levels in the ß cells (11, 12). Pancreatic glucokinase possesses a promoter and first exon that are different from those of the hepatic isoenzyme (13) and has been shown to be regulated differentially than the liver isoenzyme (14). In these studies, we report the effect of biotin on glucokinase activity and mRNA levels as well as on insulin gene expression and secretion, in two different models: pancreatic islets from normal rats and islets isolated from eight to nine weeks biotin deficient rats.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Adult islet culture
Pancreatic islets were isolated from overnight food-deprived Wistar male rats (200–250 g) using collagenase digestion and harvesting islets on a Ficoll gradient, as reported by Hiriart and Ramirez (15). Islets were hand picked in a stereoscopy microscope and were suspended in biotin-free DMEM medium containing 5.5 mM glucose, 400 U/ml penicillin, and 200 mg/liter streptomycin (Life Technologies, Inc., Grand Island, NY) and 10% FBS depleted of biotin by streptavidin-Sepharose (2) chromatography. Islets were distributed equally into 60-mm tissue culture dishes (Costar, Cambridge, MA) and were incubated at 37 C in a humidified atmosphere of 5% CO2. After 2–4 h of plating, cells were treated or not with biotin for different times as indicated in the text.

Glucokinase assay
Approximately 350–400 islets for each experiment were harvested and centrifuged at 1,200 rpm. Tissue pellets were lysed in 500 µl reporter lysis buffer (Promega Corp., Madison, WI), vortexed and cell membranes disrupted by three freeze-thaw cycles. Five hundred microliters of GK buffer consisting of 50 mM Tris (pH 7.6), 4 mM EDTA, 150 mM KCl, 4 mM Mg2SO4, and 2.5 mM dithiothreitol were added. The lysates were then centrifuged at 4 C for 1 h at 35,000 x g, in a Beckman Coulter, Inc. ultracentrifuge model Optima TLX. Supernatants were recovered, and enzymatic activity was assayed as described previously by Walker and Parry (16), using NAD (Sigma, St. Louis, MO) as coenzyme. Glucose-6-phosphate dehydrogenase from Leuconostoc mesenteroides (Sigma), was used as coupling enzyme. Correction for hexokinase activity was applied by substracting the activity measured at 0.5 mM glucose from the activity measured at 100 mM glucose. Protein concentrations were determined by the Bradford assay (17).

Messenger RNA analysis
Glucokinase mRNA was quantified using bDNA technology in a 96-microwell format as we previously described for quantification of insulin preRNA (18). This sensitive technique have shown to detect as few as 104 molecules of RNA (18). All components, including buffers and DNA reagents were obtained from Chiron Corp. (Emeryville, CA). RNA was extracted by either Trizol (Life Technologies, Inc.) or by cell lysis with 400 µl of extraction buffer (78 mM HEPES. pH 8.0/12.5 mM EDTA, pH 8.0/6.27 mM LiCl/1.6 lithium lauryl sulfate/proteinase K (1 mg/ml)/single stranded DNA (19 µg/ml)/7.8% formamide/0.05% sodium azide/0.05% Proclin 300]. RNA samples from approximately 300 islets were mixed with 200 µl extraction buffer, along with proteinase K and glucokinase capture and label probes, loaded in the microwell plate, sealed with an adhesive-backed mylar plate sealer (Microtiter Plate Sealer, Chiron Corp.), and incubated overnight at 63 C in a plate heater to capture the targeted nucleic acids to the oligonucleotide-modified microwell surface. After cooling at room temperature for 10 min., cells were washed twice with wash A (Chiron Corp.). Fifty microliters of bDNA amplifier solution containing the bDNA amplifier probe at 1 pmol/ml in amplifier diluent (Chiron Corp.) was added and hybridized at 53 C, for 30 min. After cooling and washing as described above, 50 µl of a mixture containing alkaline phosphatase-conjuged label probes (2 pmol/ml) in label diluent (Chiron Corp.) was added and hybridized at 53 C, for 15 min. The plate was cooled and washed twice in buffer A as above and then washed three times with wash solution B (Chiron Corp.). Finally, 50 µl of chemiluminescent sustrate (Lumiphos 530), an enzyme-triggerable dioxetane substrate for alkaline phosphatase, were added and the plate was incubated at 37 C for 25 min. Light emission was measured in a luminometer at 37 C. Each sample was assayed in triplicate. Each sample was standardized to actin mRNA.

Insulin secretion
Islets were isolated and cultured as described above. After 24 h of treatment without or with biotin [10-6 M], cells were washed twice with secretion buffer containing 20 mM HEPES, 115 mM NaCl, 5 mM NaHCO3, 4.7 mM KCL, 2.6 mM CaCl2, 1.2 mM KH2PO4, and 1.2 mM MgSO4 (pH 7.4). Islets were then incubated for 1 h in secretion buffer containing D-glucose as indicated in the text and figure legends. Insulin concentration was analyzed by RIA (ICN Biomedical, Costa Mesa, CA).

Biotin-deficient rats
Weaned male Wistar rats age 21 days were provided free access to biotin-deficient diet or to normal control diet. The biotin-deficient diet consisted of pellets containing 30% egg white by weight (ICN Nutritional Biochemicals, Nutley, NJ.) The normal control diet consisted of the same pellets that were used in the deficient diet but supplemented with d-biotin (5 mg/kg of pellets). Rats deprived of biotin for 8 weeks showed signs of deficiency, including alopecia, scaly dermatitis, poor weight gain, and spectacle eye. The activities of the biotin-dependent enzymes, propionyl-CoA carboxylase and pyruvate carboxylase in liver homogenates of biotin-deficient rats were less than 50% of that in liver homogenates of normal rats.

Statistics
Data are presented as mean ± SE. Individual comparisons were evaluated by Student’s paired two tailed t test. Multiple comparisons were evaluated by one-way ANOVA. The significance level chosen was P < 0.05.


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Biotin effect on pancreatic glucokinase activity
We investigated the effect of different concentrations of biotin on glucokinase activity in islets isolated from adult normal rats. As shown in Fig. 1Go, 48 h incubation with biotin concentrations as low as 10-8 M increased significantly (P < 0.05) glucokinase activity, biotin concentrations of 10-7 M produced twice the activity observed on the control, a further increase was achieved at a concentrations of 10-6 M. In the same experimental model we also assessed the time course of biotin effect. As can be seen in Fig. 2Go, vitamin concentrations of 10-6 M increased significantly (P < 0.005) glucokinase by 68.9 ± 16% and 142.6 ± 17% at 24 and 48 h, respectively; no effect on glucokinase activity was observed at 12 h of treatment. The microscopic analysis found no morphological differences between the control and biotin treated islet cultures.



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  		Figure 1. Effect of different concentrations of biotin on glucokinase activity in primary cultures of islets. Islets were isolated from normal rats by collagenase digestion as described in Materials and Methods. Islets were cultured for 48 h in the absence or in the presence of the designated concentrations of biotin. Each bar represents the mean percentages ± SE of glucokinase activity of four to six independent experiments. (Control glucokinase activity = 20.5 ± 3 pmol/h·islet). Significance was assessed by one-way ANOVA (**) P <= 0.005.

 


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  		Figure 2. Time course effect of biotin on glucokinase activity in primary cultures of islets. Islets from normal rats were isolated by collagenase digestion as described in Materials and Methods and cultured for the indicated periods of time in either the absence or presence of [10-6 M] of biotin. Each bar represents the mean percentages ± SE of glucokinase activity of seven independent experiments. (Control glucokinase activity = 22.5 ± 3 pmol/h·islet). Significance was assessed by one-way ANOVA (**) P <= 0.005.

 
Biotin effect on glucokinase mRNA levels
We determined if the stimulatory effect of biotin on glucokinase activity was related to an increase on glucokinase gene expression. Because glucokinase mRNA levels are low, we adapted the branched DNA (bDNA) assay, a sensitive signal amplification technique, to measure glucokinase mRNA levels. Biotin concentrations of 10-6 M for 12 h produced a relative increase of 41.5 ± 13% in glucokinase RNA levels, this stimulatory effect was increased to 81.3 ± 19% at 24 h and was sustained up to 48 h incubation with the vitamin (Fig. 3Go).



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  		Figure 3. Effect of biotin on glucokinase mRNA levels. Glucokinase mRNA was quantified using bDNA technology. Islets isolated from normal rats were cultured for the indicated periods of time in either the absence or presence of [10-6 M] biotin. Each sample was standardized to actin. Data are expressed as relative to that measured in islets without treatment. Each value represents the mean ± SE of four to eight independent experiments. Significance was assessed by one-way ANOVA (**) P <= 0.005.

 
Insulin secretion and mRNA levels
Because glucokinase activity is a determinant of insulin secretion (11, 12), we analyzed the effect of biotin on insulin release. As can be seen in Fig. 4Go, 24 h of treatment with 10-6 M biotin increased insulin secretion by 43.6 ± 5% and by 53.7 ± 6.8% at 5.5 and 16 mM glucose respectively. We also determined the effect of biotin on insulin mRNA levels by the bDNA method. Treatment with 10-6 M biotin for 24 h increased insulin message by 42.7± 17% n = 5.1 (P < 0.05) n = 4. A similar increase was observed after 24 h of vitamin treatment.



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  		Figure 4. Effect of biotin on insulin secretion. Islets from normal rats were cultured in the absence or presence of [10-6 M] biotin. After 24 h incubation, islets were washed and then incubated in 2 ml secretion buffer containing 5.5 or 16 mM glucose. After 1 h incubation, medium was collected. The insulin concentration was analyzed by RIA. Clear bars, Untreated islets; shaded bars, biotin-treated islets. Data are expressed as mean percentages ± SE of insulin concentration (absolute values: control adult 5.5 mM glucose = 16.4 ± 2 µU/islet·h; n = 4 experiments. (Insulin secretion ratios 16/5.5 mM glucose: control = 2.33 ± 0.4, biotin = 2.52 ± 0.4. Significance was assessed by Student’s paired two-tailed t test. *, P <= 0.05; **, P <= 0.005.

 
Effect of biotin deficiency on glucokinase
We also investigated the effect of biotin deficiency on glucokinase activity and mRNA levels. Islets isolated from 8- to 9-week biotin-deficient rats showed about 50% of the glucokinase activity observed on control rats (Fig. 5AGo). Measurements of glucokinase RNA confirmed that mRNA levels of the biotin deficient rats were decreased to about half the values observed in the control rats (Fig. 5BGo).



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  		Figure 5. Effect of biotin deficiency on glucokinase activity and mRNA levels. Islets from eight to nine weeks biotin deficient rats were isolated by collagenase digestion. Glucokinase mRNA or activity was determined as described in Materials and Methods. A, Glucokinase activity, each bar represents the mean percentages ± SE of glucokinase activity of four independent experiments. (Control glucokinase activity = 37.3 ± 5 pmol/h·islet). B, Glucokinase mRNA levels, each bar represents the mean percentages ± SE of four to five independent experiments. (Control ratio glucokinase/actin mRNA = 0.66 ± 0.9 arbitrary light units). Significance was assessed by Student’s paired two-tailed t test. *, P <= 0.05, **, P <= 0.005.

 
Effect of biotin deficiency on insulin secretion
Islets isolated from 8- to 9-week biotin-deficient rats showed decreased insulin secretion. As can be seen in (Fig. 6Go), the insulin secretion ratio between 5.5 and 16 mM glucose was decreased by half in the deficient rat.



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  		Figure 6. Effect of biotin deficiency on insulin secretion. Islets from eight to nine weeks biotin deficient rats were isolated by collagenase digestion. Fresh isolated islets were incubated in 2 ml secretion buffer containing 5.5 or 16 mM glucose. After 1 h incubation, medium was collected. The insulin concentration was analyzed by RIA. Data are expressed as mean percentages ± SE of insulin concentration (absolute values: control adult 5.5 mM glucose = 36.6 ± 6 µU/islet/h; deficient 28.5 ± 2.2 n = 3 experiments). Significance was assessed by Student’s paired two-tailed t test. *, P <= 0.05

 

   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
In the present study, we demonstrate that biotin can affect the pancreatic islet phenotype by increasing glucokinase activity as well as insulin secretion and mRNA levels. Our studies found that biotin augmented glucokinase activity at concentrations as low as 10 nM. Doses of biotin that correspond to its levels in plasma (100 to 300 nM), (9, 19) increased twice the enzyme activity, suggesting a physiological effect of the vitamin on pancreatic glucokinase. These results disagree with a previous report by Borboni et al. (20) showing the inability of physiological concentrations of biotin to increase glucokinase activity in the RIN 1046–38 cell line. In their work, the authors observed modest increases of 26–30% on glucokinase activity at pharmacological doses of biotin of 1,000–10,000 nM. These modest increases strongly contrast to the 142.6% observed in our study in the isolated islets. This difference is one of the multiple distinct features found between the function of tumoral insulin-produced cell lines and normal pancreatic islets (21, 22, 23) and indicate the importance of using cultured islets to ensure the applicability of the results to normal physiology. Although we did not find differences on the islet morphology between the control and the biotin treated islets, we cannot rule out the possibility that in some way biotin enhances viability of the islet and therefore maintains glucokinase synthesis and insulin release during culture. The effects of biotin found in our studies support several observations indicating that physiological levels of biotin are important in the maintenance of normal glucose metabolism (5, 6, 9).

Biotin has been shown to regulate several hepatic genes (2, 3, 4) including PEPCK but does not affect the PEPCK renal isoform (4). In this report, we demonstrate that biotin can regulate nonhepatic genes. Pancreatic and hepatic glucokinase were found to be regulated in a similar positive manner by biotin; however, several differences exist: In cultured hepatocytes and the rats in vivo, hepatic glucokinase message and activity are increased by biotin as rapidly as 2 h after treatment (24, 3) however concentrations of 10-6 M biotin are required to elicit its action (24). In contrast, in the pancreatic islets the response to biotin is slow, requiring 12 h to observe mRNA increases, but the effect of biotin was produced at vitamin concentrations of 10-8 M.

The normal adult pancreatic ß cells regulate blood glucose concentrations through insulin secretion. In these cells, glucokinase functions as the glucose sensor, by regulating the rate of glycolysis and the production of signaling molecules required for insulin secretion. The use of cultured islets in our studies allows us to determine if biotin affects insulin secretion at physiological levels of glucose. Our results show that biotin increases insulin secretion at normoglycemic and hyperglycemic conditions. In the pancreatic cell line RIN 1046–38, Borboni et al. (20) found that biotin did not affect insulin secretion. This important discrepancy may be explained by the fact that this cell line secretes insulin at subphysiological glucose concentrations, concentrations at which glucokinase activity is not the key factor controlling insulin secretion (21). Our results modify the previous concept derived from Borboni results suggesting the physiological unimportance of biotin on islets and, again, emphasize the importance of using normal islets to study pancreatic physiology.

Changes of glucokinase activity produced by gene mutations or by transgenesis cause concomitant changes of insulin secretion (25, 26, 27). This study constitutes the first evidence that glucokinase gene expression can be affected by nutritional manipulations, and that these changes affect insulin secretion. It might be possible, however, that biotin influences insulin release as part of the prosthetic group of acetyl-CoA carboxylase. This enzyme catalyzes the formation of malonyl-CoA, a metabolite that has been proposed to play an important role in the metabolic signal transduction for insulin secretion (28, 29). Nevertheless, because the doses of biotin used in our investigation were two orders of magnitude higher than the Km (4.7 - 8.2 x 10-9) reported for the synthesis of active acetyl-CoA carboxylase (30, 31) it seems improbable that, in our study, increases in the production of malonyl-CoA would account for the increased insulin secretion produced by biotin.

Insulin mRNA levels are regulated in response to different metabolic factors (32). In the present study, we demonstrated that biotin produced a modest but statistically significant increase in insulin mRNA levels. It has been reported that when the rate in glucose phosphorylation is increased, glycolysis is accelerated and the insulin promoter is activated (33); so, the augmentation of glucose phosphorylation produced by biotin induction of glucokinase activity might account for the increases observed in insulin mRNA levels. Future studies in our laboratory will investigate the mechanism by which biotin increases insulin mRNA levels.

We extended our studies by analyzing the effect of biotin deficiency on glucokinase expression and activity, as well as insulin secretion. Eight to nine weeks of biotin deficiency decreased by half the pancreatic islet glucokinase activity and mRNA levels. Our data are similar to those observed with hepatic glucokinase (34), where biotin deficiency reduced glucokinase activity by about 45%.

Insulin secretion in islets isolated from biotin deficient rats was shown to be impaired. Supporting our observations, Furokawa et al. (35) found that plasma insulin levels in response to an oral glucose load were lower in the biotin deficient state of osteogenic disorder Shinogi rats. A decrease on glucokinase activity may account for the altered insulin secretion in these rats. However, we cannot rule out the possibility that other mechanisms related to the vitamin deficiency, such as decreased activities of biotin dependent enzymes, in particular acetyl-CoA carboxylase, may be involved. Further studies will be required to determine the precise mechanism involved in the impaired secretion observed in biotin deficiency.

Defects in biotin metabolism could contribute to diabetes. Studies by Maebashi et al. (9) found that in 43 noninsulin-dependent diabetes mellitus (NIDDM) patients, the serum biotin concentration was significantly lower than in control subjects (56.7 ± 4.8 vs. 96.8 ± 3.1 nmol/liter, respectively; P < 0.01). Furthermore an inverse correlation between serum biotin concentration and fasting blood glucose level (r =-0.74) has been observed (9). Oral glucose tolerance was shown to be impaired in biotin deficient rats (36). On the other hand, the diabetic state appears to be ameliorated by biotin treatment. In the genetically diabetic KK mice, biotin treatment lowered postprandial glucose levels and improved tolerance to glucose (7). Reduced hyperglycemia was observed in a group of insulin-dependent diabetes mellitus (IDDM) receiving 16 mg/day biotin for 1 week (8). This improvement has been also observed in NIDDM patients, which decreased about 45% hyperglycemic fasting blood glucose levels after 1 month treatment with oral doses of 9 mg/day biotin (9). Several mechanisms may account for the glycemia improvement produced by the vitamin: biotin as cofactor of lipogenic enzymes may increase fatty acid synthesis and consequently glucose utilization. Its stimulatory effect on hepatic glucokinase may increase glycogen synthesis as well as oxidative phosphorylation (36). Finally, as our results suggest, the stimulatory effect produced by the vitamin on pancreatic glucokinase and on glucose-induced insulin secretion, can also account for the amelioration of glycemia.


   Acknowledgments
 
The authors are grateful to Dr. Raul Jairo Hernandez Valencia for his help in the animal care. We thank Celeste Arranz and Sumiko Morimoto for their help in the insulin RIA assay.


   Footnotes
 
1 This work was supported by Grants Direccion General de Asuntos del Personel Academico (DGAPA) IN210894, Universidad California Mexus (to C.F.-M. and M.S.G.), and NIH-RO1-DK-48281 (to M.S.G.). Back

Received April 26, 1999.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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