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Coenzyme Q10 and insulin secretion in vitro
Diabetes Research and Clinical
Practice 33 (1996) 135-136
Letter to the Editor
Coenzyme Q 10 and insulin secretion in vitro I. Conget”,“,
J.M. Manzanares”,
A. Barrientosb,
F. Cardellachb, R. Gomis”
“Endocrinology Unit, Hospital Clinic, Villarroel 170, 08036 Barcelona, Spain bInternal Medicine Unit, Hospital Clinic, Villarroel 170, 08036 Barcelona, Spain
Dear Sir,Defects in some mitochondrial enzymes have been related to the appearance of diabetes in animal models and humans [l-3]. In addition to this, a diminution of mtDNA content has been related to long-lasting impairment of insulin secretion [4,5], and particular attention has been focused in maternally-inherited diabetes and deafness syndrome, a pathological condition related to mutations of mtDNA [6,7]. In this context, some authors have described the effect of coenzyme QIO treatment in a patient with maternally inherited ‘diabetes and deafness syndrome’ [8] and they did not find any improvement on insulin secretion after 6 months with this therapy while finding a partial restoration on mitochondrial muscle function. From this point of view, we tested the effect of different concentrations of coenzyme QlO on Dcell function in vitro. To assess insulin secretion, batches of eight rat islets were incubated for 90 min at 37°C in 1.0 ml bicarbonated-buffered medium containing D-glucose 11.1 mM [9] and increasing concentrations of coenzyme QlO (Coenzyme Q,“, Sigma, St. Louis, MO, USA) of 0, 2, 4 * Corresponding 2215454
author. Tel.: + 34 3 2275400; fax: + 34 3
and 8 PM. In our experimental conditions and at all tested concentrations, coenzyme QlO failed to produce any significative modification of insulin release, although the concentrations used in our study were higher than those achieved in plasma of patients with mitochondrial myopathy treated with the coenzyme [lO,ll]. Nevertheless, when the higher concentration of the coenzyme was used, there was 25% increment on insulin release (307 f 32 vs 385 Ifr 30 pU.islet-l.90 min’, 0 and 8 PM coenzyme QlO respectively, n = 14 in both experimental conditions, mean f SEM). It should be mentioned that in the interpretation of our results, we have to consider not only the possibility that a cells are less sensitive than other tissues to coenzyme QlO but also the presence of interspecies discrepancies. Moreover, one can note that this lack of efficacy on normal D cells does not preclude the possibility of an effect on 13cell with genetic impairment of mitochondrial function as in maternally inherited ‘diabetes and deafness syndrome’. It should be also underlined that the possible effect of coenzyme QlO upon insulin release could also depend obviously on a number of other factors related to experimental conditions, such as D-glucose concentration, use of other substrates than D-glucose, length of exposure to the coenzyme, etc.
0168-8227/96/$15.00 0 1996 Elsevier Science Ireland Ltd. All rights reserved PII SOl68-8227(96)01278-S
136
I. Conget et al. /Diabetes
Research and Clinical Practice 33 (1996) 135-136
In the future, new approaches to the study of mitochondrial respiration in islet cells [ 121 could allow us to further explore the effect of such substances on mitochondrial activity in either normal or pathological conditions.
References [l] Ostenson, C.G., Abdel-Halim, S.M., Rasschaert, J., Malaisse-Lagae, F., Meuris, S., Sener, A., Efendic, S. and Malaisse, W.J. (1993) Deficient activity of FAD-linked glycerophosphate dehydrogenase in islets of GK rats. Diabetologia 36, 722-726. [2] Sener, A., Herberg, L. and Malaisse, W.J. (1993) FADlinked glycerophosphate dehydrogenase deficiency in pancreatic islets of mice with hereditary diabetes. FEBS Letts 316, 224221. [3] Fernandez-Alvarez, J., Conget, I., Rasschaert, J., Sener, A., Gomis, R. and Malaisse, W.J. (1994) Enzymatic, metabolic and secretory patterns in human islets of type 2 (non-insulin-dependent) diabetic patients. Diabetologia 37, 177-181. [4] Welsh, N., Palbo, S. and Welsh, M. (1991) Decreased mitochondrial gene expression in isolated islets of rats injected neonatally with streptozotocin. Diabetologia 34, 6266631. [5] Serradas, P., Giroix, M-H., Saulnier, C., Gangnerau, M.N., Borg, L.A.H., Welsh, M., Portha, B. and Welsh, N. (1995) Mitochondrial deoxyribonucleic acid content is specifically decreased in adult, but not fetal, pancreatic islets of the Goto-Kakizaki rat, a genetic model of non-insulin-dependent diabetes. Endocrinology 136, 562335631.
WI Alcolado,
J.C., Majid, A., Brockington, M., Sweeney, M.G., Morgan, R., Rees, A., Harding, A.E. and Barnett, A.H. (1994) Mitochondrial gene defects in patients with NIDDM. Diabetologia 37, 3722376. [71 Ballinger, S.W., Shoffner, J.M., Hedaya, E.V., Trounce, I., Polak, M.A. and Koontz, D.A. (1992) Maternally transmitted diabetes and deafness associated with a 10.4 kb mitochondrial DNA deletion. Nature Genetics 1, 11~ 15 181Silvestre-Aillaud, P., BenDahan, D., Paquis-Fluckinger, V., Pouget, J., Pelissier, J.F., Desnuelle, C., Cozzone, P.J. and Vialettes, B. (1995) Could coenzyme QlO and L-carnitine be a treatment for diabetes secondary to 3243 mutation of mtDNA? Diabetologia 35, 1485- 1486. J.I., Sarri, Y., Gonzalez-Clemente, J.M., [91 Conget, Casamitjana, R., Vives, M. and Gomis, R. (1994) Deleterious effect of Dithizone-DMSO staining on insulin secretion in rat and human pancreatic islets. Pancreas 9, 1577160. VOI Bresolin, N., Bet, L., Moggio, M., Comi, G., Nador, F., Ferrante, C., Carenzi, A. and Scarlato, G. (1988) Clinical and biochemical correlations in mitochondrial myopathies treated with coenzyme Qra. Neurology 38, 892899. 1111Matthews, P.M., Ford, B., Dandurand, R.J., Dandurand, R.J., Eidelman, D.H., O’Connor, D., Sherwin, A., Karpati, G., Andermann, F. and Arnold, D.L. (1993) Coenzyme Q,a with multiples vitamins is generally ineffective in treatment of mitochondrial disease. Neurology 43, 8844890. [121Manzanares, J.M., Barrientos, A., Conget, I., Mire, O., Gomis, R. and Cardellach, F. (1995) Mitochondrial respiratory chain activity in pancreatic islet cells. Polarographic studies. Diabetologia 38 (suppl. l), A95.
Practice 33 (1996) 135-136
Letter to the Editor
Coenzyme Q 10 and insulin secretion in vitro I. Conget”,“,
J.M. Manzanares”,
A. Barrientosb,
F. Cardellachb, R. Gomis”
“Endocrinology Unit, Hospital Clinic, Villarroel 170, 08036 Barcelona, Spain bInternal Medicine Unit, Hospital Clinic, Villarroel 170, 08036 Barcelona, Spain
Dear Sir,Defects in some mitochondrial enzymes have been related to the appearance of diabetes in animal models and humans [l-3]. In addition to this, a diminution of mtDNA content has been related to long-lasting impairment of insulin secretion [4,5], and particular attention has been focused in maternally-inherited diabetes and deafness syndrome, a pathological condition related to mutations of mtDNA [6,7]. In this context, some authors have described the effect of coenzyme QIO treatment in a patient with maternally inherited ‘diabetes and deafness syndrome’ [8] and they did not find any improvement on insulin secretion after 6 months with this therapy while finding a partial restoration on mitochondrial muscle function. From this point of view, we tested the effect of different concentrations of coenzyme QlO on Dcell function in vitro. To assess insulin secretion, batches of eight rat islets were incubated for 90 min at 37°C in 1.0 ml bicarbonated-buffered medium containing D-glucose 11.1 mM [9] and increasing concentrations of coenzyme QlO (Coenzyme Q,“, Sigma, St. Louis, MO, USA) of 0, 2, 4 * Corresponding 2215454
author. Tel.: + 34 3 2275400; fax: + 34 3
and 8 PM. In our experimental conditions and at all tested concentrations, coenzyme QlO failed to produce any significative modification of insulin release, although the concentrations used in our study were higher than those achieved in plasma of patients with mitochondrial myopathy treated with the coenzyme [lO,ll]. Nevertheless, when the higher concentration of the coenzyme was used, there was 25% increment on insulin release (307 f 32 vs 385 Ifr 30 pU.islet-l.90 min’, 0 and 8 PM coenzyme QlO respectively, n = 14 in both experimental conditions, mean f SEM). It should be mentioned that in the interpretation of our results, we have to consider not only the possibility that a cells are less sensitive than other tissues to coenzyme QlO but also the presence of interspecies discrepancies. Moreover, one can note that this lack of efficacy on normal D cells does not preclude the possibility of an effect on 13cell with genetic impairment of mitochondrial function as in maternally inherited ‘diabetes and deafness syndrome’. It should be also underlined that the possible effect of coenzyme QlO upon insulin release could also depend obviously on a number of other factors related to experimental conditions, such as D-glucose concentration, use of other substrates than D-glucose, length of exposure to the coenzyme, etc.
0168-8227/96/$15.00 0 1996 Elsevier Science Ireland Ltd. All rights reserved PII SOl68-8227(96)01278-S
136
I. Conget et al. /Diabetes
Research and Clinical Practice 33 (1996) 135-136
In the future, new approaches to the study of mitochondrial respiration in islet cells [ 121 could allow us to further explore the effect of such substances on mitochondrial activity in either normal or pathological conditions.
References [l] Ostenson, C.G., Abdel-Halim, S.M., Rasschaert, J., Malaisse-Lagae, F., Meuris, S., Sener, A., Efendic, S. and Malaisse, W.J. (1993) Deficient activity of FAD-linked glycerophosphate dehydrogenase in islets of GK rats. Diabetologia 36, 722-726. [2] Sener, A., Herberg, L. and Malaisse, W.J. (1993) FADlinked glycerophosphate dehydrogenase deficiency in pancreatic islets of mice with hereditary diabetes. FEBS Letts 316, 224221. [3] Fernandez-Alvarez, J., Conget, I., Rasschaert, J., Sener, A., Gomis, R. and Malaisse, W.J. (1994) Enzymatic, metabolic and secretory patterns in human islets of type 2 (non-insulin-dependent) diabetic patients. Diabetologia 37, 177-181. [4] Welsh, N., Palbo, S. and Welsh, M. (1991) Decreased mitochondrial gene expression in isolated islets of rats injected neonatally with streptozotocin. Diabetologia 34, 6266631. [5] Serradas, P., Giroix, M-H., Saulnier, C., Gangnerau, M.N., Borg, L.A.H., Welsh, M., Portha, B. and Welsh, N. (1995) Mitochondrial deoxyribonucleic acid content is specifically decreased in adult, but not fetal, pancreatic islets of the Goto-Kakizaki rat, a genetic model of non-insulin-dependent diabetes. Endocrinology 136, 562335631.
WI Alcolado,
J.C., Majid, A., Brockington, M., Sweeney, M.G., Morgan, R., Rees, A., Harding, A.E. and Barnett, A.H. (1994) Mitochondrial gene defects in patients with NIDDM. Diabetologia 37, 3722376. [71 Ballinger, S.W., Shoffner, J.M., Hedaya, E.V., Trounce, I., Polak, M.A. and Koontz, D.A. (1992) Maternally transmitted diabetes and deafness associated with a 10.4 kb mitochondrial DNA deletion. Nature Genetics 1, 11~ 15 181Silvestre-Aillaud, P., BenDahan, D., Paquis-Fluckinger, V., Pouget, J., Pelissier, J.F., Desnuelle, C., Cozzone, P.J. and Vialettes, B. (1995) Could coenzyme QlO and L-carnitine be a treatment for diabetes secondary to 3243 mutation of mtDNA? Diabetologia 35, 1485- 1486. J.I., Sarri, Y., Gonzalez-Clemente, J.M., [91 Conget, Casamitjana, R., Vives, M. and Gomis, R. (1994) Deleterious effect of Dithizone-DMSO staining on insulin secretion in rat and human pancreatic islets. Pancreas 9, 1577160. VOI Bresolin, N., Bet, L., Moggio, M., Comi, G., Nador, F., Ferrante, C., Carenzi, A. and Scarlato, G. (1988) Clinical and biochemical correlations in mitochondrial myopathies treated with coenzyme Qra. Neurology 38, 892899. 1111Matthews, P.M., Ford, B., Dandurand, R.J., Dandurand, R.J., Eidelman, D.H., O’Connor, D., Sherwin, A., Karpati, G., Andermann, F. and Arnold, D.L. (1993) Coenzyme Q,a with multiples vitamins is generally ineffective in treatment of mitochondrial disease. Neurology 43, 8844890. [121Manzanares, J.M., Barrientos, A., Conget, I., Mire, O., Gomis, R. and Cardellach, F. (1995) Mitochondrial respiratory chain activity in pancreatic islet cells. Polarographic studies. Diabetologia 38 (suppl. l), A95.