Pancreatic Alpha-cell Dysfunction Contributes To The Disruption Of Glucose Homeostasis And Compensatory Insulin Hypersecretion In Glucocorticoid-treated Rats

Glucocorticoid (GC)-based therapies can cause insulin resistance (IR), glucose intolerance, hyperglycemia and, occasionally, overt diabetes. Understanding the mechanisms behind these metabolic disorders could improve the management of glucose homeostasis in patients undergoing GC treatment. For this purpose, adult rats were treated with a daily injection of dexamethasone (1 mg/kg b.w., i.p.) (DEX) or saline as a control for 5 consecutive days. The DEX rats developed IR, augmented glycemia, hyperinsulinemia and hyperglucagonemia. Treatment of the DEX rats with a glucagon receptor antagonist normalized their blood glucose level. The characteristic inhibitory effect of glucose on glucagon secretion was impaired in the islets of the DEX rats, while no direct effects were found on α-cells in islets that were incubated with DEX in vitro. A higher proportion of docked secretory granules was found in the DEX α-cells as well as a trend towards increased α-cell mass. Additionally, insulin secretion in the presence of glucagon was augmented in the islets of the DEX rats, which was most likely due to their higher glucagon receptor content. We also found that the enzyme 11βHSD-1, which participates in GC metabolism, contributed to the insulin hypersecretion in the DEX rats under basal glucose conditions. Altogether, we showed that GC treatment induces hyperglucagonemia, which contributes to an imbalance in glucose homeostasis and compensatory β-cell hypersecretion. This hyperglucagonemia may result from altered α-cell function and, likely, α-cell mass. Additionally, blockage of the glucagon receptor seems to be effective in preventing the elevation in blood glucose levels induced by GC administration. © 2014 Rafacho et al.94EFSD; European Foundation for the Study of DiabetesOrtsäter, H., Sjöholm, A., Rafacho, A., Regulation of Glucocorticoid Receptor Signaling and the Diabetogenic Effects of Glucocorticoid Excess (2012) State of the Art of Therapeutic Endocrinology, pp. 1-28. , 1st ed. Magdeldin S, Ed. Rijeka, InTechRhen, T., Cidlowski, J.A., Antiinflammatory action of glucocorticoids: New mechanisms for old drugs (2005) N Engl J Med, 353, pp. 1711-1723Schäcke, H., Döcke, W.D., Asadullah, K., Mechanisms involved in the side effects of glucocorticoids (2002) Pharmacol Ther, 96, pp. 23-43Wajngot, A., Giacca, A., Grill, V., Vranic, M., Efendic, S., The diabetogenic effects of glucocorticoids are more pronounced in low- than in high-insulin responders (1992) Proc Natl Acad Sci USA, 89, pp. 6035-6039Schneiter, P., Tappy, L., Kinetics of dexamethasone-induced alterations of glucose metabolism in healthy humans (1998) Am J Physiol, 275, pp. E806-E813Nicod, N., Giusti, V., Besse, C., Tappy, L., Metabolic adaptations to dexamethasone-induced insulin resistance in healthy volunteers (2003) Obesity Research, 11 (5), pp. 625-631Rafacho, A., Quallio, S., Ribeiro, D.L., Taboga, S.R., Paula, F.M., The adaptive compensations in endocrine pancreas from glucocorticoid-treated rats are reversible after the interruption of treatment (2010) Acta Physiol, 200, pp. 223-235Rafacho, A., Abrantes, J.L., Ribeiro, D.L., Paula, F.M., Pinto, M.E., Morphofunctional alterations in endocrine pancreas of short- and long-term dexamethasone-treated rats (2011) Horm Metab Res, 43, pp. 275-281Van Raalte, D.H., Nofrate, V., Bunck, M.C., Van Iersel, T., Elassaiss Schaap, J., Acute and 2-week exposure to prednisolone impair different aspects of beta-cell function in healthy men (2010) Eur J Endocrinol, 162, pp. 729-735Van Raalte, D.H., Ouwens, D.M., Diamant, M., Novel insights into glucocorticoid-mediated diabetogenic effects: Towards expansion of therapeutic options? (2009) Eur J Clin Invest, 39, pp. 81-93Karlsson, S., Ostlund, B., Myrsen-Axcrona, U., Sundler, F., Ahren, B., Beta cell adaptation to dexamethasone-induced insulin resistance in rats involves increased glucose responsiveness but not glucose effectiveness (2001) Pancreas, 22 (2), pp. 148-156. , DOI 10.1097/00006676-200103000-00007Rafacho, A., Cestari, T.M., Taboga, S.R., Boschero, A.C., Bosqueiro, J.R., High doses of dexamethasone induce increased beta-cell proliferation in pancreatic rat islets (2009) Am J Physiol Endocrinol Metab, 296, pp. E681-E689Rafacho, A., Marroquí, L., Taboga, S.R., Abrantes, J.L., Silveira, L.R., Glucocorticoids in vivo induce both insulin hypersecretion and enhanced glucose sensitivity of stimulus-secretion coupling in isolated rat islets (2010) Endocrinology, 151, pp. 85-95Wise, J.K., Hendler, R., Felig, P., Influence of glucocorticoids on glucagon secretion and plasma amino acid concentrations in man (1973) J Clin Invest, 52, pp. 2774-2782Mu, J., Jiang, G., Brady, E., Dallas-Yang, Q., Liu, F., Chronic treatment with glucagon antagonist lowers glucose and moderately raises circulating glucagon and glucagon-like peptide 1 without severe alpha cell hypertrophy in diet-induced obese mice (2011) Diabetologia, 54, pp. 2381-2391Henquin, J.C., Rahier, J., Pancreatic alpha cell mass in European subjects with type 2 diabetes (2011) Diabetologia, 54, pp. 1720-1725Quesada, I., Tudurí, E., Ripoll, C., Nadal, A., Physiology of the pancreatic alpha-cell and glucagon secretion: Role in glucose homeostasis and diabetes (2008) J Endocrinol, 199, pp. 5-19Cummings, B.P., Bremer, A.A., Kieffer, T.J., D'Alessio, D., Havel, P.J., Investigation of the mechanisms contributing to the compensatory increase in insulin secretion during dexamethasone-induced insulin resistance in rhesus macaques (2013) J Endocrinol, 216, pp. 207-215Jensen, D.H., Aaboe, K., Henriksen, J.E., Vølund, A., Holst, J.J., Steroid-induced insulin resistance and impaired glucose tolerance are both associated with a progressive decline of incretin effect in first-degree relatives of patients with type 2 diabetes (2012) Diabetologia, 55, pp. 1406-1416Gromada, J., Ding, W.-G., Barg, S., Renstrom, E., Rorsman, P., Multisite regulation of insulin secretion by cAMP-increasing agonists: Evidence that glucagon-like peptide 1 and glucagon act via distinct receptors (1997) Pflugers Archiv European Journal of Physiology, 434 (5), pp. 515-524. , DOI 10.1007/s004240050431Moens, K., Flamez, D., Van Schravendijk, C., Ling, Z., Pipeleers, D., Schuit, F., Dual glucagon recognition by pancreatic beta-cells via glucagon and glucagon-like peptide 1 receptors (1998) Diabetes, 47 (1), pp. 66-72Soriano, S., Gonzalez, A., Marroquí, L., Tudurí, E., Vieira, E., Reduced insulin secretion in protein malnourished mice is associated with multiple changes in the beta-cell stimulus-secretion coupling (2010) Endocrinology, 151, pp. 3543-3554Marroquí, L., Batista, T.M., Gonzalez, A., Vieira, E., Rafacho, A., Functional and structural adaptations in the pancreatic α-cell and changes in glucagon signaling during protein malnutrition (2012) Endocrinology, 153, pp. 1663-1672Nunes, E.A., Gonçalves-Neto, L.M., Ferreira, F.B.D., Santos, C., Fernandes, L.C., Glucose intolerance induced by glucocorticoid excess is further impaired by co-administration with β-hydroxy-β-methylbutyrate in rats (2013) Appl Physiol Nutr Metab, 38, pp. 1137-1146Unson, C.G., Gurzenda, E.M., Merrifield, R.B., Biological activities of des-His1[Glu9]glucagon amide, a glucagon antagonist1 (1989) Peptides, 10 (6), pp. 1171-1177. , DOI 10.1016/0196-9781(89)90010-7Huypens, P., Ling, Z., Pipeleers, D., Schuit, F., Glucagon receptors on human islet cells contribute to glucose competence of insulin release (2000) Diabetologia, 43 (8), pp. 1012-1019. , DOI 10.1007/s001250051484Montanya, E., Téllez, N., Pancreatic remodeling: Beta-cell apoptosis, proliferation and neogenesis, and the measurement of beta-cell mass and of individual beta-cell size (2009) Methods Mol Biol, 560, pp. 137-158Swali, A., Walker, E.A., Lavery, G.G., Tomlinson, J.W., Stewart, P.M., 11beta-Hydroxysteroid dehydrogenase type 1 regulates insulin and glucagon secretion in pancreatic islets (2008) Diabetologia, 51, pp. 2003-2011Beaudry, J.L., D'Souza, A.M., Teich, T., Tsushima, R., Riddell, M.C., Exogenous glucocorticoids and a high-fat diet cause severe hyperglycemia and hyperinsulinemia and limit glucose responsiveness in young male Sprague-Dawley rats (2013) Endocrinology, 154, pp. 3197-3208Dirlewanger, M., Schneiter, P., Paquot, N., Jequier, E., Rey, V., Tappy, L., Effects of glucocorticoids on hepatic sensitivity to insulin and glucagon in man (2000) Clinical Nutrition, 19 (1), pp. 29-34. , DOI 10.1054/clnu.1999.0064Marco, J., Calle, C., Hedo, J.A., Villanueva, M.L., Enhanced glucagon secretion by pancreatic islets from prednisolone-treated mice (1976) Diabetologia, 12, pp. 307-311Meier, J.J., Ueberberg, S., Korbas, S., Schneider, S., Diminished glucagon suppression after β-cell reduction is due to impaired α-cell function rather than an expansion of α-cell mass (2011) Am J Physiol Endocrinol Metab, 300, pp. E717-E723Poy, M.N., Hausser, J., Trajkovski, M., Braun, M., Collins, S., miR-375 maintains normal pancreatic alpha- and beta-cell mass (2009) Proc Natl Acad Sci U S A, 106, pp. 5813-5818Moens, K., Heimberg, H., Flamez, D., Huypens, P., Quartier, E., Ling, Z., Pipeleers, D., Schuit, F., Expression and functional activity of glucagon, glucagon-like peptide I, and glucose-dependent insulinotropic peptide receptors in rat pancreatic islet cells (1996) Diabetes, 45 (2), pp. 257-261Turban, S., Liu, X., Ramage, L., Webster, S.P., Walker, B.R., Optimal elevation of β-cell 11β-hydroxysteroid dehydrogenase type 1 is a compensatory mechanism that prevents high-fat diet-induced β-cell failure (2012) Diabetes, 61, pp. 642-652Diederich, S., Quinkler, M., Mai, K., Schöneshöfer, M., Baehr, V., In vivo activity of 11β-hydroxysteroid dehydrogenase type 1 in man: Effects of prednisolone and chenodesoxycholic acid (2011) Horm Metab Res, 43, pp. 66-71Pereira, C.D., Azevedo, I., Monteiro, R., Martins, M.J., 11β-Hydroxysteroid dehydrogenase type 1: Relevance of its modulation in the pathophysiology of obesity, the metabolic syndrome and type 2 diabetes mellitus (2012) Diabetes Obes Metab, 14, pp. 869-88