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.
Department of Physiological Sciences, Center of Biological Sciences, Federal University of Santa Catarina (UFSC), Florianópolis, Brazil.
Alex
A
Rafacho
Department of Physiological Sciences, Center of Biological Sciences, Federal University of Santa Catarina (UFSC), Florianópolis, Brazil.
Luiz M
LM
Gonçalves-Neto
Department of Structural and Functional Biology, Institute of Biology, and Obesity and Comorbidities Research Center (OCRC), State University of Campinas (UNICAMP), Campinas, Brazil.
Junia C
JC
Santos-Silva
Institute of Bioengineering and the Biomedical Research Center in Diabetes and Associated Metabolic Disorders (CIBERDEM), Miguel Hernández University, Elche, Spain.
Paloma
P
Alonso-Magdalena
Institute of Bioengineering and the Biomedical Research Center in Diabetes and Associated Metabolic Disorders (CIBERDEM), Miguel Hernández University, Elche, Spain.
Beatriz
B
Merino
Department of Biology, Institute of Biosciences, Humanities and Exact Sciences, São Paulo State University (UNESP), São José do Rio Preto, Brazil.
Sebastião R
SR
Taboga
Department of Structural and Functional Biology, Institute of Biology, and Obesity and Comorbidities Research Center (OCRC), State University of Campinas (UNICAMP), Campinas, Brazil.
Everardo M
EM
Carneiro
Department of Structural and Functional Biology, Institute of Biology, and Obesity and Comorbidities Research Center (OCRC), State University of Campinas (UNICAMP), Campinas, Brazil.
Antonio C
AC
Boschero
Institute of Bioengineering and the Biomedical Research Center in Diabetes and Associated Metabolic Disorders (CIBERDEM), Miguel Hernández University, Elche, Spain.
Angel
A
Nadal
Institute of Bioengineering and the Biomedical Research Center in Diabetes and Associated Metabolic Disorders (CIBERDEM), Miguel Hernández University, Elche, Spain.
Ivan
I
Quesada
D000818:Animals; D001786:Blood Glucose / Q000187:drug effects* / Q000378:metabolism; D002478:Cells, Cultured; D003907:Dexamethasone / Q000008:administration & dosage / Q000009:adverse effects*; D004334:Drug Administration Schedule; D050416:Glucagon-Secreting Cells / Q000187:drug effects / Q000473:pathology / Q000502:physiology*; D005938:Glucocorticoids / Q000008:administration & dosage / Q000009:adverse effects*; D006706:Homeostasis / Q000187:drug effects*; D006946:Hyperinsulinism / Q000097:blood / Q000139:chemically induced*; D007274:Injections, Intraperitoneal; D007328:Insulin / Q000378:metabolism*; D007333:Insulin Resistance; D000078790:Insulin Secretion; D008297:Male; D051381:Rats; D017208:Rats, Wistar
D001786:Blood Glucose; D005938:Glucocorticoids; D007328:Insulin; D003907:Dexamethasone