Dexamethasone during late gestation exacerbates peripheral insulin resistance and selectively targets glucose-sensitive functions in beta cell and liver.
We examined whether low-dose dexamethasone administration during late pregnancy modifies hepatic and/or peripheral insulin action or glucose-stimulated insulin secretion. Dexamethasone (100 microg/kg maternal body weight/d) was administered via an osmotic minipump from d 14--19 of gestation. Maternal glucose-insulin homeostasis was assessed on d 19 of pregnancy in the postabsorptive state. Insulin secretion and glucose tolerance was assessed after iv glucose, and insulin action examined during insulin infusion at euglycemia. Dexamethasone treatment during late pregnancy elicited fasting hyperinsulinaemia (by 88%; P < 0.001) and hyperglycaemia (by 20%; P < 0.05), and enhanced endogenous glucose production (by 29%; P < 0.001). Insulin secretion and rates of glucose disappearance after iv glucose were greatly impaired (by 44% and 39% respectively; P < 0.05). Suppression of endogenous glucose production by insulin was enhanced by dexamethasone treatment, but insulin's ability to promote glucose clearance was diminished. We demonstrate that excess maternal glucocorticoids during late pregnancy impairs glucose-stimulated insulin secretion and insulin-simulated glucose clearance but enhances insulin's ability to suppress endogenous glucose production. The data also indicate that elevated maternal glucocorticoids impair adaptations of the endocrine pancreas to pregnancy in vivo in that insulin hypersecretion in response to deteriorating peripheral insulin action is no longer apparent, leading to impaired glucose tolerance.
Holness
M J
MJ
Department of Diabetes and Metabolic Medicine, Division of General and Developmental Medicine, St. Bartholomew's and the Royal London School of Medicine and Dentistry, Queen Mary, University of London, London, E1 4NS, United Kingdom. m.j.holness@qmw.ac.uk
Sugden
M C
MC
D000818:Animals; D001835:Body Weight / Q000187:drug effects; D003907:Dexamethasone / Q000494:pharmacology*; D004435:Eating / Q000187:drug effects; D005260:Female; D005938:Glucocorticoids / Q000494:pharmacology*; D005947:Glucose / Q000493:pharmacokinetics / Q000494:pharmacology / Q000502:physiology*; D006943:Hyperglycemia / Q000139:chemically induced; D006946:Hyperinsulinism / Q000139:chemically induced / Q000503:physiopathology; D007275:Injections, Intravenous; D007328:Insulin / Q000378:metabolism; D007333:Insulin Resistance; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000187:drug effects* / Q000502:physiology; D020738:Leptin / Q000097:blood; D008099:Liver / Q000187:drug effects* / Q000502:physiology; D019518:Postprandial Period; D011247:Pregnancy; D011248:Pregnancy Complications / Q000139:chemically induced; D011270:Pregnancy, Animal / Q000187:drug effects* / Q000502:physiology; D051381:Rats; D017208:Rats, Wistar
D005938:Glucocorticoids; D007328:Insulin; D020738:Leptin; D003907:Dexamethasone; D005947:Glucose