Insulin action during late pregnancy in the conscious dog

Abstract

Our aim was to assess the magnitude of peripheral insulin resistance and whether changes in hepatic insulin action were evident in a canine model of late (3rd trimester) pregnancy. A 3-h hyperinsulinemic (5 mU·kg Ϫ1 ·min Ϫ1 ) euglycemic clamp was conducted using conscious, 18-h-fasted pregnant (P; n ϭ 6) and nonpregnant (NP; n ϭ 6) female dogs in which catheters for intraportal insulin infusion and assessment of hepatic substrate balances were implanted ϳ17 days before experimentation. Arterial plasma insulin rose from 11 Ϯ 2 to 192 Ϯ 24 and 4 Ϯ 2 to 178 Ϯ 5 U/ml in the 3rd h in NP and P, respectively. Glucagon fell equivalently in both groups. Basal net hepatic glucose output was lower in NP (1.9 Ϯ 0.1 vs. 2.4 Ϯ 0.2 mg·kg Ϫ1 ·min Ϫ1 , P Ͻ 0.05). Hyperinsulinemia completely suppressed hepatic glucose release in both groups (Ϫ0.4 Ϯ 0.2 and Ϫ0.1 Ϯ 0.2 mg·kg Ϫ1 ·min Ϫ1 in NP and P, respectively). More exogenous glucose was required to maintain euglycemia in NP (15.2 Ϯ 1.3 vs. 11.5 Ϯ 1.1 mg·kg Ϫ1 ·min Ϫ1 , P Ͻ 0.05). Nonesterified fatty acids fell similarly in both groups. Net hepatic gluconeogenic amino acid uptake with high insulin did not differ in NP and P. Peripheral insulin action is markedly impaired in this canine model of pregnancy, whereas hepatic glucose production is completely suppressed by high circulating insulin levels. insulin resistance; hepatic glucose production; lipolysis; ketogenesis; gluconeogenesis LATE PREGNANCY IS ACCOMPANIED by alterations in many metabolic processes, involving multiple maternal tissues, that allow the mother to balance her own nutritional needs with the increasing requirements of utero-placental-fetal tissues (14, 21). In the basal state, hepatic glucose production and ketogenesis are increased, indicating altered basal liver function, and fat and protein metabolism are clearly affected (1, 6 -8, 14, 21, 23, 24). Pregnancy is accompanied by the development of marked whole body insulin resistance in a variety of species (2,4,5,18,20,26,27,32,33). Use of the hyperinsulinemic euglycemic clamp technique in pregnant women revealed a marked reduction in the glucose infusion rate (up to ϳ24%) required to maintain euglycemia compared with nonpregnant controls, even with pharmacological elevation of insulin to levels of ϳ600 U/ml (33). Similar results obtained in clamp studies utilizing very high insulin levels in the pregnant rat (26) and rabbit (18) specifically revealed the significant attenuation of insulin's ability to stimulate glucose uptake in peripheral tissues in pregnancy.The techniques necessary to make thorough assessments of hepatic substrate metabolism are too invasive for use in pregnant women. We recently described a conscious canine model of pregnancy (8) that employs chronic catheterization techniques to make such assessments. We showed that this canine model has basal characteristics similar to those of pregnant women, indicating that it would be useful for studying the regulation of metabolic changes during pregnancy. The aims of the present study were to fur...

Pregnancy impairs the counterregulatory response to insulin-induced hypoglycemia in the dog

“…Basal insulin concentrations tended to be lower in the pregnant dogs, as we have previously shown (10,11). The reduction in basal insulin concentrations may provide a mechanism to allow hepatic R a in the dog to reach adequate rates for late pregnancy.…”

“…Since the tracer method cannot distinguish between maternal and utero/placental/fetal R d , we could not delineate how either maternal or fetal R d changed with insulin-induced hypoglycemia. Nevertheless, because the overall R d rate was the same in both groups in response to insulin infusion, maternal R d was clearly less than that in the nonpregnant group, reflecting the insulin resistance associated with pregnancy (3,10,26,34,44,45).…”

Concentração Sérica De Glicose, Colesterol, Triglicerídeos E Frutosamina Em Cadelas Gestantes

“…Apesar desta afirmação, tal característica não foi observada nesta pesquisa, pois 75% das cadelas apresentavam-se normoglicêmicas e apenas uma foi encontrada com hiperglicemia (Tabela 1). Aliado a isso no terço final da gestação, os níveis séricos do hormônio diabetogênico prolactina estão elevados o que contribui para a resistência à insulina (Connolly et al, 2004). Das gestantes inseridas no projeto apenas 4 (20%) delas encontravam-se no terço final da gestação, não sendo observado hiperglicemia em nenhuma delas.…”

“…O perfil hormonal durante a gestação em cadelas está associado ao aumento de progesterona no plasma de 1ng/ml (anestro) para níveis superiores de 45ng/mL durante a gestação (Pöpple et al, 2013). No terço final da gestação, os níveis séricos de prolactina (hormônio diabetogênico) estão elevados o que contribui para a resistência à insulina (Connolly et al, 2004).…”

Characterization and Comparison of Insulin Resistance Induced by Cushing Syndrome or Diestrus against Healthy Control Dogs as Determined by Euglycemic- Hyperinsulinemic Glucose Clamp Profile Glucose Infusion Rate Using an Artificial Pancreas Apparatus

“…1c). Evaluation of insulin resistance using the EHGC has been rarely reported for dogs; however, it is an applicable method for use with dogs [4][5][6]. Unfortunately, 1 major obstacle preventing its increased use with dogs though, is frequent blood sampling for glucose measurement and adjusting GIR.…”