Maternal Hypothyroidism in Rats Reduces Placental Lactogen, Lowers Insulin Levels, and Causes Glucose Intolerance

• Published in: Endocrinology (Philadelphia) 2022-02, Vol.163 (2), p.1
• Main Authors: Kent, Nykola Louise, Atluri, Sharat Chandra, Cuffe, James Sebastian Martin
• Format: Article
• Language: English
• Subjects: Adipose tissue; Animals; Beta cells; Blood; Dextrose; Diabetes; Diabetes mellitus; Diabetes, Gestational; Disease Models, Animal; Drinking water; Endocrinology; Fatty Acids, Nonesterified - metabolism; Female; Females; Gene expression; Genes; Glucose; Glucose intolerance; Glucose Intolerance - complications; Glucose tolerance; Glucose tolerance tests; Homeostasis; Hypothyroidism; Hypothyroidism - complications; Hypothyroidism - metabolism; Insulin; Insulin - blood; Insulin - metabolism; Intolerance; Lipids; Medical examination; Muscles; Phenotypes; Placenta; Placenta - metabolism; Placental Lactogen - metabolism; Pregnancy; Pregnancy complications; Pregnancy, Animal; Rats; Rats, Sprague-Dawley; Skeletal muscle; Somatotropin; Thyroid hormones; Triglycerides; Triglycerides - metabolism; Type 2 diabetes
• ISSN: 0013-7227; 1945-7170
• DOI: 10.1210/endocr/bqab231

Hypothyroidism increases the incidence of gestational diabetes mellitus (GDM) but the mechanisms responsible are unknown. This study aimed to assess the pathophysiological mechanisms by which hypothyroidism leads to glucose intolerance in pregnancy. Hypothyroidism was induced in female Sprague-Dawley rats by adding methimazole (MMI) to drinking water at moderate (MOD, MMI at 0.005% w/v) and severe (SEV, MMI at 0.02% w/v) doses from 1 week before pregnancy and throughout gestation. A nonpregnant cohort received the same dose for the same duration but were not mated. On gestational day 16 (GD16), or nonpregnant day 16 (NP16), animals were subjected to an intraperitoneal glucose tolerance test. Tissues and blood samples were collected 4 days later. Hypothyroidism induced a diabetic-like phenotype by GD16 in pregnant females only. Pregnant MOD and SEV females had reduced fasting plasma insulin, less insulin following a glucose load, and altered expression of genes involved in insulin signaling within skeletal muscle and adipose tissue. Hypothyroidism reduced rat placental lactogen concentrations, which was accompanied by reduced percentage β-cell cross-sectional area (CSA) relative to total pancreas CSA, and a reduced number of large β-cell clusters in the SEV hypothyroid group. Plasma triglycerides and free fatty acids were reduced by hypothyroidism in pregnant rats, as was the expression of genes that regulate lipid homeostasis. Hypothyroidism in pregnant rats results in a diabetic-like phenotype that is likely mediated by impaired β-cell expansion in pregnancy. This pregnancy-specific phenomenon is likely due to reduced placental lactogen secretion.