SUN-637 The Impact of Hyperandrogenemia and Western-Style Diet on Post-Pregnancy Metabolism in Nonhuman Primates

Polycystic ovary syndrome (PCOS) often is associated with hyperandrogenemia and an increased incidence of obesity and type 2 diabetes. To understand the separate and combined effects of androgens and obesity on reproductive and metabolic parameters, our group established a nonhuman primate model consisting of animals receiving either testosterone (T, mean value of 1.4 ng/mL), an obesogenic western-style diet (WSD, 36% of calories from fat compared to 16% in normal monkey chow), or a combination of T+WSD. T+WSD increased insulin resistance compared to WSD alone after three years of treatment and reduced fertility. Those T+WSD animals that became pregnant had a mild worsening of glucose homeostasis during pregnancy. The current study sought to determine how T+WSD affected post-pregnancy metabolic health and whether T+WSD led to the worsening of insulin resistance after pregnancy. Intravenous glucose tolerance tests (ivGTT) were performed 1) before pregnancy, 2) approximately 3-4 months after C-section, which occurred between gestational day 130-135 (3rd trimester), and 3) one year post C-section. All animal groups tended to show increases in weight, BMI, and body fat percentage after pregnancy. Both WSD groups (WSD and T+WSD) had higher overall weights, BMI, and body fat percentages. Measures of insulin sensitivity such as fasting insulin, glucose, and insulin area under the curves during an ivGTT and homeostatic model of insulin resistance (HOMA-IR) all increased over time, but there were no differences between groups. The lack of treatment effect on measures of insulin resistance may be due to the fact that animals that did not become pregnant had significantly higher indices of insulin resistance. Experimental animals underwent a second round of fertility trials thereby allowing for a comparison of glucose homeostasis for those animals that became pregnant in both the 1st and 2nd trial. The WSD group demonstrated increased fasting glucose and glucose AUC during an early third trimester ivGTT in the second pregnancy compared to the first. The control, T, and T+WSD groups did not show significant differences in glucose homeostasis between the first and second pregnancy. These findings indicate that WSD consumption may increase the risk of worsened glucose homeostasis after pregnancy and during subsequent pregnancies. Testosterone, either in isolation or in combination with WSD, did not appear to have a significant impact on post-pregnancy metabolism or worsen metabolic outcomes in a second pregnancy.

The effect of pregnancy on nitrogen retention, maternal insulin sensitivity, and mRNA abundance of genes involved in energy and amino acid metabolism in gilts

Twenty-one of each pregnant (P) and nonserviced, nonpregnant (NP) sister-pairs of gilts were selected to investigate the effect of pregnancy on protein deposition (Pd; whole body and maternal), insulin sensitivity, and mRNA abundance of genes involved in energy and AA metabolism. Between breeding (study day 0) and day 111, P and NP gilts received 2.16 kg of the experimental diet (3.34 Mcal ME/kg, 17.6% crude protein, 0.78% standardized ileal digestible lysine) that was formulated to meet the estimated ME requirements of pregnant gilts (and meet or exceed AA requirements). Nitrogen balances were conducted on day 63 and 102 ± 0.2 of the study during 4-d periods. Blood samples were collected on day 43, 56, 71, 85, 98, and 108 ± 0.3 of the study to determine plasma concentrations of fasted IGF-1, estradiol (E2), and estrone sulfate (E1S). Frequently sampled intravenous glucose tolerance tests (FSIGTT) were conducted on day 75 ± 0.7 in 6 P and 5 NP gilts and on day 107 ± 0.4 in 17 P and 17 NP gilts and the MINMOD approach was applied to evaluate whole body insulin sensitivity and pancreatic responsiveness. Longissimus muscle (LM) and s.c. adipose tissue (AD) samples were excised from 12 P and 12 NP gilts at day 111 ± 0.4 of the study after euthanasia to determine mRNA abundance of key genes. Whole body Pd was greater (P < 0.001) at day 102 and maternal Pd was lower (P < 0.002) at day 63 and 102 for P compared to NP gilts. Plasma concentrations of E1S and E2 increased (P < 0.05) with study day for P gilts and remained constant for NP gilts, which coincided with reduced plasma concentrations of IGF-1 and increased estrogen receptor alpha (ESR1) mRNA abundance in LM of P gilts. Glucose effectiveness was not different between P and NP gilts, but whole body insulin sensitivity was lower (P = 0.004) in P compared to NP gilts on day 75 and 107, which corresponded with reduced mRNA abundances of SLC2A4, HK2, SREBF1, and FASN, and increased abundances of PDK4 and PPARGC1A in LM and AD. When fed identically, P gilts had greater whole body Pd at day 102, which reflects Pd in the pregnancy-associated tissues (at the expense of maternal Pd), likely driven by estrogen-stimulated insulin resistance in peripheral tissue and subsequent modulation of gene expression relating to glucose metabolism.

Hidden Metabolic Disturbances in Women with Normal Glucose Tolerance Five Years after Gestational Diabetes

Background. The study aimed to assess whether women with prior gestational diabetes (pGDM), despite maintenance of normal glucose tolerance (NGT) five years after delivery, display metabolic disturbances compared to healthy controls.Methods. 45 pGDM with NGT were compared to 18 women without a history of GDM (CON), matched for age (37.0 ± 4.1 versus 35.2 ± 5.3,P=ns) and BMI (24.3 ± 3.1 versus 23.3 ± 3.3,P=ns). Metabolic parameters were derived from oral and intravenous glucose tolerance tests; furthermore lipid profile, C-reactive protein (CRP), adiponectin, leptin, and glucagon were assessed.Results. Five years postpartum, pGDM had increased glucose concentrations during the OGTT (AUC: 1.12 ± 0.15 versus 1.0 ± 0.12 mol/L*min,P=0.003) and insulin sensitivity was decreased compared to CON (OGIS: 467.2 ± 64.1 versus 510.6 ± 53.1 mL/min*m2,P=0.01). pGDM had lower adiponectin (8.1 ± 2.6 versus 12.6 ± 5.3,P<0.008) but increased waist circumference and CRP compared to CON.Conclusions. Despite diagnosis of normal glucose tolerance, pGDM are characterized by hyperglycemia and insulin resistance compared to healthy controls, accompanied by decreased adiponectin and increased CRP concentrations, thus linking metabolic disturbances to an increased cardiovascular risk in pGDM.

Evaluating the Mechanisms of Improved Glucose Homeostasis after Bariatric Surgery in Ossabaw Miniature Swine

Background. Roux-en-Y gastric bypass (RYGB) is the most common bariatric operation; however, the mechanism underlying the profound weight-independent effects on glucose homeostasis remains unclear. Large animal models of naturally occurring insulin resistance (IR), which have been lacking, would provide opportunities to elucidate such mechanisms. Ossabaw miniature swine naturally exhibit many features that may be useful in evaluating the anti diabetic effects of bariatric surgery.Methods. Glucose homeostasis was studied in 53 Ossabaw swine. Thirty-two received an obesogenic diet and were randomized to RYGB, gastrojejunostomy (GJ), gastrojejunostomy with duodenal exclusion (GJD), or Sham operations. Intravenous glucose tolerance tests and standardized meal tolerance tests were performed prior to, 1, 2, and 8 weeks after surgery and at a single time-point for regular diet control pigs.Results. High-calorie-fed Ossabaws weighed more and had greater IR than regular diet controls, though only 70% developed IR. All operations caused weight-loss-independent improvement in IR, though only in pigs with high baseline IR. Only RYGB induced weight loss and decreased IR in the majority of pigs, as well as increasingAUCinsulin/AUCglucose.Conclusions. Similar to humans, Ossabaw swine exhibit both obesity-dependent and obesity-independent IR. RYGB promoted weight loss, IR improvement, and increasedAUCinsulin/AUCglucose, compared to the smaller changes following GJ and GJD, suggesting a combination of upper and lower gut mechanisms in improving glucose homeostasis.