Increased hepatic peroxisome proliferator-activated receptor coactivator-1α expression precedes the development of insulin resistance in offspring of rats from severe hyperglycemic mothers.

BACKGROUND: Prenatal hyperglycaemia may increase metabolic syndrome susceptibility of the offspring. An underlying component of the development of these morbidities is hepatic gluconeogenic molecular dysfunction. We hypothesized that maternal hyperglycaemia will influence her offsprings hepatic peroxisome proliferator-activated receptor coactivator-1α (PGC-1α) expression, a key regulator of glucose production in hepatocytes. METHOD: We established maternal hyperglycaemia by streptozotocin injection to induce the maternal hyperglycaemic Wistar rat model. Offspring from the severe hyperglycemia group (SDO) and control group (CO) were monitored until 180 days after birth. Blood pressure, lipid metabolism indicators and insulin resistance (IR) were measured. Hepatic PGC-1α expression was analyzed by reverse transcription polymerase chain reaction and Western blotting. mRNA expression of two key enzymes in gluconeogenesis, glucose-6-phosphatase (G-6-Pase) and phosphoenolpyruvate carboxykinase (PEPCK), were analyzed and compared. RESULTS: In the SDO group, PGC-1α expression at protein and mRNA levels were increased, so were expression of G-6-Pase and PEPCK (P < 0.05). The above effects were seen prior to the onset of IR. CONCLUSION: The hepatic gluconeogenic molecular dysfunction may contribute to the metabolic morbidities experienced by this population.

[Effects of severe hyperglycaemia in pregnancy and early overfeeding on islet development and insulin resistance].

OBJECTIVE: Study the effects of early overfeeding in the adult offspring of mother with severely hyperglycaemia in pregnancy to islet development and insulin resistance. METHODS: Thirty healthy female Wistar rats were mated with 10 male Wistar rats and the morning on which sperm were found in three different visual fields of the vaginal smear was designated pregnancy day 1. The pregnant rats were intraperitoneally administered with Streptozotocin (STZ, 50 mg/L) on 5th day of pregnancy, and blood glucose exceeded 20 mmol/L to induce severely gestational diabetes mellitus (SDM) model. The pregnant Wistar rats were assigned to two experimental groups: SDM (n = 16) and control (n = 8). Litter size reduction in the lactation period induced early postnatal overfeeding model. Offspring were divided into three groups according to the level of blood glucose in pregnancy and feeding patterns in lactation: (1) control group (CG): euglycemia in pregnancy, eight pups in lactation; (2) severely gestational diabetes mellitus-normal feeding (SDM-N): severely gestational diabetes mellitus, eight pups in lactation; (3) severely gestational diabetes mellitus-overfeeding (SDM-O): severely gestational diabetes mellitus, four pups lactation. At the end of the lactation period, all pups were fed standard laboratory chow adlibitum until the date of the experiments. Offspring body weight was measured weekly after ablactation. Serum insulin was measured by enzyme-linked immunosorbent assay (ELISA) and pancreatic islet morphology was analyzed by immunohistochemistry (IHC) in all three groups at 26 weeks of age. RESULTS: (1) Blood glucose of pregnant Wistar rats: SDM (28.3 ± 5.1) mmol/L was statistically higher than control (6.3 ± 1.4) mmol/L (P < 0.05). (2) Growth rates of body weight in 3-7 weeks and 3-9 weeks: SDM-N: (4.6 ± 1.3)% and (6.8 ± 2.5)%, SDM-O: (3.2 ± 0.7)% and (4.6 ± 1.2)%, CG: (2.9 ± 0.6)% and (4.1 ± 0.8)%. The growth rates of body weight in SDM-N and SDM-O were both significantly higher than those in CG (P < 0.05). (3) Body weight at 26 weeks: CG: (486 ± 132) g, SDM-N: (387 ± 115) g, SDM-O: (382 ± 122) g. There was no statistical difference among the three groups (P > 0.05). (4) Fasting plasma glucose (FPG), fasting insulin (FINS), homeostasis model of insulin resistance (HOMA-IR) and insulin sensitivity index (ISI): at 26 weeks, the SDM-offspring has normal FPG, but more insulin was needed to keep it normal. The insulin level of SDM-O [(12.6 ± 3.3) mU/L] was statistically higher than those of SDM-N [(10.9 ± 3.3) mU/L] and CG [(8.6 ± 0.8) mU/L] (P < 0.05). The ISI of SDM-O (0.020 ± 0.006) was significantly smaller than its HOMA-IR (2.40 ± 0.62, P < 0.05). (5) The morphological change of pancreatic islet: The islets of CG and SDM-N were round or ellipse and have clear boundary between endocrine and exocrine parts and the ß cells distributed equally. However, SDM-O islets were not of uniform size and most of islets were hyperplasia and hypertrophy. (6) Relative ß cell area of pancreas, ß-cell area and islet size: SDM-O: (1.81 ± 0.31)%, (57.1 ± 3.2)% and (39,067 ± 3308) µm(2); SDM-N:(1.34 ± 0.43)%, (60.9 ± 0.6)% and (30,570 ± 4824) µm(2); CG: (1.11 ± 0.26)%, (63.7 ± 2.7)% and (26,443 ± 4431) µm(2). SDM-O has significantly increasing ß-cell mass, hypertrophic islet size and slightly decreasing ß-cell percentage compared with other two groups (P < 0.05). CONCLUSIONS: The exposure of severely hyperglycemia in pregnancy induces low weight infant and postnatal catch-up growth leading to the possibility of insulin resistance (IR) in adult and early postnatal overfeeding will accelerate such course. Islet morphology of SDM-N has no significant change, indicating that maternal diabetes mainly affected ß-cell function but not islet morphological features. SDM overfeeding results in early impairment of islet morphology and function, indicating that the compensation ability of islets has already been impaired and the risk of further development of impaired glucose tolerance (IGT) and diabetes. In conclusion, the nutritional environment in early life (duration of pregnancy and lactation) participate in the metabolic programming in adulthood.