Effects of maternal periconceptional undernutrition in sheep on offspring glucose-insulin axis function into adulthood.

Maternal periconceptional undernutrition (PCUN) affected fetal pancreatic maturation in late gestation lambs and impaired glucose tolerance in 10-month-old sheep. To examine the importance of the timing of maternal undernutrition around conception, a further cohort was born to PCUN ewes [undernourished for 61 d before conception (PreC), 30 d after conception (PostC), or 61 d before until 30 d after conception (PrePostC)], or normally fed ewes (Control) (n = 15-20/group). We compared glucose tolerance, insulin secretion, and sensitivity at 36 months of age. We also examined protein expression of insulin signalling proteins in muscle from these animals and in muscle from a fetal cohort (132 d of gestation; n = 7-10/group). Adult PostC and PrePostC sheep had higher glucose area under the curve than Controls (P = 0.07 and P = 0.02, respectively), whereas PreC sheep were similar to Controls (P = 0.97). PostC and PrePostC had reduced first-phase insulin secretion compared with Control (P = 0.03 and P = 0.02, respectively). PreC was similar to Control (P = 0.12). Skeletal muscle SLC2A4 protein expression in PostC and PrePostC was increased 19%-58% in fetuses (P = 0.004), but decreased 39%-43% in adult sheep (P = 0.003) compared with Controls. Consistent with this, protein kinase C zeta (PKCζ) protein expression tended to be increased in fetal (P = 0.09) and reduced in adult (P = 0.07) offspring of all PCUN ewes compared with Controls. Maternal PCUN alters several aspects of offspring glucose homeostasis into adulthood. These findings suggest that maternal periconceptional nutrition has a lasting impact on metabolic homeostasis of the offspring.

A euglycaemic/non-diabetic perinatal environment does not alleviate early beta cell maldevelopment and type 2 diabetes risk in the GK/Par rat model.

AIMS/HYPOTHESIS: We used the GK/Par rat, a spontaneous model of type 2 diabetes with early defective beta cell neogenesis, to determine whether the development of GK/Par offspring in a non-diabetic intrauterine/postnatal environment would prevent the alteration of fetal beta cell mass (BCM) and ultimately decrease the risk of diabetes later in adult life. METHODS: We used an embryo-transfer approach, with fertilised GK/Par ovocytes (oGK) being transferred into pregnant Wistar (W) or GK/Par females (pW and pGK). Offspring were phenotyped at fetal age E18.5 and at 10 weeks of age, for BCM, expression of genes of pancreatic progenitor cell regulators (Igf2, Igf1r, Sox9, Pdx1 and Ngn3), glucose tolerance and insulin secretion. RESULTS: (1) Alterations in neogenesis markers/regulators and BCM were as severe in the oGK/pW E18.5 fetuses as in the oGK/pGK group. (2) Adult offspring from oGK transfers into GK (oGK/pGK/sGK) had the expected diabetic phenotype compared with unmanipulated GK rats. (3) Adult offspring from oGK reared in pW mothers and milked by GK foster mothers had reduced BCM, basal hyperglycaemia, glucose intolerance and low insulin, to an extent similar to that of oGK/pGK/sGK offspring. (4) In adult offspring from oGK transferred into pW mothers and milked by their W mothers (oGK/pW/sW), the phenotype was similar to that in oGK/pGK/sGK or oGK/pW/sGK offspring. CONCLUSIONS/INTERPRETATION: These data support the conclusion that early BCM alteration and subsequent diabetes risk in the GK/Par model are not removed despite normalisation of the prenatal and postnatal environments, either isolated or combined.

Naturally occurring perinatal growth restriction in mice programs cardiovascular and endocrine function in a sex- and strain-dependent manner.

Perinatal growth restriction (PGR) is associated with type 2 diabetes and hypertension. Identification of an isogenic mouse model of fetal programming will facilitate mechanistic understanding. We sought to test the hypotheses that 1) PGR impairs glucose tolerance and induces hypertension; and 2) the programming phenotype is more severe in an inbred mouse strain susceptible to diabetes (C57BL/6) than in a strain without such genetic predisposition (DBA/2). PGR pups were paired at weaning with same sex normally grown littermates. Glucose and insulin tolerance tests were performed at 17 wk, and systolic blood pressure (SBP) was measured at 20 wk. Impaired glucose tolerance was evident only among female PGR mice from both strains. While PGR did not alter insulin sensitivity in either strain, female DBA/2 mice had significantly decreased insulin levels during glucose tolerance testing. SBP was increased in PGR male C57BL/6 mice (p<0.01), while heart rate was decreased in PGR male DBA/2 mice (p<0.05). These studies indicate that in isogenic mice, PGR alters endocrine and cardiovascular physiology in female and male mice, respectively. Strain-and sex-specific genetic susceptibilities emphasize the need to consider genetic predisposition when evaluating the role of the perinatal environmental in the inception of adult disease.

Birth weight is nongenetically associated with glucose intolerance in elderly twins, independent of adult obesity.

OBJECTIVES: Using a unique twin approach, we examined the extent to which birth weight is determined by genetic and nongenetic factors and whether associations between birth weight and measures of glucose metabolism are of genetic or nongenetic origin. SETTING/SUBJECTS: An oral glucose tolerance test (OGTT) was performed in a population-based cohort of twins including 138 same-sex monozygotic (MZ) and 214 dizygotic (DZ) twin pairs aged 55-73 years whose birth weight was known. Heritability of birth weight was determined and regression analyses with intra-twin pair differences of birth weight and measures of glucose metabolism, with and without adjustment for adult obesity, were performed. RESULTS: The heritability of birth weight was estimated to be 38%. We demonstrated significant nongenetic associations between birth weight and measures of glucose homeostasis in MZ twins, with a reduction in fasting plasma glucose, 120 min post-OGTT plasma glucose, fasting plasma insulin and HOMA-IR index of 15.7%, 25.5%, 26.4% and 37.2%, respectively, for every 1 kg increase in birth weight. The nongenetic negative associations between birth weight and measures of glucose intolerance were independent of adult obesity, whereas the nongenetic association between birth weight and insulin resistance persisted, although not as strongly, after adjusting for current body size. CONCLUSIONS: We demonstrated a genetic component to birth weight in elderly twins. When adjusting for this influence, we found a nongenetic negative association between birth weight and glucose tolerance as well as insulin resistance that was partially independent of adult obesity. This implies that the foetal environment influences glucose homeostasis in elderly twins.

Gestational diabetes mellitus manifests in all trimesters of pregnancy.

Screening for GDM is usually performed around 24-28 weeks of gestational age. We undertook a study to estimate the prevalence of glucose intolerance during different trimesters, as data in this aspect is sparse. A total of 4151 consecutive pregnant women irrespective of gestational weeks attending antenatal health posts across Chennai city underwent a 75 g OGTT recommended by WHO and diagnosed GDM if 2 hr PG value > or =140 mg/dl. Women who had normal OGTT at the first visit were screened with a repeat OGTT at the subsequent visits. Among the screened, 741 women (17.9%) had 2 hr PG> or =140 mg/dl and were identified to have gestational diabetes. Analysis based on gestational weeks revealed that out of the 741 GDM women, 121 (16.3%) were within 16 weeks, 166 (22.4%) were between 17 and 23 weeks and 454 (61.3%) were more than 24 weeks of gestation. Observation in this study was that 38.7% developed gestational diabetes even prior to 24th week of gestation. Out of the total 741 GDM women, 214 (28.9%) were diagnosed on repeat testing at subsequent visits. Glucose intolerance occurs in the early weeks of gestation. Women who had normal glucose tolerance in the first visit require repeat OGTT in the subsequent visits.

Maternal-fetal deprivation and the cardiometabolic syndrome.

Epidemiologic studies suggest a relationship between low birth weight and adverse cardiovascular outcomes. Risk factors such as obesity, insulin resistance, diabetes mellitus, and hypertension--the cardiometabolic syndrome--are similarly affected. These observations are now supported by numerous animal studies. The mechanisms linking low birth weight and the cardiometabolic syndrome later in life appear to be multifactorial and involve alterations in the normal cellular and physiologic systems associated with growth in an unfavorable environment. Such "fetal programming," an adaptation to a shortage of nutrients, may bring about maladaptation upon postnatal exposure to an abundance of nutrients. This review briefly summarizes the adaptive responses in various models used to induce an intrauterine growth restriction, and discusses insights into the mechanisms mediating the fetal programming of the cardiometabolic syndrome.

Programming of defective rat pancreatic beta-cell function in offspring from mothers fed a low-protein diet during gestation and the suckling periods.

Poor fetal and infant nutrition has been linked to impaired glucose tolerance in later life. We studied the effect of protein deficiency during gestation and the suckling period in a rat model and found that poor nutrition 'programmes' pancreatic beta-cell GK (glucokinase; known as the glucose sensor) and glucose-stimulated insulin secretion response in newborn, suckling and adult rat offspring. Pregnant female rats were divided into three groups: a control group was kept on a normal protein (20%) diet, another group was fed a low-protein (LP) (6%) diet during gestation and suckling periods (LP-G + S group) and another was fed a LP diet during gestation then a normal protein diet during the suckling period (LP-G group). The pulsatile glucose-stimulated insulin secretion response was acutely disrupted and the peak insulin secretion was markedly decreased in newborn and 3-week-old offspring of the LP-G + S group compared with the control group. Also, there was an altered pulsatile secretory response in adults of the LP-G + S and 3-week-old and adult offspring of the LP-G groups compared with the control group. GK protein levels, detected by Western blotting, were decreased in newborn and 3-week-old offspring of both LP-G + S and LP-G groups compared with the control groups. The Km and Vmax of GK were altered. The prenatal and postnatal LP diet appeared to have a permanent effect in increasing the affinity of GK for glucose (indicated by decreased Km values) and decreasing the Vmax. This showed that the critical period of programming of the function of GK was after birth and during the postnatal weaning period, since the adult offspring of the LP-G + S group when fed a normal protein diet showed no reversal in the Km values of the enzyme. Similar experiments in adult offspring of the LP-G group showed normalization of the Km values of GK at 3 weeks of age. In conclusion, fetal and infantile nutrition 'programmes' pancreatic beta-cell function; poor nutrition during this period caused irreversible effects on glucose homoeostatic mechanisms in the offspring, which may predispose the offspring to diabetes in later life.

Intra-uterine programming of the endocrine pancreas.

In altricial species such as the rat and mouse, there is good evidence for the intra-uterine programming of the endocrine pancreas. Changes in the intra-uterine nutritional environment cause alterations in the structure and function of the islets which have life-long effects and predispose the animal to glucose intolerance and diabetes in later life. In rodents, the islets develop relatively late in gestation and undergo substantial remodelling in the period immediately after birth. Hence, the critical window for islet development in these animals is short and readily accessible for experimental manipulation. The short life-span of these species also means that elderly animals can be studied within a reasonable time frame. In precocious species, such as guinea pigs and farm animals, intra-uterine programming of the endocrine pancreas is less well established. In part, this may be due to difficulties in identifying the critical window for development as islet formation and remodelling begin at an earlier stage of gestation and continue for longer after birth. The long life-span of these animals and the relative insulin resistance of adult ruminants compared to other species also make it difficult to establish whether fetal changes in islet development have long-term consequences. In the human, the main phase of islet development occurs during the second trimester, although remodelling occurs throughout late gestation and early childhood. There is, therefore, a relatively long period in which early changes in islet development could be reversed or ameliorated in the human. Although the human epidemiological observations suggest that the fetal origin of adult glucose intolerance is due primarily to changes in insulin sensitivity rather than to defective insulin secretion, subtle changes in islet morphology and function sustained in utero may well contribute to the increased susceptibility to type 2 diabetes observed in adults who were growth-retarded in utero.

Prostanoid production in the umbilicoplacental arterial tree relative to impaired glucose tolerance.

The purpose of this study was to investigate prostanoid synthesis in different segments of the umbilicoplacental vascular tree and its relationship to impaired maternal glucose tolerance. Segments from the umbilical artery and vein, allantochorionic artery branches, and the cotyledon artery from 21 women with diabetes or impaired glucose tolerance and 10 healthy women were studied. Production of prostacyclin (PGI2) and thromboxane (TxA2) metabolites was determined. The Mann-Whitney U test, Wilcoxon signed-ranks matched-pairs test, Kruskal-Wallis test, analysis of variance, and simple linear regression analysis were used. A two-tailed P value of < 0.05 was considered statistically significant. From the umbilical artery distal to the cotyledon artery, the PGI2 synthesis decreased and the TxA2 synthesis increased gradually towards the periphery in normal pregnancy. The PGI2/TxA2 ratio was more than 200 times higher in the umbilical artery than in the cotyledon artery. The TxA2 production tended in general to be higher in the diabetic group than in the control group, resulting in significantly lower PGI2/TxA2 ratios in some vessels. The prostanoid production was not significantly correlated to maternal HbA1c or cord C-peptide concentrations. The balance between vascular prostacyclin and thromboxane synthesis in the umbilicoplacental arterial tree changed gradually towards the periphery: the more peripheral, the lower the prostacyclin and the higher the thromboxane production. The physiological role of this phenomenon is unknown, but may be of importance for the equilibration of vascular tone between arteries of different calibers. The altered prostanoid balance found in diabetic pregnancy was not directly attributable to the degree of maternal glycemic control, but may reflect increased free radical activity and peroxide production in diabetes.