Intrauterine Hyperglycemia Research Articles

Overweight and the Metabolic Syndrome in Adult Offspring of Women with Diet-Treated Gestational Diabetes Mellitus or Type 1 Diabetes

In animal studies, exposure to intrauterine hyperglycemia increases the risk of cardiovascular disease through only partly understood epigenetic mechanisms. Human long-term follow-up studies on the same topic are few. The aim was to study the risk of overweight and the metabolic syndrome in adult offspring of women with diet-treated gestational diabetes mellitus (GDM) or type 1 diabetes, and additionally to study associations between estimates of maternal hyperglycemia and outcome in the offspring. We conducted a follow-up study of 1066 primarily Caucasian women aged 18-27 yr in the Center for Pregnant Women with Diabetes, Rigshospitalet, Copenhagen, Denmark. Offspring of women with diet-treated GDM (n = 168) and an unexposed reference group (n = 141) participated, as well as offspring of women with type 1 diabetes (n = 160) and offspring from the background population representing an unexposed reference group (n = 128). The follow-up rate was 56% (597 of 1066). Women with body mass index of at least 25 kg/m(2) were considered overweight. The metabolic syndrome was determined by the International Diabetes Federation 2006 criteria. The risk of overweight was doubled in offspring of women with diet-treated GDM or type 1 diabetes compared with offspring from the background population, whereas the risk of the metabolic syndrome was 4- and 2.5-fold increased, respectively. Offspring risk of the metabolic syndrome increased significantly with increasing maternal fasting blood glucose as well as 2-h blood glucose (during oral glucose tolerance test). Adult offspring of women with diet-treated GDM or type 1 diabetes are risk groups for overweight and the metabolic syndrome. Intrauterine hyperglycemia may in addition to genetics and other factors contribute to the pathogenesis of overweight and the metabolic syndrome.

We are what we eat

![][1] The old adage that pregnant women eat for two might be more true than ever before in the light of recent research into diet and the control of gene expression. The link between the diet of pregnant women—and, to some extent, men—during pre‐conception and the health of the fetus has been viewed mostly in terms of major risk factors such as smoking or substance abuse. However, epidemiological and molecular research is revealing a more complex and subtle picture of how a pregnant woman's eating behaviour influences the expression of her own—and possibly her fetus's—genes, and thus the long‐term health of her children. “Type II diabetes, heart disease due to obesity, insulin resistance, and hypertension are the diseases most strongly associated with maternal diet during pregnancy,” said Karen Lillycrop, who specializes in perinatal nutrition at the University of Southampton in the UK. In addition, there is growing evidence that dietary effects, which can alter the expression and control of genes, might even have been a driving force for human evolution. A recent study revealed that the greatest divergence between the genomes of humans and chimpanzees is found among genes that control metabolism and are closely associated with diet (Somel et al , 2008). The mechanisms that allow the genome to interact with environmental factors, such as diet, are epigenetic changes—a concept first proposed by the British biologist Conrad Waddington (1905–1975) in 1942 to describe the interplay between genes and the environment in determining the phenotype of an organism. Further research since Waddington's time has shown that epigenetic changes not only take place during embryonic development, but also throughout the lifetime of an organism. The same mechanisms—notably DNA methylation and histone modification—have a role in the acquisition and maintenance of epigenetic changes induced by dietary or other environmental factors. In fact, they … [1]: /embed/graphic-1.gif

High Prevalence of Type 2 Diabetes and Pre-Diabetes in Adult Offspring of Women With Gestational Diabetes Mellitus or Type 1 Diabetes

The role of intrauterine hyperglycemia and future risk of type 2 diabetes in human offspring is debated. We studied glucose tolerance in adult offspring of women with either gestational diabetes mellitus (GDM) or type 1 diabetes, taking the impact of both intrauterine hyperglycemia and genetic predisposition to type 2 diabetes into account. The glucose tolerance status following a 2-h 75-g oral glucose tolerance test (OGTT) was evaluated in 597 subjects, primarily Caucasians, aged 18-27 years. They were subdivided into four groups according to maternal glucose metabolism during pregnancy and genetic predisposition to type 2 diabetes: 1) offspring of women with diet-treated GDM (O-GDM), 2) offspring of genetically predisposed women with a normal OGTT (O-NoGDM), 3) offspring of women with type 1 diabetes (O-type 1), and 4) offspring of women from the background population (O-BP). The prevalence of type 2 diabetes and pre-diabetes (impaired glucose tolerance or impaired fasting glucose) in the four groups was 21, 12, 11, and 4%, respectively. In multiple logistic regression analysis, the adjusted odds ratios (ORs) for type 2 diabetes/pre-diabetes were 7.76 (95% CI 2.58-23.39) in O-GDM and 4.02 (1.31-12.33) in O-type 1 compared with O-BP. In O-type 1, the risk of type 2 diabetes/pre-diabetes was significantly associated with elevated maternal blood glucose in late pregnancy: OR 1.41 (1.04-1.91) per mmol/l. A hyperglycemic intrauterine environment appears to be involved in the pathogenesis of type 2 diabetes/pre-diabetes in adult offspring of primarily Caucasian women with either diet-treated GDM or type 1 diabetes during pregnancy.

Use of the alpha‐2 agonists xylazine and detomidine in the perianaesthetic period in the horse

Alpha-2 agonists have been widely used in equine anaesthesia since the clinical advent of xylazine in the 1970s (Clarke and Hall 1969; Kerr et al. 1972). Alpha-2 agonists produce sedation, muscle relaxation and analgesia by stimulation of α2 receptors centrally in the brain and spinal cord and peripherally (Hellyer et al. 2003). Two α2 agonists, xylazine and detomidine, are currently approved for use in the horse in the USA, while 2 additional drugs, romifidine and medetomidine, are approved for use in horses in other countries. Although differing in potency, α2 agonists share a common pharmacology. The degree of sedation, muscle relaxation and analgesia for a given drug is dose-dependent (England and Clarke 1996). Arterial blood pressure is initially increased due to drug-induced increases in peripheral vascular resistance (Wagner et al. 1991). The increases may be sustained (10–60 mins) when more potent α2 agonists like detomidine are used. Heart rate decreases, sinus arrhythmia and first and second degree atrioventricular blockade are common initial reflex mediated responses. Decreases in heart rate produce significant decreases in cardiac output, often to levels 50% of predrug values (Yamashita et al. 2000). Respiratory rate is usually decreased but this is offset by increases in tidal volume so that significant hypercarbia does not usually occur. Relaxation of the muscles of the upper airway occurs and can predispose the horse to respiratory stridor (Lavoie et al. 1992). Additional effects include sweating, ataxia, decreased salivation, decreased gastric secretions and gastrointestinal motility and increased urine volume. Swallowing is depressed; the passage of nasogastric tubes may therefore be more difficult and horses should be monitored for potential oesophageal obstruction. Other incidental effects of α2 agonist administration include increases in intrauterine pressure, hyperglycaemia and hypoinsulinaemia (von Reitzenstein et al. 2002). Alpha-2 agonists as analgesics

Intrauterine hyperglycemia increases insulin binding sites but not glucose transporter expression in discrete brain areas in term rat fetuses.

Diabetic pregnancy results in several metabolic and hormonal disorders, both in the embryo and the fetus of different species, including humans. Insulin is a potent modulator of brain development and is suggested to promote the differentiation and maturation of hypothalamic or related extrahypothalamic structures, which are directly involved in neural inputs to the pancreas. Because these structures are known to be specifically responsive both to insulin and glucose, we examined the effects of 48-h hyperglycemic clamps in unrestrained pregnant rats on insulin binding and glucose transporter expression in hypothalamic and extrahypothalamic-related areas of their fetal offspring. The main result was an increase in insulin binding in the ventromedial hypothalamic nucleus (VMH), the arcuate nucleus (AN), and the lateral hypothalamus (LH), and in the nucleus of the tractus solitarius (NTS) for extrahypothalamic areas (+30% in the VMH, +37% in the AN, +25.8% in the LH, and +37.3% in the NTS). The deleterious effect of brain hyperinsulinism during the late gestational stage does not seem to act through glucose transporter (GLUT) expression, inasmuch as no relationship between GLUT level and hyperinsulinism in brain areas could be observed. The specific increase in insulin binding in areas involved in the nervous control of metabolism could be a factor in the increased glucose intolerance and impairment of insulin secretion that was previously observed in the adult rats from hyperglycemic mothers.

Perinatal Outcome of Pregnancies Complicated by Diabetes and by Maternal Daily Hyperglycemia Not Related to Diabetes

We analyzed the perinatal outcome of 1,086 pregnancies classified according to the response to the 3-hour 100-gram glucose tolerance test and the diurnal glycemic profile into the Rudge groups corresponding to control pregnant women, class A gestational diabetic women, class A/B to FRH pregnant women and women with daily hyperglycemia. Despite treatment, the diabetic pregnant women and those with daily hyperglycemia presented higher mean blood glucose levels compared to controls (76.6 ± 10.2 mg/dl). The pregnancies complicated by diabetes and by daily hyperglycemia were characterized by a high incidence of prematurity, macrosomia, large for gestational age newborn infants, malformation and fetal and neonatal death, with consequent perinatal mortality. The perinatal mortality of women with daily hyperglycemia was 10 times higher than that of the controls and was similar to that of the diabetic patients. These adverse perinatal results emphasize the need for the diagnosis and control of intrauterine hyperglycemia both in diabetic pregnant women and in women with an altered diurnal glycemic profile.

EFFECT OF ACUTE GLUCOSE DEPLETION FOLLOWING GLUCOSE EXCESS ON SURFACTANT PHOSPHOLIPID SYNTHESIS IN DEVELOPING FETAL LUNG

Exposure to high glucose and insulin inhibits surfactant synthesis in vitro. We have demonstrated that fetal lung insulin receptor tyrosine kinase (TK) activity is downregulated after culture in high glucose plus insulin, with a resultant decrease in glucose uptake. To see whether relative substrate depletion following substrate excess would further diminish surfactant synthesis, 20-day fetal rat lung explants were initially cultured for 44 hours in media containing 100 mM glucose with or without 0.1 U/mL insulin, followed by a 4-hour pulse in 10 mM glucose +/- insulin or 100 mM glucose +/- insulin, after which the rate of choline incorporation into phosphatidylcholine (PC) or disaturated PC was measured. Choline incorporation was significantly lower after a 4-hour pulse in low glucose (+/- insulin) than under continuing high glucose (+/- insulin) conditions (P<.01). To determine the time required for reversal of TK downregulation in lung explants, insulin receptor TK activity was assayed after 44 hours in high glucose + insulin, followed by an additional 4, 8, 12, or 24 hours in either 10 mM glucose or continued 100 mM glucose + insulin. After 44 hours in 50 mM or 100 mM glucose + insulin, TK activity was significantly decreased (68 +/- 9 % and 57 +/- 9% of control; P<.01). When explants cultured in 100 mM glucose + insulin for 44 hours were subsequently placed in 10 mM glucose for an additional 4 or 8 hours, TK activity remained significantly downregulated (70.2 +/- 7.0% and 84.9 +/- 5.5% of control, respectively, P<.05) compared to explants cultured in low glucose throughout. However, after 12 or 24 hours in low glucose, TK activity was no longer significantly different from control values (106.5 +/- 2.1% and 106.0 +/- 19.6%, respectively). Culture of type II cells for 44 hours in 25 mM glucose + insulin, followed by an additional 4 or 24 hours in either low glucose (5.5 mM) + insulin or high glucose (25 mM) + insulin yielded similar results: TK activity was decreased 20-30% by culture in 25 mM glucose + insulin conditions (P<.05) and this downregulation continued for 4 (but not 24) hours after switching to lower glucose conditions (P<.05). Continued receptor downregulation during a period of relative substrate deprivation may adversely affect surfactant synthesis, as in some infants of diabetic mothers who experience hypoglycemia (following intrauterine hyperglycemia) in the immediate postnatal period.

Cardiac septal hypertrophy in hyperinsulinemic infants

One infant with nesidioblastosis, and five of 18 infants of diabetic mothers had echocardiographically determined septal hypertrophy (greater than or equal to 6 mm). No correlation was found between the septal hypertrophy and the presence of hypocalcemia, polycythemia, birth asphyxia, or other observed clinical findings. All of the infants with septal hypertrophy, however, had profound hypoglycemia shortly after birth in contrast to those infants without septal hypertrophy. Macrosomic IDM have intrauterine hyperglycemia and hyperinsulinemia. The presence of profound neonatal hypoglycemia is consistent with the metabolic effects of significant neonatal hyperinsulinemia which is also present in the fetus. Infants with nesidioblastosis also have fetal hyperinsulinemia. Recent investigations have suggested an important role for insulin in the developing heart since it is rich in insulin receptors and contains marked insulin degrading capacity. Although fetal hyperglycemia has been suggested as the cause of septal hypertrophy in IDM, we hypothesize that fetal hyperinsulinemia contributes directly to the spinal hypertrophy.

The effect of maternal diabetes on adipose tissue cellularity in man and rat.

It is well recognised that the newborn of diabetic mothers may be overweight and obese, presumably due to excessive glucose and insulin levels in the fetus. Since recent evidence indicates that the number of fat cells is established early in life, we studied the effect of intrauterine hyperglycaemia and hyperinsulinaemia on adipose tissue cellularity. Six men (age range 21–26 years) and six women (age range 18–24 years) were investigated. Their weights at birth generally exceeded the average value by 2 S.D. As a group they were not obese at the time of the investigation and neither total number of fat cells, average cell size nor body fat differed significantly from controls of the same age. There was no correlation between the number of fat cells and the weight at birth. The adipose tissue cellularity in the offspring of alloxan-diabetic rats (AX) and in controls (C) of equal weight was also studied. When sacrificed (after 40 days) body weights and the weights of the epididymal and retroperitoneal fat pads were similar in the AX and C groups. However, the number of fat cells of the retroperitoneal fat pad was significantly increased in the AX group, while the cell size was slightly diminished. Cell data of the epididymal fat pads were not significantly different. The results indicate that excessive glucose and insulin levels in utero may influence the number of fat cells, but, in man, they do not seem to lead to a permanent hyperplasia of the adipose tissue.