Effects of birth weight, sex and neonatal glucocorticoid overexposure on glucose-insulin dynamics in young adult horses.

In several species, adult metabolic phenotype is influenced by the intrauterine environment, often in a sex-linked manner. In horses, there is also a window of susceptibility to programming immediately after birth but whether adult glucose-insulin dynamics are altered by neonatal conditions remains unknown. Thus, this study investigated the effects of birth weight, sex and neonatal glucocorticoid overexposure on glucose-insulin dynamics of young adult horses. For the first 5 days after birth, term foals were treated with saline as a control or ACTH to raise cortisol levels to those of stressed neonates. At 1 and 2 years of age, insulin secretion and sensitivity were measured by exogenous glucose administration and hyperinsulinaemic-euglycaemic clamp, respectively. Glucose-stimulated insulin secretion was less in males than females at both ages, although there were no sex-linked differences in glucose tolerance. Insulin sensitivity was greater in females than males at 1 year but not 2 years of age. Birth weight was inversely related to the area under the glucose curve and positively correlated to insulin sensitivity at 2 years but not 1 year of age. In contrast, neonatal glucocorticoid overexposure induced by adrenocorticotropic hormone (ACTH) treatment had no effect on whole body glucose tolerance, insulin secretion or insulin sensitivity at either age, although this treatment altered insulin receptor abundance in specific skeletal muscles of the 2-year-old horses. These findings show that glucose-insulin dynamics in young adult horses are sexually dimorphic and determined by a combination of genetic and environmental factors acting during early life.

Effects of maternal dexamethasone treatment on pancreatic ß cell function in the pregnant mare and post natal foal.

REASONS FOR PERFORMING STUDY: Synthetic glucocorticoids are used to treat inflammatory conditions in horses. In other pregnant animals, glucocorticoids are given to stimulate fetal maturation with long-term metabolic consequences for the offspring if given preterm. However, their metabolic effects during equine pregnancy remain unknown. OBJECTIVE: Thus, this study investigated the metabolic effects of dexamethasone administration on pregnant pony mares and their foals after birth. STUDY DESIGN: Experimental study. METHODS: A total of 3 doses of dexamethasone (200 µg/kg bwt i.m.) were given to 6 pony mares at 48 h intervals beginning at ≈270 days of pregnancy. Control saline injections were given to 5 mares using the same protocol. After fasting overnight, pancreatic ß cell responses to exogenous glucose were measured in the mares before, during and after treatment. After birth, pancreatic ß cell responses to exogenous glucose and arginine were measured in the foals at 2 and 12 weeks. RESULTS: In mares during treatment, dexamethasone but not saline increased basal insulin concentrations and prolonged the insulin response to exogenous glucose. Basal insulin and glucose concentrations still differed significantly between the 2 groups 72 h post treatment. Dexamethasone treatment significantly reduced placental area but had little effect on foal biometry at birth or subsequently. Foal ß cell function at 2 weeks was unaffected by maternal treatment. However, by 12 weeks, pancreatic ß cell sensitivity to arginine, but not glucose, was less in foals delivered by dexamethasone- than saline-treated mares. CONCLUSIONS: Dexamethasone administration induced changes in maternal insulin-glucose dynamics, indicative of insulin resistance and had subtle longer term effects on post natal ß cell function of the foals. The programming effects of dexamethasone in horses may be mediated partially by altered maternal metabolism and placental growth.

Neonatal glucocorticoid overexposure programs pituitary-adrenal function in ponies.

The present study tested the hypothesis that overexposure to endogenous glucocorticoids in neonatal life alters the reactivity of the hypothalamic-pituitary-adrenal (HPA) axis in ponies at 1 and 2 yr of age. Newborn foals received saline (0.9% NaCl, n = 8, control) or long-acting adrenocorticotropic hormone (ACTH1-24) (Depot Synacthen 0.125 mg intramuscularly twice daily, n = 9) for 5 d after birth to raise cortisol concentrations 5- to 6-fold. At 1 and 2 yr of age, HPA axis function was assessed by bolus administration of short-acting ACTH1-24 (1 µg/kg intravenous) and insulin (0.5 U/kg intravenous) to induce hypoglycemic on separate days. Arterial blood samples were taken at 5 to 30-min intervals before and after drug administration to measure plasma ACTH and/or cortisol concentrations. There were no differences in the basal plasma ACTH or cortisol concentrations or in the cortisol response to exogenous ACTH1-24 with neonatal treatment or age. At 1 and 2 yr of age, the increment in plasma ACTH but not cortisol at 60 min in response to insulin-induced hypoglycemia was greater in ponies treated neonatally with ACTH than saline (P < 0.05). Neonatal cortisol overexposure induced by neonatal ACTH treatment, therefore, alters functioning of the HPA axis in adult ponies.

Sex-associated differences in pancreatic ß cell function in healthy preweaning pony foals.

REASONS FOR PERFORMING STUDY: Pancreatic ß cells are responsive to a range of stimuli during early post natal life in healthy pony foals. However, little is known about whether these responses are sex-linked. OBJECTIVES: To determine pancreatic ß cell responses to the insulin secretagogues, glucose, arginine and tolbutamide, in fillies and colts during the first 3 months after birth. STUDY DESIGN: In vivo experiment examining sex differences in pancreatic ß cell function in foals. METHODS: Female (n = 8) and male (n = 5) pony foals were infused i.v. with glucose (0.5 g/kg bwt 40% dextrose), arginine (100 mg/kg bwt) or tolbutamide (10 or 20 mg/kg bwt) over 5 min, at 48 h intervals, to assess pancreatic ß cell function at ages 2 and 12 weeks. Blood samples (4 ml) were taken through a jugular catheter at -30, -15 and 0 min (immediately before) and 5, 15, 30, 45, 60, 90 and 120 min after glucose, arginine and tolbutamide administration for measurements of plasma glucose, α-amino-nitrogen and insulin concentrations. RESULTS: The maximum increment in plasma insulin concentration in response to glucose was significantly higher in female (395 ± 58 ng/l) than male (172 ± 37 ng/l, P<0.05) pony foals 2 weeks after birth and the area under the insulin curve was significantly greater in females at this age. At 12 weeks, the insulin increment in response to glucose was significantly greater in fillies 45 min post infusion. The ß cell responses to arginine and tolbutamide were not sex-linked at either age. CONCLUSIONS: These data show that in ponies, fillies have a greater ß cell response to glucose than colts in early post natal life. Since glucose clearance was unaffected by sex, the results suggest that fillies may be less insulin sensitive than colts shortly after birth. Innate sex differences in the secretion and action of insulin in early post natal life may influence tissue development and growth with potentially more long-term metabolic consequences.

Glucocorticoid overexposure in neonatal life alters pancreatic beta-cell function in newborn foals.

Studies in humans and animals have linked abnormal programming of adult tissue function to excess glucocorticoids during perinatal development. The current study investigated the hypothesis that physiological variations in glucocorticoid concentrations during early neonatal life of the foal alter the secretory responses of the pancreatic ß cells 2 and 12 wk after treatment. Spontaneously delivered foals received either saline or long-acting ACTH for 5 d from 1 d after birth to maintain an endogenous rise in cortisol concentrations. Starting at d 10, pancreatic ß cell function was studied using an intravenous (i.v.) glucose tolerance test, an i.v. arginine challenge, and an i.v. tolbutamide challenge. The maximum increment in plasma insulin achieved in response to exogenous glucose was less in ACTH-treated foals at both 2 and 12 wk of age (P<0.05). By 12 wk of age, developmental changes also occurred in the magnitude and biphasic pattern of glucose-stimulated insulin release. The area under the insulin curve during the early phase of insulin secretion (0 to 30 min) was not different between the 2- and 12-wk-old animals but was significantly greater during the later phase (30 to 120 min) at 12 wk than at 2 wk (P<0.05). Arginine infusion induced a brief 5 to 15 min increase in plasma concentrations of insulin that was not different in saline- and ACTH-treated foals. The ß-cell response to tolbutamide infusion was rapid and monophasic, and there was no difference (P>0.05) in the area under the insulin curve with treatment at 2 or at 12 wk. However, after tolbutamide, plasma insulin concentrations remained increased for a longer period in the ACTH-treated than in the saline-treated foals at 12 wk of age (P<0.05). Hence, this is the first study to show altered pancreatic ß-cell function after ACTH-induced glucocorticoid overexposure during early postnatal life in foals.

Pancreatic endocrine function in newborn pony foals after induced or spontaneous delivery at term.

REASONS FOR PERFORMING STUDY: During the switch from parenteral to enteral nutrition at birth, endocrine glands such as the pancreas must assume a glucoregulatory role for the first time if the neonate is to survive the transition to extrauterine life. OBJECTIVES: To determine the adaptations in pancreatic endocrine function during the neonatal period in term pony foals delivered by different methods. METHODS: By measuring insulin and glucagon concentrations, pancreatic alpha and beta cell responses to exogenous glucose (0.5 g/kg bwt) and arginine (100 mg/kg bwt) and to endogenous muzzling for 90 min were determined periodically over the first 10 post natal days in foals born spontaneously (n = 8) or by induction of labour with oxytocin at term (n = 7). RESULTS: Pancreatic alpha and beta cell function changed with post natal age in a manner related to the method of delivery. Induced foals had 2-3 fold greater beta cell responses to exogenous glucose and arginine, despite similar glucose and alpha-amino nitrogen clearances compared with spontaneously delivered foals. Pancreatic beta cell responses to glucose decreased by 50% while those to arginine doubled with increasing age in induced but not spontaneously delivered foals. In contrast, pancreatic alpha cell responses to arginine doubled with increasing age in foals born spontaneously but not by induction. These differences in pancreatic endocrine cell function with delivery method were associated with 2-3 fold higher cortisol levels in the induced foals and with differences in the absolute and age-related changes in basal concentrations of glucose, alpha-amino nitrogen and insulin. CONCLUSIONS: Induced delivery leads to changes in pancreatic beta cell sensitivity to glucose and/or tissue insulin resistance in association with persistent neonatal hypercortisolaemia. POTENTIAL RELEVANCE: The altered post natal development of pancreatic endocrine function with induced delivery may compromise glucoregulation and adaptation to enteral nutrition in neonatal foals with potential consequences long after birth.

Hypothalamic-pituitary-adrenal axis function in pony foals after neonatal ACTH-induced glucocorticoid overexposure.

REASONS FOR PERFORMING THE STUDY: The effects of overexposure to glucocorticoids during early life of the foal on the subsequent HPA programming of the hypothalamic-pituitary-adrenal axis are unknown. OBJECTIVES: To test the hypotheses that excess glucocorticoid exposure in early life subsequently increases both basal plasma concentrations of cortisol and the adrenocortical responsiveness to exogenous adrenocorticotropic hormone (ACTH). METHODS: Foals received either saline (0.9% NaCl, n = 9) or long-acting ACTH (0.125 mg i.m. b.i.d., n = 6) for 5 days from Day 1 to increase endogenous cortisol concentrations. Long-term indwelling catheters were inserted under local anaesthesia into the jugular veins of foals aged 2 and 12 weeks. After recovery, short-acting ACTH1-24 was given as a single i.v. injection (2 microg/kg bwt) and blood samples were taken at 5-30 min intervals before and after ACTH administration to measure plasma cortisol concentrations. RESULTS: Basal plasma cortisol concentrations were higher in ACTH- than in saline-treated foals at age 3 weeks, but not at 13 weeks. There were no significant differences in either the time profile or the area under the cortisol curve in response to ACTH between the 2 groups. CONCLUSIONS: These data suggest that ACTH-induced overexposure to glucocorticoids during early post natal life of the foal does not have a programming effect on HPA axis function at 13 weeks. In foals, the effects of ACTH-induced overexposure to glucocorticoids, if any, may not become apparent until much later in life in a long-lived species such as the horse. POTENTIAL RELEVANCE: These studies suggest that clinical and other stressful conditions that raise plasma cortisol concentrations during early life are unlikely to programme cardiovascular and metabolic function in horses in the short term.

Development of insulin and proinsulin secretion in newborn pony foals.

At birth, the endocrine pancreas must assume a glucoregulatory role if the neonate is to survive the transition from parenteral to enteral nutrition. In species like the horse, neonatal hypoglycaemia is common, which suggests that the glucoregulatory mechanisms are not always fully competent at birth. Hence, this study examined pancreatic beta cell function in newborn foals during nutritional adaptation over the first 10 days post partum. Over a 48 h period at three time intervals after birth (days 1-2, 5-6 and 9-10 post partum), the beta cell responses to suckling and to intravenous administration of glucose, arginine and saline were measured in seven normal pony foals. Basal plasma concentrations of proinsulin, but not insulin or glucose, increased significantly between days 1 and 10. Suckling caused a gradual increase in plasma glucose, which was accompanied by a significant increase in plasma insulin concentrations 15 min after the onset of suckling on days 5 and 9, but not day 1. There was no significant change in plasma proinsulin concentrations in response to suckling at any age. At all ages studied, glucose and arginine administration stimulated an increase in the plasma concentrations of insulin and proinsulin; these beta cell responses did not change significantly with postnatal age. The insulin responses to glucose were significantly greater than those of arginine at each time period. Glucose clearance was significantly slower on day 1 than subsequently. Proinsulin and glucose, but not insulin, concentrations decreased significantly after saline administration at all three ages. At each time period, there was a significant positive relationship between the plasma insulin and proinsulin concentrations, the slope of which was significantly shallower on days 1-2 than subsequently. These results show that equine beta cells are responsive to glucose and arginine and release both insulin and proinsulin during the immediate postnatal period. They also suggest that newborn foals may be insulin resistant on the first day after birth.

Modular PH and C2 domains in membrane attachment and other functions.

The pleckstrin homology and C2 domains are modular protein structures involved in mediating intermolecular interactions. Although they represent distinct domains, there are several parallels regarding their function and type of interactions in which they participate. Both domains are stable structural entities that incorporate variable regions which, in different proteins, can be adapted to perform a specific function through binding to membrane phospholipids or specific protein ligands. A number of recent examples illustrate the function of some of these domains in regulated membrane attachment, with an important role in many cellular signalling pathways.

Biological maturation and social development: A longitudinal study of some adjustment processes from mid-adolescence to adulthood.

The role of biological maturity in behaviors in adolescence which most often are considered as negative by adults was investigated for a normal group of girls. In mid-adolescence early matured girls were found to play truant, smoke hashish, get drunk, pilfer, ignore parents' prohibitions, considerably more often than did late maturing girls. These differences between biological age groups were mediated by the association with older peer groups and they leveled out in late adolescence. Data on alcohol consumption and crime at adult age showed little association with biological maturation. A hypothesis was tested suggesting that early biological maturation may have negative long-term consequences within the education domain. In accord with this assumption, a considerably smaller percentage of girls among the early maturers had a theoretical education above the obligatory nine-year compulsory schooling than among the late maturing girls. The association between biological maturation and adult education was significant also after controlling for standard predictors of education, such as the girls' intelligence and the social status of the home. The requirement of conducting longitudinal studies when investigating issues connected with maturation was strongly emphasized.