Biomedical subjects

Stephen G Matthews

Publications and source records attributed to Stephen G Matthews.

25 records · Page 2Linked to original sources

PubMed2004

Partial leptin restoration increases hypothalamic-pituitary-adrenal activity while diminishing weight loss and hyperphagia in streptozotocin diabetic rats.

Chronic leptin administration at pharmacologic doses normalizes food intake and body weight in streptozotocin (STZ)-diabetic rats. We examined the metabolic effects of acute partial physiological leptin restoration in STZ-diabetic rats by using subcutaneous osmotic mini pumps. Groups: (1) Rats infused with vehicle (DV); (2) rats infused with recombinant murine methionine leptin (DL) at 4.5 microg . (kg body weight . d)(-1); (3)pair-fed rats (DP) given a food ration matching that consumed by the DL group. A fourth group of nondiabetic, normal (N) rats was also studied to assess normal metabolic efficiency, hypothalamic-pituitary-adrenal (HPA) activity and sympathoadrenal activity. Following leptin infusion, food consumption by DL rats was significantly lower than in DV rats. Paradoxically, despite a similar food intake to that of the DP group, which demonstrated a 40% reduction in body mass, DL rats increased their initial body weight by approximately 20% (P < .05). Plasma corticosterone and ACTH concentrations were elevated by 2-fold to 3-fold in DL versus N, DP, and DV rats. In the pars distalis, glucocorticoid receptor (GR) mRNA levels were significantly higher in DL and DP rats compared with N and DV rats. Our results suggest that partial restoration of physiologic leptin: (1) successfully reduces hyperphagia while allowing body weight gain in STZ-diabetic rats; (2) increases corticosterone levels in STZ-diabetic rats, which may in turn counteract the anorexic effects of diabetes; and (3) is associated with increased pituitary GR mRNA levels, despite elevated corticosterone levels, suggesting that leptin may interfere with the negative feedback regulation of the HPA axis.

Adrenocorticotropic Hormone↗

PubMed2004

Programming of the hypothalamo-pituitary-adrenal axis: serotonergic involvement.

The ability of the early environment to programme the developing hypothalamo-pituitary-adrenal (HPA) axis has been reported in several animal species. There is considerable evidence that a similar process can occur in the human, and that long-term alterations in HPA function are associated with altered susceptibility to disease in later life. The phenotype of HPA function following early manipulation depends on the timing and intensity of the manipulation as well as the gender of the fetus/neonate. There is considerable interplay between the developing HPA and the reproductive axes and emerging evidence indicates that this interaction is modified by early environmental manipulation. Studies are rapidly unravelling the mechanisms that underlie developmental programming of the HPA axis. In this context, the serotonergic system has been identified as a primary system involved in this process. Understanding the mechanisms involved in neuroendocrine programming will facilitate the development of interventions aimed at reversing or ameliorating the impact of an adverse intrauterine environment.

Animals↗

PubMed2003

Glucocorticoids and sex-dependent development of brain glucocorticoid and mineralocorticoid receptors.

We have previously shown that repeated antenatal synthetic glucocorticoid exposure has sex-specific effects on hypothalamic-pituitary-adrenal development in the fetal and adult guinea pig. However, little is known about the mechanisms that underlie these sex-specific outcomes. In the current study we demonstrated that glucocorticoid receptors (GR) and mineralocorticoid receptors (MR) exhibit sex differences in their temporal and spatial expression during fetal and early postnatal life. During development, we observed decreased GR mRNA in the paraventricular nucleus, decreased MR mRNA and MR protein in the hippocampus, and increased GR mRNA and GR protein in the hippocampus. We have also shown that on gestational d 50, maternally administered betamethasone (BETA) reduces fetal plasma ACTH and cortisol concentrations. BETA significantly affected hippocampal MR protein expression, and this effect was greatest in males. BETA was unable to autoregulate GR protein during fetal life, indicating that regulation of brain corticosteroid receptors is fundamentally different in fetal compared with adult life. The sex differences in the pattern of GR and MR expression during development may indicate different windows of vulnerability to prenatal glucocorticoid exposure in fetal life.

Adrenocorticotropic Hormone↗

PubMed2002

Early programming of the hypothalamo-pituitary-adrenal axis.

The ability of the early environment to program the hypothalamo-pituitary-adrenal (HPA) axis has been documented in several species. There is considerable evidence that a similar process can also occur in humans. Studies of animals indicate that the phenotype of HPA function following early manipulation depends on the timing and intensity of the manipulation, in addition to the gender of the fetus or neonate. There is considerable interplay between the HPA and the hypothalamo-pituitary-gonadal axes, and emerging evidence indicates that this interaction is modified by early environmental manipulation. Studies are rapidly unraveling the mechanisms that underlie developmental programming of the HPA axis. Understanding these mechanisms could hold the key to the development of therapeutic interventions aimed at reversing the impact of an adverse intrauterine or neonatal environment.

Adrenal Glands↗

PubMed2002

Effects of recurrent hyperinsulinemia with and without hypoglycemia on counterregulation in diabetic rats.

To understand the mechanisms whereby recurrent hypoglycemia increases the risk of subsequent hypoglycemia, it was necessary to differentiate the effects of recurrent hyperinsulinemia from those of hyperinsulinemic hypoglycemia. We examined basal and hypoglycemic endocrine function in normal rats, streptozotocin-diabetic controls, and diabetic rats exposed to 4 days of 2 episodes/day of hyperinsulinemic hypoglycemia (DH) or hyperinsulinemic hyperglycemia (DI). DH and DI rats differentiated the effects of hyperinsulinemia from those of hypoglycemia. In diabetic controls, basal plasma ACTH tended to be increased, and plasma corticosterone, plasma somatostatin, and pancreatic prosomatostatin and proglucagon mRNA were increased (P < 0.05) vs. normal rats. These parameters were normalized in DH and DI rats. In diabetic controls, glucagon, epinephrine, norepinephrine, corticosterone, and peak glucose production responses to hypoglycemia were reduced (P < 0.05) vs. normal rats. In DI rats, epinephrine responses were normalized. Conversely, DH rats displayed marked further impairment of epinephrine and glucose production responses and increased peripheral insulin sensitivity (P < 0.05 vs. diabetic controls). Both insulin regimens partially normalized glucagon and fully normalized norepinephrine and corticosterone responses. In summary, recurrent hyperinsulinemia in diabetic rats normalized most pituitary-adrenal, sympathoadrenal, and pancreatic parameters. However, concurrent hypoglycemia further impaired epinephrine and glucose production responses and increased insulin sensitivity. We conclude that 1) recurrent hypoglycemia may increase the risk of subsequent hypoglycemia by increasing insulin sensitivity, and 2) epinephrine counterregulation is particularly sensitive to impairment by recurrent hypoglycemia.

Adrenocorticotropic Hormone↗

PubMed2002

Hyperactivation of the hypothalamo-pituitary-adrenocortical axis in streptozotocin-diabetes is associated with reduced stress responsiveness and decreased pituitary and adrenal sensitivity.

Although increased hypothalamo-pituitary-adrenocortical (HPA) activity has been reported in diabetic patients, the mechanisms underlying hyperactivation are still unclear. We investigated whether alterations in pituitary, adrenal and/or glucocorticoid negative feedback sensitivity in diabetes are responsible for 1) the impaired HPA response to stress and 2) basal hyperactivation of the HPA axis. Normal control, untreated streptozotocin-diabetic and insulin-treated diabetic rats were chronically catheterized. Eight days following surgery, pituitary-adrenal function was monitored throughout the day. Stress responsiveness was evaluated using 20 min of restraint on d 10. Thereafter, the rats were treated with CRH (0.5 microg/kg), ACTH(1-24) (75ng/kg) or dexamethasone (25 microg/kg) iv on d 12, 14, and 16 to evaluate pituitary, adrenal and glucocorticoid feedback sensitivity, respectively. Plasma ACTH and corticosterone (B) concentrations in untreated diabetic rats were significantly higher at 0800 h, but no different at 1300 h or 1800 h. Insulin treatment of diabetic rats normalized ACTH and B concentrations at 0800 h. The pituitary-adrenal response to restraint was greatly diminished in untreated diabetic rats, whereas insulin treatment partially restored this response in diabetic rats. Administration of CRH and ACTH revealed reduced pituitary and adrenal sensitivity in untreated diabetic animals compared with both control and insulin-treated diabetic animals. The dexamethasone suppression test indicated decreased glucocorticoid negative feedback sensitivity in diabetic rats, which was restored with insulin treatment. In conclusion, these studies demonstrate that: 1) impaired stress responsiveness of the diabetic HPA axis involves both decreased pituitary and adrenal sensitivity; and 2) basal hyperactivation of the diabetic HPA axis in the morning is due, in part, to decreased glucocorticoid negative feedback sensitivity.

Adrenal Glands↗

PubMed2002

Diabetes impairs hypothalamo-pituitary-adrenal (HPA) responses to hypoglycemia, and insulin treatment normalizes HPA but not epinephrine responses.

We recently established that in addition to plasma adrenocorticotrophic hormone (ACTH) and corticosterone, hypothalamic corticotrophin-releasing hormone (CRH) mRNA and hippocampal type 1 glucocorticoid receptor (GR1) mRNA were also upregulated in uncontrolled streptozotocin-induced diabetes. In the current study, control, diabetic, and insulin-treated diabetic rats underwent a hyperinsulinemic-hypoglycemic glucose clamp to evaluate central mechanisms of hypothalamo-pituitary-adrenal (HPA) and counterregulatory responses to insulin-induced hypoglycemia. Increases in plasma ACTH, corticosterone, and epinephrine were significantly lower in diabetic rats versus controls. Insulin treatment restored ACTH and corticosterone but not epinephrine responses to hypoglycemia in diabetic rats. Glucagon and norepinephrine responses to hypoglycemia were not affected by diabetes or insulin treatment. In response to hypoglycemia, hypothalamic CRH mRNA and pituitary proopiomelanocortin mRNA expression increased in control and insulin-treated but not in untreated diabetic rats. Arginine vasopressin mRNA was unaltered by hypoglycemia in all groups. Interestingly, hypoglycemia decreased hippocampal GR1 mRNA expression in control and insulin-treated diabetic rats but not in diabetic rats. In contrast, type 2 glucocortoid receptor (GR2) mRNA was not altered by hypoglycemia. In conclusion, despite increased basal HPA activity, HPA responses to hypoglycemia were markedly reduced in uncontrolled diabetes. We speculate that the defect in CRH response could be related to the defective GR1 response. It is intriguing that insulin treatment restored the HPA response to hypoglycemia but, surprisingly, not the deficient epinephrine response. This is important because during severe hypoglycemia, epinephrine is an important counterregulatory hormone.

Adrenal Glands↗