Gender differences in the relationship between heart rate control and adiposity in young children: a cross-sectional study (EarlyBird 33).

BACKGROUND: The role of the autonomic nervous system in the complex link between insulin resistance and cardiovascular risk remains unclear. Increased sympathetic nervous system activity has been implicated in the pathophysiology of insulin resistance but is confounded by a number of factors. METHODS: We have therefore examined the relationship among cardiac autonomic control, insulin resistance, habitual physical activity, resting energy expenditure (REE), and anthropometric variables in a subset (107 boys, 101 girls, age 9 +/- 0.25 yr) of the EarlyBird cohort. Cardiac autonomic activity was assessed using time domain and power spectral density analysis methods of heart rate variability. Insulin resistance was measured using homeostasis model assessment of insulin resistance (HOMA2-IR). RESULTS: Girls, in comparison to boys, showed significantly higher resting heart rate and lower systolic blood pressure (BP); were more insulin resistant; undertook less physical activity, and had lower fat-free mass and REE. Increasing fasting insulin and increasing insulin resistance were associated with increasing BP. CONCLUSION: The data suggest early gender differences in predictors of cardiac autonomic control. Pubertal staging was not undertaken in this study, and we plan to evaluate this in future studies to further clarify these associations.

Chronic fatigue: is it endocrinology?

Fatigue and stress-related illnesses often become diagnoses of exclusion after extensive investigation. 'Tired all the time' is a frequent reason for referral to the endocrine clinic, the implicit question being--is there a subtle endocrine pathology contributing to the patient's symptoms? Often initial assessment suggests not but there are no clear data to address the question of whether overt pathology will develop in the future. This study observed outcomes after five years in 101 consecutive and unselected referrals to secondary care for 'fatigue?cause', where initial assessment did not suggest treatable endocrine pathology. The findings suggest that the clinical diagnosis of fatigue, based on history and tests to exclude anaemia, hypothyroidism and diabetes, is secure: these patients do not subsequently demonstrate excess morbidity and mortality, and their presenting symptoms are not early features of significant endocrine pathology.

Gender differences in the relationship between leptin, insulin resistance and the autonomic nervous system.

OBJECTIVES: Leptin, an important hormonal regulator of body weight, has been shown to stimulate the sympathetic nervous system (SNS) in vitro although the physiological relevance remains unclear. Increased SNS activity has been implicated in the pathogenesis of insulin resistance and an increased cardiovascular risk. We have therefore investigated the relationship between leptin, insulin resistance and cardiac autonomic activity in healthy young adults. 130 healthy men and women age 20.9 years were studied. Insulin sensitivity was assessed using the IVGTT and minimal model with simultaneous measures of leptin. Cardiac autonomic activity was assessed using spectral analysis of heart rate variability. RESULTS: Women showed significantly higher fasting leptin, heart rate and cardiac sympathetic activity, and lower insulin sensitivity. Men showed inverse correlations between insulin resistance and heart rate, and between insulin resistance and cardiac sympatho-vagal ratio. Women, in contrast, showed no SNS relationship with insulin resistance, but rather an inverse correlation between leptin and the sympatho-vagal ratio, suggesting that leptin in women is associated with SNS activity. The correlation remained significant after adjustment for BMI and waist-to-hip ratio (beta=-0.33 and p=0.008). CONCLUSION: Insulin resistance and SNS activity appear to be linked, although the relationship showed marked gender differences, and the direction of causality was unclear from this cross-sectional study. Leptin appears to exert a greater effect on the SNS in women, possibly because of their greater fat mass.

Hypothalamic ATP-sensitive K + channels play a key role in sensing hypoglycemia and triggering counterregulatory epinephrine and glucagon responses.

It has been postulated that specialized glucose-sensing neurons in the ventromedial hypothalamus (VMH) are able to detect falling blood glucose and trigger the release of counterregulatory hormones during hypoglycemia. The molecular mechanisms used by glucose-sensing neurons are uncertain but may involve cell surface ATP-sensitive K(+) channels (K(ATP) channels) analogous to those of the pancreatic beta-cell. We examined whether the delivery of sulfonylureas directly into the brain to close K(ATP) channels would modulate counterregulatory hormone responses to either brain glucopenia (using intracerebroventricular 5-thioglucose) or systemic hypoglycemia in awake chronically catheterized rats. The closure of brain K(ATP) channels by global intracerebroventricular perfusion of sulfonylurea (120 ng/min glibenclamide or 2.7 microg/min tolbutamide) suppressed counterregulatory (epinephrine and glucagon) responses to brain glucopenia and/or systemic hypoglycemia (2.8 mmol/l glucose clamp). Local VMH microinjection of a small dose of glibenclamide (0.1% of the intracerebroventricular dose) also suppressed hormonal responses to systemic hypoglycemia. We conclude that hypothalamic K(ATP) channel activity plays an important role in modulating the hormonal counterregulatory responses triggered by decreases in blood glucose. Our data suggest that closing of K(ATP) channels in the VMH (much like the beta-cell) impairs defense mechanisms against glucose deprivation and therefore could contribute to defects in glucose counterregulation.

Role of corticotrophin-releasing hormone in the impairment of counterregulatory responses to hypoglycemia.

We have explored the role of individual elements of the hypothalamic pituitary adrenal axis on the pathogenesis of hypoglycemia-associated autonomic failure. Five groups of male Sprague-Dawley rats were used. Control animals had 3 days of sham treatment followed by a hyperinsulinemic/hypoglycemic glucose clamp on day 4. A second group underwent 3 days of antecedent insulin-induced hypoglycemia then a subsequent clamp. Three more groups underwent pretreatment with corticosterone, adrenocorticotrophic hormone (ACTH), or corticotrophin-releasing hormone (CRH) mirroring the glucocorticoid response of the hypoglycemic group. Subsequent counterregulatory responses showed marked differences. CRH- (and insulin-treated) animals showed markedly reduced epinephrine responses (CRH 1,276 +/- 404 pg/ml, controls 3,559 +/- 563 pg/ml; P < 0.05). In contrast, ACTH pretreatment augmented epinephrine responses (6,681 +/- 814 pg/ml; P = 0.007 versus controls); corticosterone pretreatment caused a similar but nonsignificant enhancement. The same pattern was seen for norepinephrine. CRH pretreatment also suppressed glucagon responses to hypoglycemia (control 157 +/- 21, CRH 68 +/- 10 pg/ml; P = 0.004). The addition of a CRH receptor 1 (CRHr1) antagonist to the antecedent CRH reversed the subsequent suppression of epinephrine. These findings suggest that CRH acting via CRHr1 plays an important role in the sympathoadrenal downregulation seen in this rodent model of antecedent hypoglycemia; this action is not mediated via activation of the hypothalamic-pituitary-adrenal axis.

Do sensor glucose levels accurately predict plasma glucose concentrations during hypoglycemia and hyperinsulinemia?

OBJECTIVE: The MiniMed Continuous Glucose Monitoring System (CGMS) measures subcutaneous interstitial glucose levels that are calibrated against three or more fingerstick glucose levels daily. The objective of the present study was to examine whether the relationship between plasma and interstitial fluid glucose is altered by changes in plasma glucose and insulin levels and how such alterations might influence CGMS performance. RESEARCH DESIGN AND METHODS: Arterialized plasma glucose, sensor glucose, and interstitial fluid glucose were measured by microdialysis in 11 healthy subjects during a 1.0 mU. kg(-1). min(-1) stepped euglycemic-hypoglycemic-hyperglycemic (plasma glucose approximately 5, 3.1, and 8.6 mmol/l, respectively) insulin clamp that raised plasma insulin to approximately 360-390 pmol/l. RESULTS: When the CGMS was calibrated versus plasma glucose levels before insulin infusion, basal sensor and plasma glucose were similar (5.0 +/- 0.3 vs. 5.2 +/- 0.3 mmol/l, respectively); dialysate glucose was 3.3 +/- 0.9 mmol/l. During the hyperinsulinemic-euglycemia study (plasma glucose 4.9 +/- 0.3 mmol/l), dialysate glucose fell by 30-35%, accompanied by a significant reduction in sensor glucose (to 3.7 +/- 0.6 mmol/l; P < 0.001 vs. plasma). Subsequently, sensor levels remained lower than plasma values during mild hypoglycemia (2.5 +/- 0.6 vs. 3.1 +/- 0.3 mmol/l; P < 0.01) and during recovery from hypoglycemia (7.3 +/- 1.2 vs. 8.6 +/- 0.6; P < 0.01). However, when the CGMS was calibrated against plasma glucose levels before and during each step of the clamp, sensor glucose levels increased throughout the study and did not differ from plasma glucose values during hypoglycemia. CONCLUSIONS: Although hyperinsulinemia may contribute to modest discrepancies between plasma and sensor glucose levels, the CGMS is able to accurately track acute changes in plasma glucose when calibrated across a range of plasma glucose and insulin levels.

Hypoglycemia reduces the blood-oxygenation level dependent signal in primary auditory and visual cortex: a functional magnetic resonance imaging study.

Studies of the effects of hypoglycemia on the brain using neurocognitive testing have suggested that mainly complex functions subserved by secondary and tertiary cortex are affected by mild to moderate hypoglycemia and that intensively treated patients with Type I diabetes mellitus (T1DM) may have altered sensitivity to the central nervous system effects of hypoglycemia. Functional magnetic resonance imaging provides a sensitive, regionally-specific probe of possible neurophysiologic changes related to hypoglycemia in the brain. Eleven intensively-treated T1DM patients and 11 matched non-diabetic controls took part in a 2-day protocol in which functional magnetic resonance imaging (MRI) was used to measure changes in the patterns of brain activation produced by simple auditory and visual stimuli in different conditions. On one day, participants were euglycemic the entire time. On the other day, an initial 50-min euglycemic period was followed by a 50-min hypoglycemic period. Results indicated that hypoglycemia reduced the amplitude of the blood-oxygenation level dependent response in primary auditory and visual cortex to simple auditory and visual stimuli. The latency and duration of the transient hemodynamic response function were not affected. Responses to hypoglycemia were similar in diabetic and non-diabetic participants. These results suggest that mild to moderate hypoglycemia may alter the balance of blood flow and oxygen extraction when glucose levels are lowered. Intensively-treated T1DM, with its attendant frequent hypoglycemic episodes, did not seem to alter hypoglycemic responses in primary visual and auditory cortex.

The influence of insulin on circulating ghrelin.

Ghrelin is a novel peptide that acts on the growth hormone (GH) secretagogue receptor in the pituitary and hypothalamus. It may function as a third physiological regulator of GH secretion, along with GH-releasing hormone and somatostatin. In addition to the action of ghrelin on the GH axis, it appears to have a role in the determination of energy homeostasis. Although feeding suppresses ghrelin production and fasting stimulates ghrelin release, the underlying mechanisms controlling this process remain unclear. The purpose of this study was to test the hypotheses, by use of a stepped hyperinsulinemic eu- hypo- hyperglycemic glucose clamp, that either hyperinsulinemia or hypoglycemia may influence ghrelin production. Having been stable in the period before the clamp, ghrelin levels rapidly fell in response to insulin infusion during euglycemia (baseline ghrelin 207 +/- 12 vs. 169 +/- 10 fmol/ml at t = 30 min, P < 0.001). Ghrelin remained suppressed during subsequent periods of hypoglycemia (mean glucose 53 +/- 2 mg/dl) and hyperglycemia (mean glucose 163 +/- 6 mg/dl). Despite suppression of ghrelin, GH showed a significant rise during hypoglycemia (baseline 4.1 +/- 1.3 vs. 28.2 +/- 3.9 microg/l at t = 120 min, P < 0.001). Our data suggest that insulin may suppress circulating ghrelin independently of glucose, although glucose may have an additional effect. We conclude that the GH response seen during hypoglycemia is not regulated by circulating ghrelin.