Angela Barini

Relationship between autonomic neuropathy, 24-h blood pressure profile, and nephropathy in normotensive IDDM patients.

OBJECTIVE To evaluate the relationship between autonomic neuropathy, nephropathy, and 24-h blood pressure (BP) pattern in insulin-dependent diabetes mellitus (IDDM). RESEARCH DESIGN AND METHODS We studied 30 normotensive IDDM patients without overt nephropathy, divided into two groups and matched for age, duration of diabetes, and HbA1 according to the presence of cardiovascular autonomic neuropathy. We simultaneously measured 24-h BP and urinary albumin excretion rate (UAE) on urine collections timed overnight and at 2-h intervals during the day. RESULTS Mean day and night systolic and diastolic BP values did not significantly differ between the groups. Mean night albuminuria was significantly higher in patients with autonomic neuropathy than in those without (61.4 ± 104.6 [mean ± SD] vs. 16 ± 25.2 μg/min, P < 0.04). The percentages day-night changes in systolic BP, diastolic BP, and UAE were significantly lower in neuropathic patients (systolic BP: 2.4 ± 7.7 vs. 9.6 ± 4.2%, P < 0.001; diastolic BP: 8.4 ± 6.9 vs. 15.5 ± 5.4%, P < 0.002; UAE: – 8 ± 99.4 vs. 49.3 ± 29.4%, P < 0.02) and were inversely related to autonomic score, index of autonomic neuropathy degree (r = –0.54, P < 0.002; r = –0.58, P < 0.001; and r = –0.53, P < 0.005, respectively). In patients with autonomic neuropathy, 2-h day periods and day and night UAE were more strongly related, respectively, to mean 2-h day periods (r = 0.58, P < 0.0001), day systolic BP (r = 0.67, P < 0.04), and night systolic BP (r = 0.69, P < 0.04) than in patients without autonomic neuropathy (2-h day periods: r = 0.32, P < 0.001; day: r = 0.37, NS; night: r = 0.35, NS). CONCLUSIONS Autonomic neuropathy in IDDM patients is associated with reduced nocturnal falls in BP and UAE and with a stronger relationship of UAE to systolic BP. We suggest a pathogenetic role of autonomic neuropathy in the development of diabetic nephropathy through changes in nocturnal glomerular function and by enhanced kidney vulnerability to hemodynamic effects of BP.

Corticotropin-releasing hormone inhibition of gonadotropin secretion during the menstrual cycle

To determine whether corticotropin-releasing hormone (CRH) exerts an inhibitory action on gonadotropin secretion in normal fertile women, the effects of CRH on luteinizing hormone (LH), follicle-stimulating hormone (FSH), and cortisol secretion were studied during the menstrual cycle. CRH had no effect on LH release during the midfollicular phase of the cycle. By contrast, IV injection of 100 micrograms CRH elicited significant decreases in LH concentrations during late follicular (-50%) and midluteal (-52%) phases of the cycle. LH concentrations decreased during the four-hours following injection of CRH and returned to those observed during the control period five hours after injection. Similarly, CRH elicited a significant decrease in FSH secretion during the midluteal phase of the cycle. CRH injection induced an increase in cortisol release during all phases of the cycle. These data demonstrate that exogenous CRH administration results in inhibition of gonadotropin secretion in late follicular and midluteal phases of the cycle. These results suggest that elevated endogenous CRH levels resulting in increased cortisol secretion could contribute to decreased gonadotropin secretion and, thus, disruption of reproductive function during stressful conditions in women.

Effects of GLP-1 on Forearm Vasodilator Function and Glucose Disposal During Hyperinsulinemia in the Metabolic Syndrome

OBJECTIVE Patients with the metabolic syndrome (MetS) have impaired insulin-induced enhancement of vasodilator responses. The incretin hormone glucagon-like peptide 1 (GLP-1), beyond its effects on blood glucose, has beneficial actions on vascular function. This study, therefore, aimed to assess whether GLP-1 affects insulin-stimulated vasodilator reactivity in patients with the MetS. RESEARCH DESIGN AND METHODS Forearm blood flow responses to acetylcholine (ACh) and sodium nitroprusside (SNP) were assessed in MetS patients before and after the addition of GLP-1 to an intra-arterial infusion of saline (n = 5) or insulin (n = 5). The possible involvement of oxidative stress in the vascular effects of GLP-1 in this setting was investigated by infusion of vitamin C (n = 5). The receptor specificity of GLP-1 effect during hyperinsulinemia was assessed by infusing its metabolite GLP-1(9-36) (n = 5). The metabolic actions of GLP-1 were also tested by analyzing forearm glucose disposal during hyperinsulinemia (n = 5). RESULTS In MetS patients, GLP-1 enhanced endothelium-dependent and -independent responses to ACh and SNP, respectively, during hyperinsulinemia (P < 0.001 for both), but not during saline (P > 0.05 for both). No changes in vasodilator reactivity to ACh and SNP were seen after GLP-1 was added to insulin and vitamin C (P > 0.05 for both) and after GLP-1(9-36) was given during hyperinsulinemia (P > 0.05 for both). Also, GLP-1 did not affect forearm glucose extraction and uptake during hyperinsulinemia (P > 0.05 for both). CONCLUSIONS In patients with the MetS, GLP-1 improves insulin-mediated enhancement of endothelium-dependent and -independent vascular reactivity. This effect may be influenced by vascular oxidative stress and is possibly exerted through a receptor-mediated mechanism.

Nonalcoholic fatty liver disease is associated with increased GHBP and reduced GH/IGF-I levels

Introduction  Nonalcoholic fatty liver disease (NAFLD) has been described in adult GH deficiency syndrome. Furthermore, chronic liver disease can be associated with significant changes in levels of IGF‐I, GH‐binding protein (GHBP), IGF‐binding proteins (IGFBPs) and acid‐labile subunit (ALS). However, the effect of liver steatosis on the GHBP production has not been investigated yet.

Tumor Necrosis Factor-α Antagonism Improves Vasodilation During Hyperinsulinemia in Metabolic Syndrome

OBJECTIVE—Obesity is associated with chronic inflammation due to overproduction of proinflammatory cytokines, including tumor necrosis factor (TNF)-α. We assessed the effects of TNF-α neutralization by infliximab on vascular reactivity during hyperinsulinemia in obesity-related metabolic syndrome. RESEARCH DESIGN AND METHODS—Vascular responses to intra-arterial infusion of acetylcholine (ACh) and sodium nitroprusside (SNP) were assessed in patients with metabolic syndrome, before and after administration of infliximab. RESULTS—Patients had blunted vasodilator responses to ACh and SNP during hyperinsulinemia compared with control subjects; a potentiation of the responsiveness to both ACh and SNP, however, was observed in patients following infliximab. The antioxidant vitamin C improved the vasodilator response to ACh in patients with metabolic syndrome, but its effect was not further enhanced by concurrent administration of infliximab. CONCLUSIONS—TNF-α neutralization ameliorates vascular reactivity in metabolic syndrome during hyperinsulinemia, likely in relation to decreased oxidative stress, thereby suggesting an involvement of inflammatory cytokines in vascular dysfunction of these patients.

Androgen and prolactin (Prl) levels in systemic sclerosis (SSc): relationship to disease severity.

Abstract:  Testosterone (T), sex hormone‐binding globulin, (SHBG), dehydroepiandrosterone sulfate (DHEAS), and prolactin (Prl) serum levels were measured by electrochemiluminescense immunoassay (ECLIA) in 39 patients with systemic sclerosis (SSc) and compared with serum hormonal levels in control subjects matched for sex and reproductive status. A possible relationship with disease duration and disease severity was examined. Our data show an altered androgen and prolactin (Prl) status in SSc patients, in most cases related to disease duration and disease severity score. We can hypothesize that hormonal dysregulation is a consequence of the chronicity of the disease. The altered hormonal status could result in relative immunological hyperactivity contributing to enhance tissue damage and disease severity.

Influence of body mass on the hypothalamic-pituitary-adrenal–axis response to naloxone in patients with polycystic ovary syndrome

OBJECTIVE To evaluate the influence of body mass on the hypothalamic-pituitary-adrenal (HPA)-axis response to naloxone in polycystic ovary syndrome (PCOS). DESIGN Controlled clinical study. SETTING Academic research environment. PATIENT(S) Ten lean and 10 obese women with PCOS compared with 7 lean and 8 obese control subjects matched for body mass index. INTERVENTION(S) Each patient received an IV bolus of naloxone at a dosage of 125 microg/kg. MAIN OUTCOME MEASURE(S) Samples were collected 30 minutes before and 0, 15, 30, 60, 90, and 120 minutes after injection: ACTH and cortisol levels were measured in all plasma samples. RESULT(S) No significant differences were found in the ACTH and cortisol responses to opioid blockade between lean women with PCOS and lean as well as obese control subjects; conversely, obese patients with PCOS showed a higher ACTH and cortisol responses to naloxone compared with all other groups. CONCLUSION(S) Hypothalamic-pituitary-adrenal-axis abnormalities of PCOS may be central in origin and abdominal obesity seems to play a key role in the HPA-axis hyperactivity of women with PCOS when naloxone is administered.

Beneficial Effects of Apelin on Vascular Function in Patients With Central Obesity

Patients with central obesity have impaired insulin-stimulated vasodilation and increased ET-1 (endothelin 1) vasoconstriction, which may contribute to insulin resistance and vascular damage. Apelin enhances insulin sensitivity and glucose disposal but also acts as a nitric oxide (NO)–dependent vasodilator and a counter-regulator of AT1 (angiotensin [Ang] II type 1) receptor–induced vasoconstriction. We, therefore, examined the effects of exogenous (Pyr1)apelin on NO-mediated vasodilation and Ang II– or ET-1–dependent vasoconstrictor tone in obese patients. In the absence of hyperinsulinemia, forearm blood flow responses to graded doses of acetylcholine and sodium nitroprusside were not different during saline or apelin administration (both P>0.05). During intra-arterial infusion of regular insulin, however, apelin enhanced the vasodilation induced by both acetylcholine and nitroprusside (both P<0.05). Interestingly, the vasodilator effect of concurrent blockade of AT1 (telmisartan) and AT2 (PD 123,319) receptors was blunted by apelin (3±5% versus 32±9%; P<0.05). Similarly, during apelin administration, blockade of ETA receptors (BQ-123) resulted in lower vasodilator response than during saline (23±10% versus 65±12%; P<0.05). NO synthase inhibition by L-NMMA (L-N-monometylarginine) during the concurrent blockade of either Ang II or ETA receptors resulted in similar vasoconstriction in the absence or presence of apelin (P>0.05). In conclusion, in patients with central obesity, apelin has favorable effects not only to improve insulin-stimulated endothelium-dependent and endothelium-independent vasodilator responses but also to blunt Ang II– and ET-1–dependent vasoconstriction by a mechanism not involving NO. Taken together, our results suggest that targeting the apelin system might favorably impact some hemodynamic abnormalities of insulin-resistant states like obesity.

Effects of oral glucose administration on plasma growth hormone levels in women with polycystic ovary syndrome

OBJECTIVE To evaluate the sensitivity of GH secretion to the suppressive effect of oral glucose administration in women with polycystic ovary syndrome (PCOS). DESIGN Comparison of the GH response to an oral glucose load in women with PCOS and in weight-matched normally menstruating women (controls). SETTING Reproductive endocrinology unit. PATIENT(S) Eighteen obese and 11 nonobese patients and 10 obese and 10 nonobese controls. INTERVENTION(S) After an overnight fast, each woman underwent a 75-g, 3-hour oral glucose tolerance test (OGTT). MEAN OUTCOME MEASURE(S) Growth hormone, glucose, and insulin responses to OGTT. RESULT(S) No significant differences in the glycemic and insulinemic responses were found between the patients and the weight-matched controls. No decrease in plasma GH was observed in both obese and nonobese patients and in obese controls during the OGTT, whereas a significant GH decrease occurred in nonobese controls 60 and 120 minutes after glucose intake. CONCLUSION(S) Oral glucose administration was unable to suppress GH levels in nonobese as well as in obese women with PCOS and in obese control women. These data suggest that both PCOS and obesity are associated with a reduced sensitivity of GH secretion to glucose suppression.

Corticotropin-releasing hormone inhibition of paradoxical growth hormone response to thyrotropin-releasing hormone in insulin-dependent diabetics

A paradoxical growth hormone (GH) response to thyrotropin-releasing hormone (TRH) has been observed in type 1 diabetic patients and was hypothetically attributed to a reduced hypothalamic somatostatin tone. We have previously reported that corticotropin-releasing hormone (CRH) inhibits GH response to growth hormone-releasing hormone (GHRH) in normal subjects, possibly by an increased release of somatostatin. To study the effect of CRH on anomalous GH response to TRH, we tested with TRH (200 micrograms intravenously [IV]) and CRH (100 micrograms IV) + TRH (200 micrograms IV) 13 patients (six males and seven women) affected by insulin-dependent diabetes mellitus. A paradoxical GH response to TRH was observed in seven of 13 patients, one man and six women. In these subjects, the simultaneous administration of CRH and TRH significantly reduced the GH response to TRH, as assessed by both the maximal GH mean peak +/- SE (2.18 +/- 0.67 v 9.2 +/- 1.26 micrograms/L, P less than 0.005) and the area under the curve (AUC) +/- SE (187 +/- 32 v 567 +/- 35 micrograms.min/L, P less than .001). CRH had no effect on TRH-induced thyroid-stimulating hormone (TSH) release. Our data demonstrate that the paradoxical GH response to TRH in patients with type 1 diabetes mellitus is blocked by CRH administration. This CRH action may be due to an enhanced somatostatin release. Our data also show that exogenous CRH has no effect on TSH response to TRH, thus suggesting the existence of separate pathways in the neuroregulation of GH and TSH secretion.