Sex-difference of multifactorial intervention on cardiovascular and mortality risk in DKD: post-hoc analysis of a randomised clinical trial.

OBJECTIVE: Women with type 2 diabetes experience higher cardiovascular and mortality risk than men possibly because of a sub-optimal cardio-protective treatment. We evaluated whether an intensive multifactorial therapy (MT) produces similar protective effect on development of adverse outcomes in women and men. RESEARCH DESIGN AND METHODS: Nephropathy in Diabetes type 2 study is an open-label cluster randomized trial comparing the effect of Usual Care (UC) or MT of main cardiovascular risk factors (blood pressure < 130/80 mmHg, HbA1c < 7%, LDL < 100 mg/dL, and total cholesterol < 175 mg/dL) on cardiovascular and mortality risk in patients with type 2 diabetes. In this post-hoc analysis, we stratified patients by sex to compare the occurrence of MACEs (primary endpoint) and all-cause death (secondary endpoint) between women (104 MT and 105 UC) and men (103 MT and 83 UC). RESULTS: Achievement of therapeutic goals was similar by sex, with 44% and 47% of women and men in MT achieving at least 3 targets vs. 16% and 20% of women and men in UC. During a median follow-up of 13.0 years, we recorded 262 MACE (48.5% in women) and 189 deaths (53.6% in women). Compared to the UC group, the risk of MACE in the MT group was reduced by 52% in women and by 44% in men (P = 0.11). Conversely, the reduction in mortality risk by MT was greater in women (44% versus 12%, P = 0.019). CONCLUSIONS: MT similarly reduces the risk of MACEs in either sex. This therapeutic approach is associated with a survival advantage in women as compared with men and it may represent an important rationale to motivate physicians in overcoming their therapeutic inertia often encountered in female patients as well as to encourage patients of both sexes at improving their adherence to multidrug therapy.

Perspectives of nuclear diagnostic imaging in diabetic cardiomyopathy.

Diabetic cardiomyopathy is a ventricular dysfunction in the absence of coronary artery disease, valvular or hypertensive heart disease. The mechanisms underlying diabetic cardiomyopathy may involve metabolic disturbances, myocardial fibrosis, small vessel disease, microcirculation abnormalities, cardiac autonomic neuropathy and insulin resistance. Diagnostic problems emerge because no specific disease pattern characterizes the disease and because there may be coexistence in diabetes of coronary artery disease and hypertension as independent but compounding causes of biochemical, anatomical and functional alterations impairing cardiac function. In this paper we will review the role of nuclear imaging today, concentrating on the diagnostic capabilities of radionuclide ventriculography, to study the effect of insulin resistance and, more extensively, gated-single photon emission computed tomography with Tc-99m labelled agents. A broad analysis will be dedicated to: 1) positron emission tomography using perfusion agents, with the potential to quantify resting and stress blood flow and coronary flow reserve; 2) radionuclide procedures evaluating aerobic and anaerobic cardiac metabolism; and 3) cardiac neurotransmission imaging, studying the autonomic neuropathy.

The role of bright liver echo pattern on ultrasound B-mode examination in the diagnosis of liver steatosis.

AIM: The observation of bright liver echo pattern on ultrasound is commonly considered a sign of hepatic steatosis. However, the interference of liver fibrosis on sensitivity and specificity of bright liver echo pattern has caused many to question its effectiveness as a diagnostic tool. The objective of this study was to evaluate the sensitivity, specificity and predictive values of bright liver echo pattern for liver steatosis. PATIENTS AND METHODS: We studied 235 consecutive patients suspected of having liver disease of various aetiologies. Median age was 52 years (range, 17-72 years), and there was a male/female ratio of 1:18. All patients underwent ultrasound examination before liver biopsy and was performed by two operators. The presence or absence of bright liver echo pattern and posterior attenuation or areas with different patterns of fat infiltration were noted. Histologic evaluation was performed and graded by Ishak score. Steatosis was categorised as absent, 0-2%, 3-29% to 30-49% or >50%. RESULTS: Interobserver concordance was high. Bright liver echo pattern was found in 67% of patients with steatosis of any degree and 89% of patients with steatosis of >or=30%. Only three patients without steatosis, who had a low Ishak score, demonstrated bright liver echo pattern on ultrasonography. The sensitivity, specificity, positive predictive value and negative predictive value of bright liver echo pattern for steatosis were 64%, 97%, 96.0% and 65%, respectively. Among the subgroup of patients who had steatosis of >or=30%, the sensitivity, specificity, positive predictive value and negative predictive value of bright liver echo pattern were 91%, 93%, 89% and 94%, respectively. The sensitivity, specificity, positive predictive value and negative predictive value of posterior attenuation and/or skip areas associated with bright liver echo pattern for steatosis were 89.7%, 100%, 100% and 92.3%, respectively. Univariate analysis showed bright liver echo pattern to be associated only with steatosis and not with fibrosis. CONCLUSION: We concluded that the presence of bright liver echo pattern is a sign of liver steatosis and that liver fibrosis does not interfere with ultrasound measurements. Posterior attenuation and/or skip areas are closely related to steatosis of >or=30%.

Beta-endorphin-induced inhibition and stimulation of insulin secretion in normal humans is glucose dependent.

This study evaluated the effect of human beta-endorphin on pancreatic hormone levels and their responses to nutrient challenges in normal subjects. Infusion of 0.5 mg/h beta-endorphin caused a significant rise in plasma glucose concentrations preceded by a significant increase in peripheral glucagon levels. No changes occurred in the plasma concentrations of insulin and C-peptide. Acute insulin and C-peptide responses to intravenous pulses of different glucose amounts (0.33 g/kg and 5 g) and arginine (3 g) were significantly reduced by beta-endorphin infusion (P less than .01). This effect was associated with a significant reduction of the glucose disappearance rates, suggesting that the inhibition of insulin was of biological relevance. beta-Endorphin also inhibited glucose suppression of glucagon levels and augmented the glucagon response to arginine. To verify whether the modification of prestimulus glucose level could be important in these hormonal responses to beta-endorphin, basal plasma glucose concentrations were raised by a primed (0.5 g/kg) continuous (20 mg kg-1.min-1) glucose infusion. After stabilization of plasma glucose levels (350 +/- 34 mg/dl, t = 120 min), beta-endorphin infusion caused an immediate and marked increase in plasma insulin level (peak response 61 +/- 9 microU/ml, P less than .01), which remained elevated even after the discontinuation of opioid infusion. Moreover, the acute insulin response to a glucose pulse (0.33 g/kg i.v.) given during beta-endorphin infusion during hyperglycemia was significantly higher than the response obtained during euglycemia (171 +/- 32 vs. 41 +/- 7 microU/ml, P less than .01).(ABSTRACT TRUNCATED AT 250 WORDS)

Acetylsalicyclic acid restores acute insulin response reduced by furosemide in man.

Prostaglandin E (PGE) infusion in normal man inhibits the acute insulin response to glucose. In order to determine whether endogenously released PGE might also inhibit insulin secretion, glucose-stimulated insulin responses were investigated in normal volunteers after furosemide (40 mg i.v.), a stimulator of endogenous PGE synthesis. Acute insulin response to glucose (20 g i.v.) was significantly reduced by furosemide (response before furosemide: 36 +/- 5 muU/ml; after furosemide: 26 +/- 5 muU/ml, m +/- SE, mean change 3--10 min, N = 8, P less than 0.01), whereas glucose disappearance rates were not modified after furosemide. Infusion of lysine acetylsalicylate (LAS), an inhibitor of endogenous PGE synthesis, completely reversed the inhibitory effect of furosemide on insulin secretion and also augmented acute insulin response to glucose (response before furosemide + LAS: 41 +/- 6 muU/ml; during furosemide + LAS: 50 +/- 7 muU/ml, N = 10, P less than 0.02). This effect was associated with an increase in glucose disappearance rates (P less than 0.05). These findings demonstrate that (1) furosemide inhibits glucose-induced acute insulin responses and (2) LAS completely reverses the inhibitory effect of furosemide and also accelerates glucose disposal. It is suggested that furosemide acts via the release of endogenous PGEs, which are known to inhibit insulin responses in man.

Colchicine and insulin secretion in man.

The present study is aimed at investigating the effect of acute and chronic colchicine administration on insulin secretion in humans. Acute insulin response to glucose (0.33 g/kg) was significantly decreased by colchicine (3 mg i.v.). In fact, this response (mean change 2-10 min insulin) was 44 +/- 8 microunits/ml before and 32 +/- 6 microunits/ml after colchicine administration (P less than 0.01). As a consequence of this, glucose disappearance rates were reduced (P less than 0.05). Infusion of lysine acetylsalicylate (LAS), an inhibitor of endogenous PG synthesis, completely reversed the inhibitory effect of colchicine upon insulin secretion and also augmented acute insulin response to glucose (response before colchicine + LAS = 45 +/- 8 microunits/ml; response after colchicine + LAS = 51 +/- 9 microunits/ml, P less than 0.05). This effect was associated with an increase in glucose disappearance rates (P less than 0.05). The 10-day treatment with colchicine (2 mg daily) caused a significant suppression of insulin secretion induced by oral glucose (100 g) and significantly increased the plasma glucose concentrations following the test (P less than 0.05). These findings demonstrate that (1) both acute and chronic colchicine administration inhibit glucose-induced insulin secretion and deteriorate glucose tolerance in humans, and (2) LAS completely reverses these negative effects of colchicine. An increased synthesis of endogenous PGE, which are known to inhibit insulin secretion in humans, might account for the inhibiting effect of colchicine on insulin secretion.

Effects of insulin-glucose infusion on left ventricular function at rest and during dynamic exercise in healthy subjects and noninsulin dependent diabetic patients: a radionuclide ventriculographic study.

OBJECTIVES: The aim of this study was to evaluate: 1) the effects of insulin administration on left ventricular ejection fraction (LVEF) during exercise, and 2) the eventual impairment of the cardiovascular response to insulin in noninsulin dependent diabetes mellitus. BACKGROUND: Insulin influences the cardiovascular system, but its effect on left ventricular function has yet to be established. METHODS: The effects of normal saline (test A) and insulin-glucose (insulin = 1.7 mU x kg(-1) x min(-1); glucose = 6 mg x kg(-1)min(-1)) (test B) infusions on systolic and diastolic functions at rest and during dynamic exercise were examined by radionuclide ventriculography. Twenty-two noninsulin-dependent diabetic patients and 22 gender, age and body mass index matched healthy subjects were investigated. RESULTS: Both groups had normal scintigraphic parameters at rest and during dynamic exercise. Rest- and stress-LVEF as well as rest- and stress-peak filling rate were significantly (p < 0.001) lower in diabetic than in healthy subjects, both in test A and B. Rest-LVEF was significantly higher during test B than it was in test A only in diabetic subjects (p < 0.01). Stress-LVEF was significantly higher (p < 0.05) during test B than it was in test A, in both groups. Insulin-glucose infusion did not modify rest- and stress-peak filling rate in either group. No difference in left ventricular end diastolic volume and in mean blood pressure was found between test A and B at rest and during exercise in either group. A significant linear correlation between LVEF and the index of insulin sensitivity was found in diabetic patients. CONCLUSIONS: In both normal and diabetic humans, insulin induces a very important rise in LVEF after submaximal work. However, the rise is significantly lower in diabetic than in nondiabetic subjects. The increase in exercise-LVEF on insulin is likely due to an enhancement of ventricular contractility. Insulin resistance could justify the lower angioscintigraphic indexes in diabetic subjects.

Detection of early sympathetic cardiovascular neuropathy by squatting test in NIDDM.

OBJECTIVE: To determine the role of the squatting test in the detection of early sympathetic neuropathy in patients with non-insulin-dependent diabetes mellitus (NIDDM). RESEARCH DESIGN AND METHODS: Three groups of nonsmoking, nonobese subjects were studied: 10 healthy subjects, 10 NIDDM patients without autonomic neuropathy (AN), and 10 NIDDM patients with AN defined by the presence of a pathological deep-breathing value. All subjects were given three postural tests: lying-to-standing, sitting-to-standing, and squatting test. Heart rate (HR) and finger arterial pressure were recorded with a noninvasive technique. RESULTS: Blood pressure (BP) fall (expressed as decremental area) was not significantly different among the groups at standing up after sitting or lying. By contrast, a significantly greater BP drop occurred in NIDDM patients with AN (1,123 +/- 245 mm2) compared with NIDDM patients without AN (460 +/- 232 mm2) or normal subjects (429 +/- 138 mm2, P < 0.001). The HR increase after all the orthostatic maneuvers was smaller in diabetic patients with AN (P < 0.01) compared with that recorded in other groups. Significant correlations were observed between BP fall after squatting and either the expiration:inspiration ratio at deep breathing (r = -0.77, P < 0.001) or the duration of diabetes (r = 0.76, P < 0.001). CONCLUSIONS: The intrinsic orthostatic load of the squatting test, which is greater than conventional postural maneuvers, makes the squatting test an easy and useful test to detect early orthostatic dysregulation in NIDDM.

Calcitonin, a diabetogenic hormone?

The effect of calcitonin on oral glucose tolerance and on insulin, C-peptide, glucagon, and GH secretion has been investigated in man. Eight subjects with normal glucose tolerance and eight with impaired glucose tolerance (IGT) were studied. Each subject received two oral glucose tolerance tests (100 g) in random order, one under basal conditions and the other during the simultaneous in administration of salmon calcitonin (100 Medical Research Council Units). In all subjects, calcitonin exaggerated the rise in plasma glucose after oral sugar. The integrated areas under the plasma glucose curves were 4,400 +/- 840 mg/dl.min (normals) and 8,708 +/- 1,840 mg/dl.min (IGT) without calcitonin, and 8,208 +/- 1,700 mg/dl. min (normals) and 19,500 +/- 3,500 mg/dl. min (IGT) with calcitonin (P less than 0.01). Plasma insulin and C-peptide responses to glucose were significantly reduced (P less than 0.01) by calcitonin at all times after the start of the test in both normal and IGT groups. The inhibitory action of oral glucose on glucagon secretion was partially prevented by calcitonin (P less than 0.01). Moreover, calcitonin completely blunted the GH rebound occurring at the end of the test. These findings demonstrate that calcitonin impairs glucose tolerance in man by both inhibiting glucose-induced insulin secretion (primary effect) and reducing glucose-mediated glucagon suppression (accessory effect). These effects of calcitonin could be explained by a decrease in the cytosolic Ca2+ concentration in both alpha- and beta-cells.

Glucagon secretion in patients with hypoparathyroidism: effect of serum calcium on glucagon release.

The aim of the present study was to evaluate the influence of changes in the serum calcium concentration upon glucagon secretion in man. For this purpose, a group of subjects with either idiopathic (four cases) or secondary (two cases) hypoparathyroidism was submitted to an arginine test (0.5 g/kg) before and after the correction of hypocalcemia. In the presence of hypocalcemia, the glucagon response to the amino acid was modest and delayed (glucagon peak, 150 +/- 28 pg/ml). The acute correction of hypocalcemia produced a striking increase in basal glucagon levels (125 +/- 24 vs. 75 +/- 15 pg/ml; P less than 0.01) and restored the glucagon peak in response to arginine (270 +/- 50 pg/ml; P less than 0.01). The increase in plasma glucose triggered by arginine was augmented under normocalcemic conditions, while the pattern of plasma insulin response was quite similar. These results indicate that glucagon secretion in man is critically dependent on the serum calcium concentration.

Altered metabolic and hormonal responses to epinephrine and beta-endorphin in human obesity.

Catecholamines and endogenous opioid peptides are released in response to stress. Exogenous infusions of epinephrine and beta-endorphin (both in doses of 15, 50, and 80 ng/kg.min sequentially, each dose lasting 30 min) were used to mimic short term stress in both normal weight (body mass index, less than 25 kg/m2) and obese (body mass index, greater than 30 kg/m2) subjects. Fasting plasma insulin, C-peptide, and beta-endorphin concentrations were significantly higher in the obese than in the normal subjects (P less than 0.01-0.005). In lean subjects epinephrine produced significant increases in plasma glucose levels, but no appreciable changes in plasma insulin, C-peptide, or glucagon. Infusion of beta-endorphin in the same subjects caused plasma glucose and glucagon to rise, but insulin and C-peptide levels did not change. The simultaneous infusion of epinephrine and beta-endorphin produced a glycemic response which, although greater, was not significantly different than the sum of the responses to the individual hormone infusions. However, the two hormones had a synergistic interaction on plasma glucagon levels [total glucagon response, 2275 +/- 370 pg/min.mL (ng/min.L); sum of single effects, 750 +/- 152 (+/- SE) pg/min.mL (ng/min.L); P less than 0.01]. The plasma epinephrine [207 +/- 21, 607 +/- 70, and 1205 +/- 134 pg/mL (1130 +/- 115, 3640 +/- 382, and 6577 +/- 691 pmol/L] and beta-endorphin [875 +/- 88, 1250 +/- 137, and 1562 +/- 165 pg/mL (250 +/- 25, 358 +/- 39, and 447 +/- 47 pmol/L] concentrations attained during the infusions of each single hormone were not different from those recorded during the combined hormonal infusion. In obese subjects epinephrine raised plasma glucose levels and caused dose-related increments of plasma glucagon concentrations. Plasma insulin and C-peptide concentrations remained low and rebounded at the end of the infusions. In the same subjects, beta-endorphin produced elevations of plasma glucose, insulin, C-peptide, and glucagon. When the combined hormonal infusion was given to obese subjects, the plasma epinephrine and beta-endorphin concentrations rose to values not significantly different from those in normal weight subjects. However, there was a dramatic increase in plasma glucose exceeding 200 mg/dL (11.1 mmol/L), which remained elevated 30 min after the infusion. The glucagon response was not greater than the sum of the single effects.(ABSTRACT TRUNCATED AT 400 WORDS)

Pulsatile insulin delivery is more efficient than continuous infusion in modulating islet cell function in normal subjects and patients with type 1 diabetes.

The respective modulating effects of continuous and intermittent insulin delivery on pancreatic islet cell function were studied in seven normal men and nine insulin-dependent (type 1) diabetic patients. In the normal men, saline or continuous (0.8 mU kg-1 min-1) or pulsatile (5.2 mU kg-1 min-1, with a switching on/off length of 2/11 min) human insulin were delivered on different days and in random order. Despite hyperinsulinemia, blood glucose was kept close to its basal value by the glucose clamp technique. The diabetic patients also were infused in random order and on different days with either saline or a smaller amount of insulin delivered continuously (0.15 mU kg-1 min-1) or in a pulsatile manner (0.97 mU kg-1 min-1 for 2 min, followed by 11 min during which no insulin was infused). In all experiments, 5 g arginine were given iv as a bolus dose 30 min before the end of the study, and plasma C-peptide and glucagon levels were determined to assess islet cell function. In the normal men, insulin administration resulted in a significant decline of basal plasma glucagon and C-peptide levels and in a clear-cut decrease in the arginine-induced glucagon response. These effects of insulin were significantly more marked when insulin was delivered in a pulsatile rather than a continuous manner. In the insulin-dependent diabetic patients, the lower dose of insulin infused continuously did not alter the basal or arginine-stimulated glucagon response. In contrast, when the same amount of insulin was delivered intermittently, arginine-induced glucagon release was greatly reduced. Thus, these data support the concept that insulin per se is a potent physiological modulator of islet A- and B-cell function. Furthermore, they suggest that these effects of insulin are reinforced when the hormone is administered in an intermittent manner in an attempt to reproduce the pulsatile physiological release of insulin.

Decreased insulin clearance as a feature of essential hypertension.

Several studies report that essential hypertension is associated with hyperinsulinemia. This condition may depend on enhanced pancreatic insulin secretion and/or a decreased MCR of the circulating hormone. Twenty-five nonobese glucose-normotolerant patients with primary hypertension were divided into 5 groups, each consisting of 5 subjects. Each group was submitted to continuous 120-min double infusion of different doses of insulin (group I, 0.025; II, 0.05; III, 0.1; IV, 0.2; V, 0.4 U/kg.h) and glucose (I, 2; II, 3.5; III, 6; IV, 8; V, 10 mg/kg.min). The same procedures were applied to 25 healthy normotensive volunteers. Basal and steady state plasma levels of glucose, insulin, and C-peptide were significantly (P less than 0.05 or less) higher in hypertensive patients than in control subjects of all groups. The MCR of insulin (milliliters per kg/min) at all insulin-glucose infusion rates was significantly (P less than 0.05 or less) lower in hypertensive than normotensive subjects. Despite the significantly higher steady state plasma insulin levels in hypertensives, the MCR of glucose (milliliters per kg/min) was significantly (P less than 0.05 or less) lower in hypertensive than normotensive subjects. These results suggest that an altered insulin removal may contribute to the hyperinsulinemia found in the essential hypertensive subjects. In addition, a defect in insulin-stimulated glucose uptake which persists at supraphysiological insulin concentrations is confirmed in this population.

Hemorheological and cardiovascular responses to beta-endorphin and naloxone in healthy subjects and in patients with essential hypertension.

The purpose of the present study was to determine if opioid agonism (beta-endorphin) and antagonism (Naloxone) exert rheological and cardiovascular effects in normal humans and in patients with essential hypertension. Eight hypertensive patients were matched for age, sex, and body habitus (body mass index, waist to hip ratio) with eight normotensive healthy subjects. In all subjects, heart rate and blood pressure (continuous automatic recording), blood and plasma viscosity, fibrinogen, hematocrit, and platelet aggregation to ADP were evaluated during an infusion of human synthetic beta-endorphin (0.5 mg/h). On a different day and in randomized order, the subjects were submitted to another beta-endorphin infusion preceded by an i.v. naloxone bolus (5 mg in 5 min). beta-Endorphin and naloxone failed to significantly alter heart rate or blood pressure in both normotensive and hypertensive subjects. In hypertensive patients, beta-endorphin significantly increased blood viscosity and ADP-induced platelet aggregation, but only the former effect was naloxone-sensitive. In normotensive subjects, beta-endorphin caused a transient but significant decrease of platelet aggregation that was reversed by naloxone. These data suggest that beta-endorphin may play some role in the inhibitory control of platelet aggregation in normal subjects. An altered responsiveness of some rheological determinants to beta-endorphin seems to be present in human hypertension.

Hyperglycemia and obesity as determinants of glucose, insulin, and glucagon responses to beta-endorphin in human diabetes mellitus.

The effect of human beta-endorphin on plasma glucose, insulin, and glucagon concentrations was studied in patients with noninsulin-dependent diabetes mellitus and in normal subjects. The subjects were divided according to their body weight into lean (body mass index, less than 25) and obese (body mass index, greater than 29.5) groups. In lean subjects, infusion of 0.5 mg/h beta-endorphin caused significant increases in peripheral plasma glucose and glucagon levels, but no change in plasma insulin. In obese subjects, there was an immediate marked increase in both plasma insulin and glucagon concentrations during the beta-endorphin infusion, but the plasma glucose response was lower than that of lean subjects. In lean diabetic patients, beta-endorphin produced significant simultaneous increments in both insulin and glucagon concentrations and significantly decreased plasma glucose levels. These hormonal responses to beta-endorphin were amplified in the obese diabetic patients. There was a significant correlation (r = 0.61; P less than 0.01) between fasting plasma glucose levels and the integrated insulin area in response to beta-endorphin. The infusion of a lower dose of beta-endorphin (0.05 mg/h) in diabetic patients produced similar increments in both insulin and glucagon levels and also decreased plasma glucose concentration. These results indicate that beta-endorphin may have important glucoregulatory effects in man depending on the dose administered, the presence of obesity, and the prevailing plasma glucose concentration.

The involvement of the opioid system in human obesity: a study in normal weight relatives of obese people.

The involvement of the opioid system in human obesity has been demonstrated, but whether the abnormalities in the endorphinergic system play a primary role in overfeeding and weight gain or represent a simple biochemical feature is still unclear. The objectives of this study were to investigate the effects of both physiological and pharmacological plasma beta-endorphin levels on some metabolic and hormonal parameters in a normal weight, but prone to obesity, young population consisting of first degree relatives of obese subjects and in body mass index-, sex, and age- matched control subjects without a family history of obesity. Each subject underwent a 1-h infusion of synthetic human beta-endorphin at a constant rate of 4.5 ng/kg.min (low rate), then after a 1-week interval, at a rate of 500 micrograms/h (high rate). Under basal conditions, there was no significant difference in plasma glucose and pancreatic hormones (insulin, C peptide, and glucagon) between the two groups, except for plasma beta-endorphin levels, which were significantly (P < 0.01) higher in relatives of obese individuals. The low rate of beta-endorphin infusion induced physiological elevations of plasma opioid levels in both groups; no significant change in plasma glucose and pancreatic products in control subjects; and a significant (at least P < 0.05) rise in plasma insulin, C peptide, and glucagon concentrations in relatives of the obese. The high rate of beta-endorphin infusion produced pharmacological elevations of opioid plasma levels in both groups; significant (at least P < 0.05) increments in plasma glucose and glucagon levels and no appreciable modification of plasma insulin and C peptide levels in the control group; and a significant (at least P < 0.05) positive response of plasma glucose, insulin, C peptide, and glucagon levels in relatives of obese subjects. These findings suggest that 1) opioid peptides at least in part play a primary, rather than secondary, role in some metabolic events of obesity; and 2) both physiological and pharmacological plasma levels of beta-endorphin are able to provoke marked islet hormone release in the early phase of human obesity.

A possible role of gamma-aminobutyric acid in the control of the endocrine pancreas.

This study examines the effect of baclofen, a specific gamma-aminobutyric acid analog which crosses the blood-brain barrier freely, upon insulin, glucagon, and GH responses to iv glucose in normal man. Normal subjects received two consecutive iv glucose tolerance tests (0.33 g/kg) before and after the acute oral administration of 5, or 10 or 20 mg baclofen, respectively, (10 subjects for each group). The dose of baclofen was divided and given 8 and 1 h before the performance of the posttreatment test. A fourth group of normal subjects served as placebo group (8 subjects). The highest dose of baclofen significantly increased insulin responses to glucose and raised basal glucagon levels (P less than 0.01). No significant change occurred with the other doses. Baclofen produced a dose-related increase in basal GH levels; a 10-fold increase was observed with the 20-mg dose. However, glucose-induced glucagon and GH suppression were not affected by baclofen. Despite the increased hormonal secretions, glucose tolerance did not change after baclofen. These results seem to indicate that gamma-aminobutyric acid may play a role in the neuroendocrine control of the pancreatic islets.

Somatostatin and insulin secretion in man. IV. The role of calcium.

In this study we evaluated the influence of changes in serum calcium concentration upon somatostatin-mediated inhibition of insulin secretion in man. For this purpose, we investigated the effect of somatostatin in a group of subjects with hypoparathyroidism before and after correction of hypocalcemia and in normal subjects made hypercalcemic by exogenous calcium administration. In the presence of hypocalcemia, somatostatin caused an almost total inhibition of glucose-induced insulin secretion. In addition, somatostatin significantly decreased glucose tolerance in those hypocalcemic patients who exhibited normal tolerance under basal conditions [glucose utilization (kG), 1.44 +/- 0.13 before vs. 0.68 +/- 0.14 during somatostatin; P < 0.02]. Glucose tolerance was unaltered in those subjects who had a decreased glucose tolerance under basal conditions (kG, 1.01 +/- 0.1 before vs. 0.88 +/- 0.16 during somatostatin; P = NS). Under normocalcemic conditions, the insulin response to glucose and glucose tolerance were significantly greater than values measured during hypocalcemia. However, somatostatin blunted the insulin response to glucose and significantly decreased glucose utilization. These inhibitory effects of somatostatin upon insulin secretion and glucose tolerance were not reversed by a concurrent infusion of calcium (serum calcium, 6.9 +/- 0.3 meq/liter) in a group of normal subjects. Our data confirm the reduced insulin secretion and glucose tolerance in hypoparathyroidism and demonstrate that the suppressive effect of somatostatin upon glucose-stimulated insulin secretion is independent of changes in serum calcium concentration over a wide range.

Impaired glucose metabolism and reduced insulin clearance in elderly hypertensives.

Diabetes mellitus and essential hypertension are characterized by a continuous rise of prevalence with aging and this association may not be casual. Thirty nonobese nondiabetic elderly patients with primary hypertension and 28 healthy normotensives matched for age, sex, and body weight were evaluated for insulin secretion (oral glucose tolerance test, day-long glycemic and insulinemic profiles), action (euglycemic moderately hyperinsulinemic glucose clamp associated with 3H-3-glucose dilution technique), and clearance (120 min insulin/glucose infusion at two prefixed doses). Compared with normotensives, hypertensive elderly patients were characterized by the following: 1) plasma insulin and C-peptide were similar in basal conditions but significantly enhanced in response to both oral glucose and a mixed meal; 2) insulin-stimulated glucose uptake was significantly impaired with a similar rate of hepatic glucose production; 3) exogenous insulin metabolic clearance rate was significantly lower at both insulin infusion rates. The multiple alterations of insulin secretion, action and metabolism found in nonobese nondiabetic elderly hypertensives seem to support a role for this hormone in the regulation of arterial blood pressure.

Influence of acetylsalicylic acid on plasma glucose, insulin, glucagon, and growth hormone levels following tolbutamide stimulation in man.

The effects of acetylsalicylic acid (ASA), a known inhibitor of prostaglandin (PG) synthesis, on plasma glucose, insulin, glucagon and growth hormone (GH) responses to tolbutamide were examined in ten normal volunteers. Treatment with 3.2 g ASA daily for 3 days caused a significant reduction in basal plasma glucose levels (p less than 0.05); by contrast, basal insulin rose from 23 +/- 2 to 31 +/- 2 microU/ml (p less than 0.01). No significant changes in the basal concentrations of glucagon and GH were found after ASA. Insulin response to tolbutamide was significantly augmented after ASA (p less than 0.01) while GH response to hypoglycemia was reduced (p less than 0.05). The pattern of plasma glucose and glucagon was not significantly modified by the treatment. Since ASA seems to have an action opposite to PGE on insulin and GH secretion, it is possible that the ASA may work through inhibition of PG synthesis.