Arginine-stimulated acute phase of insulin and glucagon secretion in diabetic subjects

To determine if both phases of glucagon secretion are excessive in diabetes, arginine was admimistered intravenously as pulses and as infusions to normal subjects, insulin-dependent diabetics, and noninsulin-requiring diabetics. The acute phase of glucagon secretion, in response to arginine pulses at four different doses (submaximal to maximal alpha-cell stimulating), was indistinguishable in terms of timing, peak levels attained, and total increments comparing controls and diabetics. During the first half of the arginine infusion (500 mg/kg over 30 min) the glucagon rise in controls and diabetics was similar (P greater than 0.1), whereas during the last half of the infusion excessive glucagon levels were seen in the diabetics. No difference in the glucagon responses to arginine administered as either a pulse or an infusion was observed between the two types of diabetics. The acute phase responses of insulin to intravenous, maximal stimulating doses of glucose (20 g) and arginine (2.5 g) were measured in five insulin-independent diabetics. Although the acute insulin response to arginine was normal, there was marked attentuation of the early beta-cell response upon stimulation by glucose. From these results we conclude that although in diabetes excessive glucagon levels are observed with chronic arginine stimulation, the acute phase of glucagon secretion in response to arginine is normal. In addition, the beta-cell in noninsulin-requiring diabetics, although acutely hyporesponsive to glucose, remains normally responsive to another stimulus, arginine.     

The relationship between concentration of growth hormone in serum and microangiopathy in patients with diabetes mellitus

OBJECTIVE: To study the relationship between growth hormone (GH) and microangiopathy in patients with diabetes mellitus in order to elucidate pathogenesis on microangiopathy in diabetics. METHODS: GH and insulin (INS) were detected by rdioimmunoassay, and blood sugar (BS) was detected by oxydase method. RESULTS: 138 NIDDM diabetics were examined. The concentration of serum GH in diabetics without microangiopathy (2.3 +/- 1.2 micrograms/L) was higher than in normal people (1.0 +/- 1.2 micrograms/L) and GH in diabetics with microangiopathy (5.74 +/- 1.94 micrograms/L) was higher than in diabetics without microangiopathy. The differences were significant (P < 0.01). As the history of diabetes went on, the level of GH in serum increased, and the incidence of microangiopathy increased too. The correlation of GH in serum with BS was parallel. The correlation of GH in serum with INS was not apparent. 27 ID-DM diabetics were examined, their level of GH in serum (6.8 +/- 3.4 micrograms/L) was higher than that of NIDDM diabetics (4.6 +/- 1.8 micrograms/L). They were all patients with microangiopathy. CONCLUSION: The rise of GH in serum may be an important pathogeny that causes microangiopathy in diabetics.     

Three dimensional stress analysis of the human femur

Plasma glucose, insulin and triglyceride changes in response to a standard breakfast and an oral glucose tolerance test have been studied in normal, obese and diabetic subjects. Mild diabetics with an abnormal oral glucose tolerance test may have normal or near-normal incremental glucose responses to a standard breakfast. A raised fasting plasma glucose is the predominant day-to-day glucose abnormality of mild diabetes. Diabetics have decreased insulin responses to oral glucose compared with the meal, and the deficient insulin response to glucose probably accounts for both the raised fasting plasma glucose levels and the abnormal oral GTT. The initial insulin response to a meal is normal in mild diabetics, and is probably stimulated by secretogogues other than glucose. The oral glucose tolerance test is apposite for the diagnosis of diabetes in view of the impaired insulin response to glucose, but accurate measurement of the basal plasma glucose may be of equal value. The diabetic and obese subjects had normal triglyceride levels, and there was no detectable impairment of disposal of the exogenous triglyceride following the breakfast.     

Growth and sexual maturation in children with insulin-dependent diabetes mellitus

Prediabetes, the interval preceding the clinical recognition of diabetes mellitus, is believed to consist of several months or years of beta-cell destruction associated with no clinically recognized signs other than possible increased growth velocity. This increased growth rate may be the result of increased insulin, increased growth hormone, or both. As insulin-dependent diabetes approaches clinical recognition, insulin deficiency becomes manifest as slowing of growth velocity and more obvious weight loss. If a prepubertal child has insulin-dependent diabetes mellitus, sexual maturation is frequently delayed and physical growth is adversely affected. Insulin is an anabolic hormone that regulates metabolic pathways involved in the production of protein, glycogen, and fat. The normal release of growth hormone and the hepatic production of insulin-like growth factor I is modulated by the action of insulin. The absence of physiologic insulin response leads to dysfunctional quantities of growth hormone, insulin-like growth factor I, and sex hormones, resulting in growth impairment and delayed sexual maturation. Delayed sexual maturation may cause concern because it has a major impact on growth and maturation of children. However, there is evidence that sex hormones have a stimulating effect on the tissue damage associated with chronic hyperglycemia. The loss of physiologic insulin release significantly affects physical growth, sexual maturation, and the chronic complications associated with insulin-dependent diabetes mellitus.     

Zinc and diabetes mellitus

In patients with type 1 and 2 diabetes was frequently found: low blood zinc levels, high zincuria, severe and ubiquitous cellular depletion of zinc, increased basal and after loading blood mineral clearance, and hyperglycaemia due to the reduction of pancreatic insulin secretion and to the reduced biological action of the hormone on liver, as a consequence of chronic zinc deficit. Strong endocellular zinc depletion in diabetics; low insulin secretion; insulin biological action decrease for zinc deficit; IG-I concentration decrease, that happens in this condition; insulin and IGF-I resistance; insulin and IGF-I receptors depletion in diabetics: are strong arguments for zinc pharmacological supplementation, in gastric protective formulation, to avoid gastroenteric problems.     

Comparison of the blood levels of insulin and growth hormone in healthy adolescents, adolescents with excessive weight and with hereditary loading with regard to diabetes mellitus

Changes in insulin and growth hormone secretion were studied in 112 children and adolescents (50 healthy ones, 40 with excessive weight, and 22 with heredity aggravated by diabetes mellitus). Three types of these changes were distinguished in healthy adolescents: normoreactive, hyperreactive, and inert. The same type of growth hormone secretion changes corresponded to each type of insulin secretion changes. There was revealed a negative correlation between the insulin and growth hormone levels in the group of healthy adolescents. Dynamic relation was noted between the indices of the mentioned hormones in the course of the test: it was stronger during the ascending than during the descending phase of the test. Glucose load proved to change the correlation between the hormones level. In the group of healthy adolescents correlation between the insulin and the growth hormone levels was greater before carbohydrate load than after it. In case of excessive weight or heredity aggravated by diabetes mellitus glucose load disturbed the correlation between the hormones: when a negative correlation existed between the insulin and growth hormone levels before the load no correlation was revealed after in. This fact confirmed the role played by excessive carbohydrate consumption in the pathogenesis of diabetes mellitus.     

Characteristics of young offspring of type 2 diabetic parents in a biracial (black-white) community-based sample: the Bogalusa Heart Study

The impact of race (black-white) and family history of type 2 diabetes mellitus on metabolic characteristics in early life was examined in a community-based sample from Bogalusa, LA. Study subjects included offspring of type 2 diabetics (n = 53, 47% black) and nondiabetics (n = 52, 40% black), with the mean age of each group ranging from 14.2 to 15.6 years. Offspring were given a 1-hour oral glucose tolerance test. Measures of body fatness such as body weight, body-mass index (BMI; weight/height2), and triceps and subscapular thicknesses were significantly higher only in white offspring of diabetics versus nondiabetics; measures of abdominal fat (waist circumference and waist-to-hip ratio) were significantly higher among offspring of diabetics of both races. Among the measures of glucose homeostasis, basal glucose, insulin, insulin-to-C-peptide ratio (a measure of hepatic insulin extraction), insulin resistance index (derived from basal glucose and insulin levels), and glucose response after glucose challenge were higher in the offspring of diabetics of both races. The differences in insulin-to-C-peptide ratio and glucose response remained significant after adjusting for BMI; further, these two variables were independently associated with parental diabetes in both races. Waist-to-hip ratio, glucose response, C-peptide response (a measure of insulin secretion) were lower, and basal insulin-to-C-peptide ratio and postglucose suppression of free fatty acids greater in blacks versus whites, regardless of status of parental diabetes. Black-white differences in postglucose suppression of free fatty acids disappeared after adjusting for BMI. Thus, blacks and whites with parental type 2 diabetes show multiple abnormalities in parameters governing glucose homeostasis early in life, and some of these traits differ between the races, regardless of status of parental diabetes.     

Neural networks in the analysis of episodic growth hormone release

Pulsatile secretion of growth hormone (GH) has been observed in healthy controls as well as acromegalic patients. In healthy adults, highly regulated secretory pulses of GH occur 4-8 times within 24 h. This episodic pattern of secretion seems to be related to the optimal induction of physiological effects at the peripheral level. In contrast to normal subjects, acromegalic patients demonstrate an irregular pattern of excessive GH release. This pattern of secretion is responsible for many systemic effects, such as the stimulation of connective tissue growth, cardiovascular and cerebrovascular disease, diabetes mellitus and arthritis. Standard methods for the analysis of pulsatile patterns of hormone secretion did not consistently separate the temporal dynamics of GH release in healthy controls and acromegalic patients under various study conditions. Using the cutting edge technology of artificial neural networks for time series prediction, we were able to achieve significant separation of both groups under various conditions by means of the predictability of their GH secretory dynamics. Improving the predictive results by using a more refined system of multiple neural networks acting in parallel (adaptive mixtures of local experts), we found that this system performed a self-organized segmentation of hormone pulsatility. It separated phases of secretory bursts and quiescence without any prior knowledge of the form of a GH pulse or a model of secretion. Comparing the predictive results for the GH dynamics with those for computer-stimulated stochastic processes, we were able to define the irregular pattern of GH secretion in acromegaly as a random autonomous process. The introduction of neural networks to the analysis of dynamic endocrine systems might help to expand the existing analytical approaches beyond counting frequency and amplitude of hormone pulses.     

Combined deficiency of thyroid stimulating hormone and growth hormone in a diabetic patient with Hashimoto thyroiditis

We report the case of a 36-year-old female patient with insulin dependent diabetes who developed hypothyroidism of pituitary origin after giving birth. She had low levels of free T4 and TSH with no response to i.v. TRH. Antimicrosome antibodies were increased (1/25000), suggesting Hashimoto's thyroiditis. The other hormones were normal except for a low level of growth hormone and insulin growth factor 1. There were no antibodies against the pituitary. MRI of the pituitary was normal. We suspect a vascular origin for this partial pituitary deficiency.     

Levodopa-stimulated growth hormone secretion and diabetic retinopathy

Since growth hormone has been implicated as a possible etiologic factor in the development of diabetic retinopathy, we examined growth hormone levels in two groups of growth-onset diabetics matched for age and duration of disease. The experimental group had definite proliferative diabetic retinopathy; the control group of growth-onset diabetics had no significant retinopathy. Basal and levodopa-stimulated levels of growth hormone were determined for each group. Growth hormone response could not be correlated with the presence or absence of diabetic retinopathy (P less than .05).     

Growth hormone and diabetes mellitus. A review of sixty-three years of medical research and a glimpse into the future?

The diabetogenic action of pituitary extracts containing growth hormone has been recognised for more than 60 years and the importance of growth hormone in the development and progression of diabetic retinopathy for more than 30 years. Hypophysectomy was the first effective treatment for retinopathy but was discontinued because of the risk of severe hypoglycaemia that it produced and the development of an alternative, less dangerous therapy--photocoagulation. The precise role and significance of growth hormone in diabetes care, however, remains to this day a mystery. The fact that modern, highly purified biosynthetic preparations of growth hormone still retain full diabetogenic potency and the fact that diabetes develops in up to 25% of patients with acromegaly indicate growth hormone's potential for involvement in the aetiology of diabetes mellitus, although most will agree that this is not likely to be an important factor in the large majority of 'idiopathic' cases. There is strong evidence to indicate a substantial hypersecretion of growth hormone in 'idiopathic' diabetes mellitus (particularly insulin-dependent cases and those with retinopathy), which appears to be more related to residual pancreatic insulin secretion than to metabolic control. Since the advent of biosynthetic growth hormone in sufficient quantity to perform trials in adults, we are more aware of growth hormone's considerable potency in the regulation of body composition, growth factor production and intermediary metabolism. In this article, we review the literature and, from this and our own work, propose a new hypothesis which links the hypersecretion of growth hormone to reduced hepatic secretion of insulin-like growth-factor I (IGF-I) as a direct result of reduced portal insulin levels in diabetes mellitus. The hypersecretion of growth hormone exposes peripheral organs such as the retina and kidney to conditions favouring the expression of growth-hormone-dependent growth factors such as IGF-I which may contribute to the development of diabetic microvascular disease by autocrine and/or paracrine effects. If this hypothesis proves to be true, it offers new opportunities for the prevention of diabetic microvascular complications through suppression of growth hormone secretion which in turn will increase insulin sensitivity and facilitate good glycaemic control.     

Behavior of C-peptide, insulin and glucose levels in blood during conditions of evaluating selected antihypertensive drugs in patients with hypertension and non-insulin-dependent diabetes (type 2)

In 60 patients divided in three groups, each of 10 non-diabetic patients with essential hypertension (h) and of 10 hypertensive type 2 (non-insulin-dependent) diabetics (h+c), aged 31-63 years, the effect of 2-week treatment with nifedipine, captopril and prazosin on glycaemia, serum insulin (IRI) and C peptide (CP) after oral and i.v. glucose loading was compared. Nifedipine resulted in higher glycaemia levels in the oral test in both groups. This drug caused in group (h), but not in group (h+c), reduction of the glucose-dependent early increases of serum IRI and CP, more marked in respect to CP, what was expressed by the decrease of the serum CP:IRI ratio. These results prove that in non-diabetic patients nifedipine reduces the early response of the B-cells to glucose, but this effect is partly compensated by decreased insulin uptake by the liver. In patients with type 2 diabetes this phenomenon has not become manifest because of absence or reduction of early glucose-dependent insulin release. After captopril in both groups lower values of glycaemia and serum IRI and CP were found. Prazosin did not change the determined blood parameters. Conclusion: nifedipine, captopril, prazosin have a small influence on secretory function of pancreatic B-cells and may be recommended for the treatment of hypertension in patients with type 2 (non-insulin-dependent) diabetes.     

Growth hormone stimulating the growth of arterial medial cells in vitro. Absence of effect of insulin

Earlier studies have shown a stimulatory effect of diabetic serum on the growth of rabbit aortic medial cell cultures. Growth media supplemented with normal serum with added insulin (50-2,000 muU./ml. serum) did not enhance the growth of the medial cell cultures. Control media containing serum from recent diabetics with low insulin concentration stimulated the growth (2p less than 0.01). Supplementation of normal serum with human growth hormone (final concentration 1-5 ng./ml. medium) resulted in a significant enhancement of growth (2p less than 0.005). The growth-promoting effect of growth hormone was not detectable with lower concentrations (0.5 ng. and 0.1 ng./ml. medium). The growth effect of the low concentration of growth hormone could not be augmented by increasing the concentration of glucose in the incubation medium. Growth hormone in an amount of 1 ng./ml. medium increased both the number of 3H-thymidine-labeled cells as identified by autoradiography and the number of mitotic bodies (2p less than 0.005 and 2 p less than 0.025). The present results demonstrate that the growth-stimulating factor(s) in diabetic human serum described earlier is not insulin but may well be growth hormone.     

Transient diabetes mellitus in a neonate. Evaluation of insulin, glucagon, and growth hormone secretion and management with a continuous low-dose insulin infusion

This neonate developed marked hyperglycemia four days after birth and required insulin therapy for eight weeks. During the acute phase of the disease, immunoreactive insulin was undetectable in portal venous serum. Neither tolbutamide nor theophylline administration significantly triggered insulin secretion. Somatostatin infusion inhibited growth hormone release but had no effect on plasma glucagon or blood glucose concentrations. At 2 1/2 months, two weeks after insulin withdrawal, the infant was still intolerant to an oral glucose load, insulin response was markedly delayed, and growth hormone secretion was paradoxical. At five months, the insulin, glucagon, and growth hormone responses to glucose and to somatostatin were normalized. Thus, in this patient, insulin secretion was transiently deficient. Peculiarities of glucagon and growth hormone secretion were also present but are more characteristic of this age group than of diabetes. The hyperglycemic state was managed by intraportal infusion of 0.1 to 0.2 IU regular insulin/kg/hour. This mode of insulin administration proved efficient, secure, and easy to manage.     

Improvement of growth hormone response to stimulation in primary aldosteronism with correction of potassium deficiency

Potassium depletion frequently occurs in primary aldosteronism and has been implicated as the cause of the impaired carbohydrate tolerance frequently associated with this syndrome. Glucose, insulin, and growth hormone regulation were studied in a 42-yr-old, male patient with an aldosterone-secreting adenoma when the patient was potassium-depleted and again after potassium repletion. Potassium repletion was documented by serial body potassium measurements, with an increase in body potassium from 2400 mEq to 2850 mEq after 400 mg spironolactone and 80 mEq supplemental potassium chloride were administered daily for 7 days. Potassium repletion resulted in improvement of the patient's glucose tolerance test, with a decrease in the peak glucose level from 184 mg/100ml to 130 mg/100ml and an increase in the peak insulin level from 46 muU/ml to 85 muU/ml. Intravenous administration of arginine resulted in a subnormal insulin response of 28 muU/ml in the base-line test and an increase to 59 muU/ml after potassium stores were repleted. Growth hormone response to arginine infusion was also initially minimal at 12.5 ng/ml, increasing markedly to 26 ng/ml after potassium replenishment. Insulin-induced hypoglycemia resulted in a depressed growth hormone response of 8 ng/ml when the patient was potassium-deficient, but a normal response of 30 ng/ml after potassium repletion. These observations demonstrate that impairment of both insulin and growth hormone responses to stimulation occur in primary aldosteronism with potassium depletion. These abnormalities may be reversed by potassium repletion.     

The short-acting insulin analog Lispro (Humalog) in the treatment of diabetes--comparison of preprandial and postprandial administration and comparison with treatment using Humulin R

The results of a clinical trial comprising 162 type 1 and 2 diabetics who took for 12 weeks Humalog in cartridges revealed that administration of this insulin before or 20 minutes after a meal does not affect the blood sugar level in a major way. None of the patients developed after Humalog administration local or general allergic manifestations. Hypoglycaemic episodes grade I and II were not more frequent during treatment with human insulins. The mean compensation of diabetes (HbA1c) remained unchanged. 80% of the diabetics are statistically significantly satisfied with Humalog treatment as compared with Humulinem R administration.     

Influence of parasympathetic dysfunction and hyperinsulinemia on the hemodynamic response to an isometric exercise in non-insulin-dependent diabetic patients

The handgrip test has long been used as a test for investigating cardiac autonomic neuropathy in diabetic patients. However, the factors involved in the hemodynamic response to the handgrip test have not been thoroughly studied. The aim of this study was to investigate blood pressure (BP) and heart rate (HR) responses to an isometric test in non-insulin-dependent diabetics (NIDDs) and to correlate the results with vagal function evaluated by three standardized tests and with plasma insulin levels. Fifty-five NIDDs, 35 of whom had one to three abnormal parasympathetic tests (PS+), were compared with 10 healthy control subjects. Fasting and postprandial plasma insulin levels were significantly higher in the PS+ than in the PS- patients. Resting HR correlated significantly with log fasting and postprandial insulin. In PS+ NIDDs, resting HR was significantly higher than in PS- patients. Age-matched comparisons also showed that resting systolic BP was significantly higher in PS+ patients than in controls. In PS- patients, the mean acceleration of HR was significantly higher than in the control group from the second to the fifth minute, and the BP response was also higher than in controls. These data suggest that (1) sympathetic response to an isometric exercise is increased in PS- NIDDs; (2) cardiac parasympathetic dysfunction is associated with a more severe insulin resistance; and (3) the subsequent higher plasma insulin level may contribute to the increase in resting HR and BP through sympathetic activation while limiting the hemodynamic response to an isometric exercise through its vasodilative effect.     

Natural estrous cycle in normal and diabetic bitches in relation to glucose and insulin tests

The influence of spontaneous "sex seasons" on blood sugar (BS) and serum insulin levels was studied in bitches with natural diabetes mellitus (DM) and normal controls, in the basal condition and during glucose and insulin tests, was studied. DM increased basal BS, reduced glucose tolerance, distribution space (DS) and clearance from blood, and induced resistance to insulin hypoglycemic action. In normals occurrence of "seasons", inconsistently modified basal BS, increased glucose tolerance and DS; during estrogenic phase (EP), these variables were above those during luteal phase (LP). In diabetics at LP, BS found in lasting condition and during glucose test were higher than in diabetic bitches at EP (respective values at anestrous (A) in between) and glucose DS was smaller. Rate of glucose clearance from blood remained unaffected by "seasons" in both dog groups. Basal serum IRI was not modified by DM or "seasons". In normals, serum IRI response to glucose load was nonsignificant during A and increased during the "seasons"; either insulin DS or the rate of insulin clearance from blood stream remained unchanged under the circumstances, the increase being mediated by insulin secretion. During EP, the increase was particularly intense and mean insulinogenic index (MII) rose. During LP, MII returned to A value, whereby diabetic states might be manifest. Serum IRI profiles during insulin test were not modified by "seasons" in normal bitches; such response in diabetic bitches was intense during A, then decreased (EP) or was later abolished (LP). Either in normal or diabetic bitches, the sensitivity to exogenous insulin hypoglycemic action remained unchanged in spite of "seasons". In diabetic bitches at A, serum IRI after glucose challenge peaked higher than in respective normal controls (insulin clearance and insulin DS were similar): they exhibited relative insulin shortage and resistance to insulin hypoglycemic action partly compensated by promoted insulin secretion. Along with "season", abolished serum IRI response to glucose load in diabetics was observed. During EP, extrapancreatic factors regulating serum IRI concentration and MII did not change in respect to A, whereby abolishment appears mediated by depressed insulin secretion. During LP, insulin antagonism in conjunction with 1) absolute insulin deficiency and 2) intense decrease in MII appears as a powerful factor exposing diabetic bitches to a severe or fatal derangement in diabetic disease.     

Kinetics of populations of enterocytes of experimental tumors of the large intestine in rats

To determine whether somatostatin, an inhibitor of glucagon and growth hormone secretion, might be useful as an adjunct to insulin the management of diabetic hyperglycaemia, seven insulin-requiring diabetic men were given somatostatin (100 microgram/h, IV) continuously for 3 days after their diabetes had been treated intensively by diet and insulin on a metabolic ward. During infusion of somatostatin and despite reduction in average insulin dose exceeding 50%, there was improvement in diabetic control as assessed by postprandial hyperglycaemia, 24-h glycosuria and the average daily serum glucose level and its fluctuation; when somatostatin was discontinued, but insulin doses held constant, diabetic control rapidly worsened. No adverse effects were observed. These results indicate that somatostatin plus insulin can be a more effective regimen than insulin alone in controlling diabetic hyperglycaemia. A longer acting and more selective somatostatin preparation may prove useful as an adjunct to insulin in the management of diabetes.     

Influence of health resort treatment on insulin and C-peptide concentration in girls with insulin-dependent diabetes

The influence of treatment in health resorts on the behaviour of C-peptide and insulin concentrations was evaluated in serum and urine of diabetics. The group examined comprised 68 girls with insulin-dependent diabetes estimated by radioimmunological methods. The study was carried out during and after health resort treatment. C-peptide initial concentrations constituted the basis for the examined and comparative group division into the following sub-groups: A--C-peptide secretion within standard limits, B--C-peptide trace secretion, and C--patients whose C-peptide concentrations were not determined. After health resort treatment a statistically significant difference of C-peptide secretion was found in serum in the groups with the well preserved secretion and that with only traces of C-peptides. A statistically significant difference in insulin concentrations was also found. Summing up, after health resort treatment of insulin-dependent diabetics with preserved only insignificant secretion of endogenous C-peptide, the secretion of this hormone increased.