Xenon and nitrogen single-breath washout curves in patients with airway obstruction

In 25 diabetics and 8 controls the insulin hypoglycemia test was performed with subsequent determination of growth hormone secretion by the radioimmunoassay method. The rise of the growth hormone level began earlier and persisted longer in diabetics as compared with controls. Juvenile diabetes was associated with a rapid secretory response of the hormone while in maturity-type diabetes the release of growth hormone in response to stimulation was excessive but delayed. A somewhat lower secretory response was found in diabetes lasting over 5 years as compared with short-lasting diabetes. The observed phenomena were not related to the absolute blood glucose level. Although the phenomenon of growth hormone hypersecretion remains yet to be explained, it seems, however, to be secondary to carbohydrate metabolism disturbance and insulin disorders.     

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.     

Lipoma of the mitral valve in a child

We report a case of pyodermia chronica glutealis complicated by acromegalic gigantism associated with hyperprolactinemia. The serum prolactin, growth hormone, adrenocorticotropic hormone, and 11-deoxycortisol levels were elevated, but the estradiol and dehydroepiandrosterone-sulphate levels were within normal limits. However, the testosterone level was very low. Histopathologically, we found sinus tracts and scarring in a specimen from the buttocks. We could not immunohistochemically detect clear androgen, growth hormone, or prolactin receptors at any site. The patient was a man with a height of 197 cm and weight of 140 kg, he had clinical features of active acromegaly such as excessive sweating and increased thickness of soft tissue. He was also diagnosed with diabetes mellitus. Under such conditions, bacteria could easily grow and lesions might have been aggravated by the heavy pressure from his weight, a possible causes of his pyodermia chronica glutealis.     

The ageing entero-insular axis

Ageing is one of the major risk factors for glucose intolerance including impaired glucose tolerance and Type II (non-insulin-dependent) diabetes mellitus. Reduced insulin secretion has been described as part of normal ageing although there is no information on age-related changes in the secretion of the major insulinotropic hormones, glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide (7-36 amide) (GLP-1). We assessed the entero-insular axis in 6 young premenopausal and 6 older postmenopausal women following treatment with oral carbohydrate. Insulin and glucose integrated responses were similar in the younger and older groups. Total integrated responses for GIP and GLP-1 were considerably greater in the older subjects. A positive correlation between age and total integrated responses for glucose (r = 0.65; p < 0.02) as well as GLP-1 (r = 0.85; p < 0.001) was seen. We hypothesise that an age-related impairment of insulin secretion to insulinotropic hormones, GIP and GLP-1, contributes to a reduction in glucose tolerance in this age group. The pronounced compensatory increase in postprandial secretion of GIP and GLP-1 provides further evidence not only for the negative feedback relation between incretin and insulin secretion but also for the importance of the entero-insular axis in the regulation of insulin secretion.     

Evidence for a catabolic role of glucagon during an amino acid load

Despite the strong association between protein catabolic conditions and hyperglucagonemia, and enhanced glucagon secretion by amino acids (AA), glucagon's effects on protein metabolism remain less clear than on glucose metabolism. To clearly define glucagon's catabolic effect on protein metabolism during AA load, we studied the effects of glucagon on circulating AA and protein dynamics in six healthy subjects. Five protocols were performed in each subject using somatostatin to inhibit the secretion of insulin, glucagon, and growth hormone (GH) and selectively replacing these hormones in different protocols. Total AA concentration was the highest when glucagon, insulin, and GH were low. Selective increase of glucagon levels prevented this increment in AA. Addition of high levels of insulin and GH to high glucagon had no effect on total AA levels, although branched chain AA levels declined. Glucagon mostly decreased glucogenic AA and enhanced glucose production. Endogenous leucine flux, reflecting proteolysis, decreased while leucine oxidation increased in protocols where AA were infused and these changes were unaffected by the hormones. Nonoxidative leucine flux reflecting protein synthesis was stimulated by AA, but high glucagon attenuated this effect. Addition of GH and insulin partially reversed the inhibitory effect of glucagon on protein synthesis. We conclude that glucagon is the pivotal hormone in amino acid disposal during an AA load and, by reducing the availability of AA, glucagon inhibits protein synthesis stimulated by AA. These data provide further support for a catabolic role of glucagon at physiological concentrations.     

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.     

Predictive neural networks for learning the time course of blood glucose levels from the complex interaction of counterregulatory hormones

Diabetes mellitus is a widespread disease associated with an impaired hormonal regulation of normal blood glucose levels. Patients with insulin-dependent diabetes mellitus (IDDM) who practice conventional insulin therapy are at risk of developing hypoglycemia (low levels of blood glucose), which can lead to severe dysfunction of the central nervous system. In large retrospective studies, up to approximately 4% of deaths of patients with IDDM have been attributed to hypoglycemia (Cryer, Fisher, & Shamoon, 1994; Tunbridge, 1981; Deckert, Poulson, & Larsen, 1978). Thus, a better understanding of the complex hormonal interaction preventing hypoglycemia is crucial for treatment. Experimental data from a study on insulin-induced hypoglycemia in healthy subjects are used to demonstrate that feedforward neural networks are capable of predicting the time course of blood glucose levels from the complex interaction of glucose counterregulatory (glucose-raising) hormones and insulin. By simulating the deficiency of single hormonal factors in this regulatory network, we found that the predictive impact of glucagon, epinephrine, and growth hormone secretion, but not of cortisol and norepinephrine, were dominant in restoring normal levels of blood glucose following hypoglycemia.     

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.     

Urinary excretion and clearance of insulin in diabetic and normal children and adolescents

Seventy-two diabetic (38 males) and 86 normal (41 males) children provided timed overnight urine collections. Fourteen of the diabetic and 33 of the normal children had concurrent overnight plasma insulin profiles. Urinary insulin clearance in the diabetic subjects was compared with excretion of albumin, growth hormone, retinol-binding protein, and N-acetyl-beta-D-glucosaminidase. In the normal subjects, urinary insulin excretion correlated with mean overnight plasma levels in the boys (r = 0.82, p < 0.001) but not in the girls (r = 0.32), and varied with puberty stage in the boys. Insulin clearance was greater in boys than girls during puberty, and fell in both sexes with advancing puberty. Insulin excretion was greater in diabetic than normal children in both sexes at all puberty stages. Insulin clearance was also greater in diabetic than normal subjects (1.05 +/- 0.1 ml min-1 1.73 m-2 vs 0.48 +/- 0.05 ml min-1 1.73 m-2, p < 0.001). Insulin excretion as a percentage of the filtered load was also greater in diabetic than normal subjects (1.9 +/- 0.27% vs 0.85 +/- 0.09%, p < 0.01). In the diabetic children, there was a correlation between urinary insulin and growth hormone excretion (r = 0.52, p < 0.02), and retinol-binding protein in those (n = 10) with higher retinol binding protein excretion (r = 0.76, p = 0.01). The value of urinary insulin excretion as a measure of free plasma insulin levels in normal and diabetic children may be limited by sex differences in renal insulin clearance, and by proximal renal tubular dysfunction in children with diabetes.     

Growth changes in children and adolescents with short-term diabetes

OBJECTIVE: Height and weight changes during the first 3 years of diabetes were prospectively followed in 152 diabetic children and adolescents. RESEARCH DESIGN AND METHODS: The study sample consisted of 152 Caucasian diabetic patients (84 boys; 68 girls) followed from diabetes onset in the Paediatric Diabetes Unit and 80 Caucasian normal subjects (49 boys; 31 girls) assessed in the Outpatient General Paediatric Clinic of the same hospital for routine examination and not affected by problems that might influence growth. Diabetic patients and control subjects were consecutively enrolled in the study between 1989 and 1992; diabetic patients with positive markers for celiac disease (positive antiendomysial antibodies) and thyroid disease (positive antimicrosomial antibodies) or any other chronic disease were not considered in the study. Mean age of diabetic patients (8.9 +/- 4.1 years) and control subjects (8.5 +/- 4.2 years) at recruitment in the study was similar. RESULTS: At onset of diabetes, the mean height expressed as the height standard deviation score (HSDS) was significantly greater than the expected values (P < 0.0001) and was independent of sex and pubertal stage. During the first 3 years of diabetes, HSDS decreased significantly (F = 6.9; P < 0.001). Meanwhile, growth velocity as standard deviation score (SDS) decreased significantly between the 1st and 2nd year (-0.12 +/- 2.1; -0.76 +/- 2.6, respectively; P < 0.05), but it was similar between the 2nd and 3rd year of diabetes. Weight expressed as SDS increased significantly during the first 2 years of diabetes but not thereafter. Height changes during the study period were independent from pubertal stage and sex. Metabolic control and insulin requirement, in our series, were not clearly related to height and weight changes. CONCLUSIONS: Diabetic patients at onset of diabetes are taller than age- and sex-matched nondiabetic subjects. During the first years of the disease, linear growth decreases independently of metabolic control and weight changes.     

A primer on the use of insulin pumps in adolescents

Optimal metabolic control to minimize long-term complications is a major treatment goal for adolescents with diabetes mellitus. Reaching this goal is extremely challenging in this population due to unique physiological changes and psychosocial variables that affect metabolic control. Continuous subcutaneous insulin infusion (CSII) may be an excellent treatment alternative for selected adolescents to help overcome some of these challenges. CSII allows for minute insulin changes at variable times throughout the day, providing greater lifestyle flexibility. The purpose of this paper is to review the use of insulin pump therapy in adolescents. Specific strategies regarding screening, initiation, and maintenance of this therapy are described, and case examples are used for illustration. Implications for nursing practice and diabetes education are discussed.     

Low insulin, IGF-I and IGFBP-3 levels in children with Prader-Labhart-Willi syndrome

It is well established that insulin-like growth factor I (IGF-I), insulin-like growth factor binding protein-3 (IGFBP-3) and insulin are low in growth hormone deficiency, but due to their dependence on nutrition, they are elevated in healthy obese children. As the presence of growth hormone deficiency in Prader-Labhart-Willi syndrome (PWS) is still controversial, we studied insulin, IGF-I and IGFBP-3 levels in 19 children with PWS (age range 0.5-14.6 years). Serum concentrations of insulin (SDS: -0.7+/-0.9, P = 0.01) and IGF-I (SDS: -0.7+/-0.8, P = 0.002) were low, but IGFBP-3 (SDS: -0.3+/-1.2, P = 0.2) was normal compared to normal weight age-matched children. Since children with PWS are typically obese, insulin, IGF-I and IGFBP-3 levels should be compared to normal obese children who present increased levels of these hormones. In comparison to data of healthy obese children reported in the literature, not only IGF-I, but also IGFBP-3 levels are low and fasting insulin levels even very low, suggesting a growth hormone deficiency.     

Muscle strength and hormonal levels in adolescents: gender related differences

The purpose of the present investigation was to study muscle strength in adolescents and its relationship to serum levels of testosterone and growth hormone in both genders. Thirty active adolescents (15 boys; age range 11 -12 y/o) participated in the first study. Isokinetic muscle strength of the dominant knee extensors (KE) was determined at 0, 12, 20, 30, 120, 180 and 240 deg/sec using a Cybex 340 dynamometer. The assessment of pubertal status was accomplished using the criteria of Tanner. Serum levels of total testosterone (T) and growth hormone (GH) were determined using radioimmunoassay techniques. Boys had higher (p< 0.001) T levels but no differences in muscle strength were detected between genders. Fifty-seven additional subjects representing three age groups (11-12 y/o, n=18; 13-14, n=21; 17-18, n=18) participated in the second study. A significant increase in peak torque (absolute and corrected for body weight) with age was observed in both genders. There were no significant gender differences in strength for the two youngest age groups, but boys were stronger than girls in the oldest age group (group 3). Testosterone and GH levels increased with age in boys but not in girls. Gender related differences in T were found in groups 2 and 3. A positive correlation (r=0,64 boys; r=0.46 girls) between testosterone levels and absolute muscle strength was seen in both genders. Our results suggest that increases in anabolic hormones precede muscle strength gains in adolescent males. In addition, gender related differences in muscle strength during adolescents cannot be explained solely on the basis of difference in body size or T levels.     

Propranolol effect on plasma glucose, free fatty acid, insulin, and growth hormone in Graves' disease

A 3-hr glucose tolerance test was performed in 12 thyrotoxic patients before and after propranolol treatment for 30 days (120 mg/day). Plasma glucose, free fatty acid, insulin, and growth hormone levels were determined on each test and compared to each other and against nine clinically healthy volunteers. In eight thyrotoxic patients (subgroup A) an improvement in carbohydrate tolerance was observed after propranolol treatment, along with a fall in the previously elevated fasting FFA; no change in plasma insulin levels was observed. Plasma growth hormone levels were higher than normal both before and after propranolol; however, a 46% glucose-induced suppression was seen in both instances. In the other four patients (subgroup B) (who had had a marked and rapid weight loss) a deterioration of the previously normal glucosnificant changes in insulin levels. Elevated fasting plasma free fatty acids remained so despite propranolol treatment. Plasma growth hormone was higher than normal before and after propranolol; a late suppression (at 120 min) and no suppression at all were seen, respectively. After propranolol treatment, subgroup B had higher plasma free fatty acid than subgroup A in the fasting state and at 30 and 180 min. It is proposed that the improvement or deterioration in carbohydrate tolerance after propranolol treatment might be related to whether or not a satisfactory propranolol-induced lipolytic blockade is achieved, leading to a decrease in plasma free fatty acid levels, improved insulin sensitivity, and better peripheral glucose utilization. Therefore, a uniform dose of propranolol will not always be sufficient to obtain adequate lipolytic blockade, particularly if the thyrotoxic patient has had a marked and rapid weight loss.     

Randomised placebo-controlled trial of human recombinant insulin-like growth factor I plus intensive insulin therapy in adolescents with insulin-dependent diabetes mellitus

BACKGROUND: Good glycaemic control in insulin-dependent diabetes mellitus (IDDM) to prevent complications may be difficult to achieve during adolescence, because abnormalities in production of growth hormone or insulin-like growth-factor-I (IGF-I) can lead to lower insulin sensitivity. Recombinant human IGF-I (rhIGF-I) given as an adjunct to insulin therapy in IDDM, might improve glycaemic control in adolescents; we investigated the effects of the addition of IGF-I in a randomised, double-blind, placebo-controlled trial. METHODS: 53 patients with IDDM (26 male, 27 female) with a median age of 16.1 years (range 10.8-20.6) and diabetes of more than 2 years' duration were randomly assigned subcutaneous rhIGF-I (20 or 40 microg/kg daily [n=18, n=18, respectively]) or placebo (n=17), both in addition to multiple-injection insulin therapy for 24 weeks. The primary endpoint, glycated haemoglobin (HbA1c) and routine biochemistry were measured every 4 weeks. Retinal photographs and glomerular-filtration rates were assessed at base line and at the end of the study. Data were analysed by intention to treat. FINDINGS: With a dose of 40 microg/kg rhIGF-I daily, we found significant reductions in HbA1c compared with placebo (p=0.03), without changes in body-mass index, rate of hypoglycaemia, insulin dose, or circulating concentrations of IGF-binding proteins 1 and 3. The greatest median change in HbA1c of -0.6% (range -2.8 to -1.5%) was seen with rhIGF-I 40 microg/kg at week 12, but was not sustained at week 24. The greatest reductions in HbA1c at week 24 were seen among patients with the greatest changes in IGF-I concentrations (r=-0442, p=0.002). Retinal photographs, renal function (glomerular filtration rate and urinary albumin excretion), and routine biochemistry showed no adverse events. INTERPRETATION: Our data confirm that rhIGF-I as an adjunct to insulin therapy can improve HbA1c values in adolescents with IDDM without overt toxic effects, but they raise questions about whether these effects can be sustained in cases of poor compliance or reduced bioefficacy.     

Studies of the impact of a liver glucokinase promoter variant on glucose tolerance and insulin sensitivity index

Because a frequently occurring nucleotide substitution at position -258 in the liver glucokinase promoter has been reported to be associated with impaired promoter activity, we have examined in Danish Caucasians whether this variant is associated with alterations in glucose tolerance and/or the insulin sensitivity index (Si). Among 246 Danish Caucasian patients with noninsulin-dependent diabetes mellitus, the allelic frequency of the -258 promoter variant was 15.2% (95% confidence interval: 12.0-18.4%) vs. 16.5% (13.2-19.8%) among 242 matched control subjects. In the control group, the glucokinase variant was not related to serum insulin or plasma glucose levels before or during an oral glucose tolerance test. Neither was the gene variant among 380 young, healthy subjects associated with altered Si or altered insulin secretion after an i.v. glucose load. We conclude that in Danish Caucasians, the -258 glucokinase promoter variant has no impact on glucose tolerance, whole-body Si, or insulin secretion.     

Glucagon-like peptide-1--a new hormone and a new drug

Glucagon-like peptide-1 (GLP-1 is an insulinotropic hormone, which is secreted from endocrine cells of the intestinal mucosa in relation to meal ingestion. It plays an important role as an incretin hormone; thus, mice with a null-muation in the gene encoding the GLP-1 receptor are glucose intolerant. In addition, GLP-1 inhibits gastrointestinal secretion and motility and is thought to act as one of the hormones of the "ileal brake". The insulinotropic effect of GLP-1 is preserved in patients with non insulin-dependent diabetes mellitus (NIDDM) and, because GLP-1 also inhibits glucagon secretion, it effectively lowers blood glucose in such, and given as an intravenous infusion it may completely normalise blood glucose. Furthermore, because its actions on insulin and glucagon secretion are dependent on the blood glucose levels it will not cause hypoglycemia. Efforts are therefore currently being made to employ GLP-1 or analogues thereof in clinical diabetes treatment, not least because recent investigations have shown that GLP-1, perhaps due to its gastrointestinal actions, is capable of reducing food intake in humans.     

Bone demarcation of the temporomandibular joint. Validity of clinical assessment of bone thickness by means of CT

OBJECTIVE: To study the effect of induced hypoglycaemia on serum levels of the placental hormones oestriol, human placental lactogen, placental growth hormone and progesterone in the third trimester of pregnancy. DESIGN: A prospective experimental investigation. SETTING: High risk pregnancy unit and diabetes research unit at Karolinska Institutet Danderyd Hospital, a university hospital. PARTICIPANTS: Ten women with insulin-dependent diabetes mellitus in the third trimester of pregnancy. METHODS: Venous blood samples were collected every 15 minutes for analyses of oestriol, progesterone, human placental lactogen and placental growth hormone, during the 150 min of a hyperinsulinaemic hypoglycaemic clamp, which maintained arterial blood-glucose level of about 2.2 mmol/l. MAIN OUTCOME MEASURES: Levels of analysed placental hormones during hypoglycaemia. RESULTS: A statistically significant increase was observed in placental growth hormone during hypoglycaemia (P < 0.0001), whereas the placental hormones progesterone, human placental lactogen and oestriol did not show changes of clinical significance. CONCLUSIONS: The increase in placental growth hormone indicates that the placenta is an endocrine organ which may take an active part in acute metabolic processes, such as here in the hormonal counterregulation of hypoglycaemia.     

The roles of time of day and sleep quality in modulating glucose regulation: clinical implications

Consistent variations in glucose regulation across the 24-hour cycle are present in normal subjects. These diurnal variations are altered in various states of impaired glucose tolerance (aging, obesity, diabetes). Changes in insulin secretion, clearance and/or action across the day have been demonstrated. Studies in subjects receiving continuous intravenous glucose infusion have shown that major alterations of glucose tolerance occur during sleep and that sleep quality markedly influences glucose utilization. Diurnal variations in glucose tolerance result from the alternation of wake and sleep states as well as from intrinsic effects of circadian rhythmicity. The important roles of physiological variations in levels of counterregulatory hormones which are markedly dependent on sleep (i.e. growth hormone) or circadian rhythmicity (i.e. cortisol) have only begun to be appreciated. The modulatory effects of sleep and circadian rhythmicity on glucose regulation may have important clinical implications for the diagnosis and treatment of abnormalities of carbohydrate metabolism.     

The characteristics of disorders in carbohydrate metabolism and insulin and C-peptide secretion in patients with chronic glomerulonephritis in developing chronic kidney failure

The authors studied hormonal regulation of carbohydrate metabolism by secretion of insulin, C-peptide in 86 patients with chronic glomerulonephritis with different functional condition of the kidneys. There was a decrease in glucose tolerance, basal and reactive hyperinsulinemia, elevated level of C-peptide (relative insulin insufficiency). Mechanism of arising changes in the carbohydrate and insulin metabolism is complex and multicomponent. This includes renal lesion and consequent inhibition of hormone metabolism. Intensification of glomerular filtration is associated with inhibition of filtration of insulin and C-peptide derivants. Accumulation of nitrogen metabolism products results in changed response of pancreatic beta-cells to glucose. General disturbances of metabolism are accompanied by increasing levels of hormonal and nonhormonal contrainsular substances.