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Objective: To validate the ability of DXA to measure total body composition before and after weight loss and the composition of the lost body mass., Design: Cross sectional and follow-up study of body composition before and after a weight loss of 10.6 +/- 6.8 kg., Subjects: 31 obese subjects with a mean body weight of 105.2 +/- 15.2 kg at baseline, and a mean body weight of 94.6 +/- 16.5 kg at follow-up., Measurements: Body composition was measured by dual X-ray absorptiometry, total body potassium counting, and high precision scales before and after a weight loss., Results: DXA and the scales showed a strong linear relation (r = 1). At baseline, however, DXA underestimated the body weight by a maximum of 3.2 kg because the subjects were too large for the scan table. After weight loss body weight measurements were accurate. Before and after weight loss the linear relations between DXA and TBK for FFM were strong (r = 0.92 and 0.93). Bland and Altman plots showed limits of agreement of +/-9 kg before and after weight loss; DXA underestimated FFM in women and overestimated FFM in men. DXA accounted for 80% of the lost body weight. The composition of the lost body mass did not differ from that estimated by TBK (7.6% FFM and 92.4% FM by TBK; 11% FFM and 89% FM by DXA)., Conclusion: DXA estimates accurately the body composition and the composition of weight loss in groups of obese subjects. However, the scan table may be too small for patients weighing more than 95 kg.

Objective: To describe sex- and age-dependent values of total and regional body composition as determined by dual-energy X-ray absorptiometry (DXA) in normal subjects, and furthermore to relate body composition measurements to blood lipids, glucose and insulin concentrations., Design: A cross-sectional study., Subjects: 173 (84 male and 89 female) healthy subjects, BMI < 30 kg/m2., Measurements: Body composition parameters including data on total bone mineral content (TBMC), total bone mineral density (TBMD), lean body soft tissue mass (LTM), total and regional fat mass (FM) were estimated in all subjects. In 87 of the subjects fasting blood glucose, S-insulin and lipid profile were measured., Results: The study population was for each sex divided into five decades for which results on body composition and blood lipids are presented. Body weight increased 2 kg per age decade, representing a significant increase in both total FM and relative FM (FM%BW) with age, and in males a central accumulation of FM. LTM decreased significantly in males but not in females, whereas TBMC and TBMD remained constant in males, but decreased in females. A significant correlation between relative FM and S-cholesterol, S-triglyceride, and in males S-insulin was found., Conclusion: The present study gives coherent data on bone mineral content, lean body soft tissue mass total and regional fat mass for 173 healthy subjects with a BMI below 30 kg/m2. Total body fat mass increases, and lean mass decreases with age. In males a simultaneous central accumulation of fat mass is observed. The well-known relationship between central obesity and lipids is confirmed even in non-obese subjects.

Whether the bioavailability of growth hormone depends on the concentration or formulation of the preparation was evaluated in 18 growth hormone-deficient patients. The design was a single-blinded, randomized cross-over study, where the patients were given a single, fixed dose subcutaneous injection of growth homrone (3 IU/m2) of 3 different preparations: (1) 4 IU/ml in a bicarbonate buffer dissolved in 0.9% benzyl alcohol (approximately 1.37 mg/ml), (2) 5.9 IU/ml in a phosphate buffer dissolved in 1.5% benzyl alcohol (approximately 2 mg/ml) and (3) 11 7 IU/ml in a phosphate buffer dissolved in 1.5% benzyl alcohol (approximately 4 mg/ml). Conventional growth hormone-therapy was withdrawn 2 days before each study period. Blood samples were drawn over a 24-hr period and assessed for growth hormone, serum insulin-like growth factor I (IGF-I), insulin and glucose. The geometric mean values (+/- geometric S.D) of the relative absorption fractions were F5.9 IU/4 IU = AUC5.9 IU/AUC4 IU = (+/- 1.139) (P = 0.66), F11.7 IU/AUC4 IU = AUC11.7 IU/AUC4 IU (1.14 +/- 1.21) (P = 0.009) AND F11.7 IU/5.9 IU = AUC11.7 IU/AUC5.9 IU = 1.12 (+/- 1.17) (P = 0.005), respectively. The 90% confidence intervals were contained within the limits of 0.80-1.25 accepted for bioequivalence. Geometric mean values (+/- geometric S.D.) of the relative observed maximum concentration, Cmax was for Cmax 5.9 IU/Cmax 4 IU = 1.04 (+/- 1.19) (P = 0.32), Cmax 11.7 IU/Cmax 4 IU = 1.24 (+/- 1.21) (P = 0.0002) and Cmax 11.7 IU/Cmax 5.9 IU = 1.19 (+/- 1.29) (P = 0.012). The median and the range values for the observed time to reach Cmax was tmax 5.9 IU/tmax 4 IU = 0.63 (0.04-1.00), tmax 11.7 IU/tmax 4 IU = 0.59 (0.06-1.0) and tmax 11.7 IU/tmax 5.9 IU = 0.90 (0.51-18.00). There were no significant differences in IGF-I, glucose and insulin profiles. Based on the upper limits of the 90% confidence intervals for relative AUC's the conclusion is that the three different preparations were bioequivalent.

Metabolic control, hypoglycaemia frequency and nasal mucosal physiology were evaluated in 31 insulin-dependent diabetics treated with intranasal insulin at mealtimes for one month and with subcutaneous fast-acting insulin for another month in a randomized crossover trial. During both periods the patients were treated with intermediate-acting insulin at bedtime. Six of the patients were withdrawn from the study during intranasal insulin therapy due to metabolic dysregulation. Insulin concentrations increased more rapidly and decreased more quickly during intranasal as compared with subcutaneous insulin administration. Metabolic control, assessed by haemoglobin A1c concentrations, deteriorated after intranasal as compared with subcutaneous insulin therapy. The bioavailability of intranasally applied insulin was low, since intranasal insulin doses were approximately 20 times higher than subcutaneous doses. The frequency of hypoglycemia was similar during intranasal and subcutaneous insulin therapy, and nasal mucosal physiology was unaffected after intranasal insulin. We conclude that due to low bioavailability and to a high rate of therapeutic failure, intranasal insulin treatment is not a realistic alternative to subcutaneous insulin injections at the present time.

Objective: To investigate the impact of obesity, fat distribution and weight loss on collagen turnover using serum concentrations of the carboxyterminal propeptide of type I procollagen (S-PICP) and the aminoterminal propeptide of type III pro-collagen (S-PIIINP) as markers for collagen turnover., Design: Blood samples were obtained once at baseline, and after 8 and 16 weeks of dietary treatment (5.0 MJ/day diet)., Setting: Outpatient clinic of Hvidovre University Hospital., Main Outcome Measures: S-PICP, S-PIIINP, fat distribution and weight loss., Results: S-PIIINP was associated with body weight (r = 0.37; P = 0.004), height (r = 0.27; P = 0.04), waist circumference (r = 0.35; P = 0.007), as well as with WHR (r = 0.33; P = 0.01) and was inversely correlated to age (r = -0.40; P = 0.002). Compared with randomly selected controls from a large pool of healthy volunteers, the obese patients had elevated S-PIIINP values before as well as during weight loss, whereas S-PICP levels were within the normal range and did not correlate with any anthropometric measures. The average weight loss after 16 weeks dietary treatment was 8.1 kg (s.d. = 0.8). S-PIIINP decreased during the 16 weeks of energy restriction (P < 0.05) and changes in S-PIIINP was correlated to body weight loss (r = 0.32; P < 0.05) and to changes in waist circumference (r = 0.34; P < 0.05) as well as changes in WHR (r = 0.30; P < 0.05)., Conclusion: S-PIIINP is elevated in obesity and associated with body fat distribution, suggesting an increased turnover of type III collagen related to obesity in general and to abdominal obesity in particular. S-PIIINP levels decreases during weight loss in obese subjects, whereas S-PICP levels seems un-related to obesity and weight loss.

To compare hospitalization into medical departments, acute admissions into a city hospital and into a district hospital were compared prospectively over a two-week period. Patients referred to the city hospital were on average older, were more frequently living alone and they had a greater amount of social care attendance in their homes. On the other hand, distribution of referral diagnoses, overall patient activity, occupational status and contact with relatives were similar in the two areas. Sub-acute or acute illness was considered the main cause of admission in both areas; the amount of admissions for social reasons was 13 percent to the city hospital versus 3 percent to the district hospital. Relevant alternatives to hospitalization seemed to exist in 50 percent of the admissions to the city hospital versus only 3 percent to the district hospital. Since patients admitted for social reasons block hospital beds for a longer time period than those admitted for other reasons, these differences may to some extent explain why length of hospital stay is longer in city hospitals than in rural ones.

To evaluate metabolic control and safety parameters (hypoglycaemia frequency and nasal mucosa physiology), 31 insulin-dependent diabetic patients were treated with intranasal insulin at mealtimes for 1 month and with subcutaneous fast-acting insulin at meals for another month in an open, crossover randomized trial. During both treatment periods the patients were treated with intermediate-acting insulin at bedtime. Six of the patients were withdrawn from the study during intranasal insulin therapy due to metabolic dysregulation. Serum insulin concentrations increased more rapidly and decreased more quickly during intranasal as compared with subcutaneous insulin administration. Metabolic control deteriorated, as assessed by haemoglobin A1c concentrations, slightly but significantly after intranasal as compared with subcutaneous insulin therapy. The bioavailability of intranasally applied insulin was low, since intranasal insulin doses were approximately 20 times higher than subcutaneous doses. The frequency of hypoglycaemia was similar during intranasal and subcutaneous insulin therapy, and nasal mucosa physiology was unaffected after intranasal insulin. We conclude that due to low bioavailability and to a high rate of therapeutic failure, intranasal insulin treatment is not a realistic alternative to subcutaneous insulin injections at the present time.

The principal mediators of glucose counterregulation (glucagon and epinephrine) use intracellular cyclic adenosine monophosphate (cAMP) to mediate glucose release. Since theophylline increases cAMP (by inhibiting its decomposition), we investigated the effect of theophylline on glucose recovery after insulin-induced hypoglycemia. Eleven healthy subjects and nine type I (insulin-dependent) diabetic patients each participated in two experiments in randomized order, receiving on both days an insulin bolus of 0.15 IU/kg soluble insulin. On one day, theophylline (intravenous [IV] bolus of 220 mg followed by IV infusion of 1 mg/kg/h) was administered from 1 hour before induction of hypoglycemia until the end of the study period. On the other day, NaCl was administered. Plasma glucose before induction of hypoglycemia was equal on the 2 study days. The plasma glucose area under the curve (AUC) was larger with theophylline than with NaCl (P = .04 for diabetic patients and P = .003 for healthy subjects). During the most active phase of glucose counterregulation, the rate of increase of plasma glucose was larger with theophylline (P = .003 for diabetic patients and P = .03 for healthy subjects). The incremental AUC for cAMP was larger with theophylline for diabetic patients (P = .01). For healthy subjects, cAMP was greater with theophylline 30 minutes after insulin (P = .03). In conclusion, glucose recovery after hypoglycemia is significantly increased when theophylline is administered in an asthma dosage before hypoglycemia is induced. This may be due to a significant enhancement of the cAMP response.

The aim of this study was to characterize the association between serum insulin-like growth factor-1 (IGF-1) and obesity, as well as fat distribution, before and during moderate energy restriction (1,200 kcal/d). In 51 females and nine males having a body mass index (BMI) between 27 and 39 kg/m2, relationships between serum IGF-1, IGF-binding protein-3 (IGFBP-3), insulin, growth hormone (GH), blood glucose, and anthropometric measurements of body fat were examined. The patients were studied before treatment and again after 8 and 16 weeks of dieting. Visceral adipose tissue (AT) was estimated by anthropometric computed tomography (CT)-calibrated equations. In females, IGF-1 was inversely associated with the abdominal sagittal diameter (SagD) and with the visceral AT (r = -.41, P = .006). No significant correlations were found between IGF-1 and BMI or other indices of adiposity. Weight loss caused a temporary increase in IGF-1 concentrations (P = .03) and continued decrements in blood glucose levels (P = .0004 at 16 weeks). A statistically significant inverse correlation between IGF-1 and blood glucose levels was present before (r = -.30, P = .02) and after 8 (r = -.37, P = .007) and 16 (r = .02, P = .02) weeks of dietary treatment. Both serum IGF-1 and insulin levels were positively correlated with serum IGFBP-3 levels (r = .34, P = .009 and r = .34, P = .008, respectively). We conclude that IGF-1 levels in obese females reflect the intraabdominal fat mass rather than obesity per se. IGF-1 and blood glucose levels are inversely correlated in obesity before and during energy restriction.

The newly discovered intestinal hormone, glucagon-like peptide-1 (GLP-1) (proglucagon 78-107amide), stimulates insulin secretion and inhibits glucagon secretion in man and may therefore be anticipated to influence hepatic glucose production. To study this, we infused synthetic GLP-1 sequentially at rates of 25 and 75 pmol.kg-1.h-1 into eight healthy volunteers after an overnight fast and measured plasma concentrations of glucose, insulin, and glucagon and glucose turnover by a technique involving infusion of 3-3H-glucose. Plasma levels of GLP-1 increased by 21.3 +/- 3.1 and 75.4 +/- 3.2 pmol/L during the infusion, changes that were within physiologic limits. In a control experiment only saline was infused. During GLP-1 infusion, plasma glucose level decreased significantly (from 5.3 +/- 0.1 to 4.7 +/- 0.1 and 4.3 +/- 0.1 pmol/L at the end of the two infusion periods). Despite this, plasma insulin level increased significantly (from 20.5 +/- 2.9 to a peak value of 33.5 +/- 5.2 pmol/L during the second period), and plasma glucagon level decreased (from 9.3 +/- 1.7 to 7.1 +/- 1.0 pmol/L). Glucose rate of appearance (Ra) decreased significantly to 75% +/- 6% of the preinfusion values during GLP-1 infusion. Glucose disappearance rate (Rd) did not change significantly, but glucose clearance increased significantly compared with saline. All parameters of glucose turnover remained constant during saline infusion. We conclude that GLP-1 may potently control hepatic glucose production and glucose clearance through its effects on the pancreatic glucoregulatory hormones. The effect of GLP-1 on glucose production is consistent with its proposed use in the treatment of type II diabetes.

We compared the hyperglycaemic effect of intranasal and intramuscular (i.m.) administration of glucagon after insulin-induced hypoglycaemia. Twelve healthy subjects were examined twice, receiving on both occasions an intravenous insulin bolus. Somatostatin and propranolol were administered to block endogenous glucose counterregulation, and glucose turnover was estimated by a 3-[3H]-glucose infusion. When hypoglycaemia was reached, the subjects received either i.m. glucagon of pancreatic extraction (1 mg) or intranasal genetically engineered glucagon (2 mg). The incremental values for plasma glucose concentrations 15 min after intranasal and i.m. administration of glucagon differed marginally. However, after 5 min the glucose appearance rate, as well as the incremental values for plasma glucose, were significantly higher for the i.m. glucagon treatment. The mean time taken for incremental plasma glucose to exceed 3 mmol.l-1 was significantly shorter for i.m. glucagon. The mean plasma glucagon level increased faster after i.m. glucagon than after intranasal glucagon, and the levels remained higher throughout the study period. We conclude that glucose recovery was significantly better after i.m. administration of glucagon than after intranasal administration. However, the differences between the incremental plasma glucose and the time for incremental plasma glucose to exceed 3 mmol.l-1 were not considered of major clinical importance.

We previously showed that intravenous insulin increased plasma noradrenaline during euglycemia and without concomitant changes in plasma adrenaline. Insulin decreased plasma volume and increased the fractional escape rate of albumin from plasma. In normal subjects, oral glucose increased heart rate, systolic blood pressure and plasma noradrenaline. These changes were absent or attenuated in diabetic patients (without neuropathy) after an oral glucose load. These responses were normalized by insulin infusion. Our results suggest that insulin facilitates the transfer of macromolecules and nutrients from the blood to the extracellular space after food intake. This process may be greatly disturbed in insulin-dependent diabetic patients.

Considerable progress has been made regarding symptomatic treatment of diabetic neuropathy. Apart from causal treatment (optimising metabolic control) a number of treatment modalities are now available for symptomatic diabetic neuropathy. The principles of symptomatic treatment depend very much upon which area of innervation is primarily affected. The optimal treatment of symptomatic diabetic neuropathy often requires the intervention of several clinical and paraclinical subspecialties.

In an out-patient weight loss study of 63 patients (54 female, 9 male), 53 completed a 16 week treatment with a low calorie diet and a 9 g/day fibre supplement. In these 53 patients, the average weight loss was 8.3 kg (s.e.m. 0.8). Waist-hip ratio (WHR) and abdominal sagittal diameter (SagD) were measured as indicators of fat distribution and visceral adipose tissue (visceral AT) was estimated by anthropometric computerized tomography calibrated equations. Four observers measured WHR and SagD ten times in eight patients. Two dietitians examined the patients throughout the clinical trial at weeks 0, 4, 8 and 16. Furthermore, two physicians examined the patients at week 12 in the trial. Two- and three-way analyses of variance were performed to estimate the contribution of single factors to the total variance. The contribution of observers, 3.2% and 3.8%, respectively, was of the same magnitude as the error variance (2.9% and 4.8% respectively) which is a measure of the intra-observer variation. The two dietitians had very similar recordings and contributed only 0.3% and 0.9% to the total variance for WHR and SagD, respectively. The contributions of the two physicians to the total variance were 0.0% for WHR and 0.4% for SagD. It is concluded that there is no need to use several observers or repeated measurements of waist, hip and SagD in clinical anti-obesity trials.

The pancreatic polypeptide (PP) response to a mixed meal was investigated in seven insulin-dependent diabetics without measurable signs of diabetic autonomic neuropathy, and in seven healthy subjects. Since acute changes in metabolic regulation might influence the meal-induced PP response, the insulin-dependent diabetic patients were studied during normo- and hyperglycemic experimental conditions at blood glucose levels of 5 and 15 mmol/l, respectively. The PP response was identical on the two occasions, the response being significantly smaller than in the healthy subjects. Thus, PP response is independent of short-term changes in metabolic control. Since the response was attenuated in the insulin-dependent diabetic patients, who had no otherwise measurable signs of neuropathy, the PP response to a meal could be a sensitive indicator of dysfunction of the reflex arc controlling PP secretion in insulin-dependent diabetic patients. Alternatively, the reduction in PP secretion in these patients reflects dysfunction of the PP secreting cells of the pancreas. Iv injection of cholecystokinin-8 elicited a small but significant increase in PP concentrations, while iv secretin did not increase PP concentrations at all in healthy subjects. These stimuli are therefore less suitable in the assessment of vagal neuropathy.

During the past decade it has been demonstrated that insulin, apart from its effects on metabolism and ion fluxes, has acute effects on the cardiovascular system and capillary permeability. Intravenous infusion of insulin in doses which increase plasma insulin to physiological levels, induced vascular dilatation and increased muscle sympathetic nerve activity during a euglycaemic glucose clamp. During similar conditions insulin increased the transcapillary escape rate of albumin and reduced plasma volume. Insulin has also an indirect effect on vascular permeability during hypoglycaemia, which is mediated by the increase in plasma adrenaline. Adrenaline infusion increased haematocrit and decreased plasma volume and intravascular albumin mass. In contrast to insulin adrenaline did not increase the transcapillary escape rate of albumin. Total autonomic blockade during insulin-induced hypoglycaemia abolished the increase in haematocrit, but did not influence the decrease in plasma volume and the increase in the transcapillary escape rate of albumin. Insulin administration may also increase urinary albumin excretion, and this effect was observed during a euglycaemic clamp. The mechanism of the increase in capillary permeability after insulin has not been elucidated. A number of morphological studies indicate that insulin may have effects on endothelial cell morphology and paraendothelial cell permeability. These results indicate that insulin, apart from its effect on peripheral blood flow, may play a role in a normal transfer of macromolecules from the blood to the extracellular space after food intake. This process may be greatly disturbed in insulin-dependent diabetic patients.

Insulin was withdrawn from 7 patients with Type I (insulin-dependent) diabetes and 4 patients with insulin-dependent diabetes secondary to chronic pancreatitis, both groups without residual beta-cell function. Median plasma glucagon concentrations rose slightly, but significantly after withdrawal of insulin in Type I diabetic patients (from 14 (range: 11-16) to 19 (14-25) pmol/l by 6 h), but not in the patients with secondary diabetes. This was accompanied by a significantly higher increase in blood glucose concentration from 5.1 (4.9-5.7) to 15.2 (12.9-18.1) mmol/l by 6 h in Type I diabetic patients compared with patients with secondary diabetes (from 4.9 (4.3-6.7) to 13.1 (10.9-13.5) mmol/l) (p less than 0.01). Beta-hydroxybutyrate increased to a similar extent in the two groups, whereas no significant increases were found in glycerol and lactate in any of the groups. Increased secretion of glucagon is not essential for the development of hyperglycemia and ketonemia in patients with diabetes secondary to chronic pancreatitis, but may augment the degree of hyperglycemia in Type I diabetic patients compared with patients having secondary diabetes.

Long term diabetes has a profound effect on the peripheral circulation. This has been demonstrated to be due to the presence of angiopathy and autonomic neuropathy, affecting autoregulation and distensibility of the vessels as well as local and central reflex regulation of the vascular resistance. Whereas the hemodynamic consequences of vascular denervation are well known (causing blood pressure maladaptation to a number of stimuli such as standing, exercise and agonist infusion) (Hilsted 1985), the consequences of disturbances in autoregulation and distensibility remain to be established.

We assessed HLA-DR types and investigated serum samples for islet-cell cytoplasmic antibodies (ICA) in 31 Danish patients with chronic pancreatitis. The antigen frequencies were compared with those in 1177 unrelated healthy Danish controls. Twenty patients had insulin-dependent diabetes and 11 had normal intravenous glucose tolerance. No significant differences in the frequencies of DR3, DR4, or DR2 were found between patients with insulin-dependent diabetes and patients with normal glucose tolerance or between any of these groups and controls. ICA were negative in all patients with chronic pancreatitis. It is concluded that the beta-cell dysfunction in insulin-dependent diabetes in chronic pancreatitis differs from that of classical insulin-dependent diabetes.

The pancreatic polypeptide (PP) response to insulin-induced hypoglycaemia was studied in 18 juvenile diabetics and was calculated as the difference between the prestimulatory PP concentration and the maximal concentration measured. The response was severely impaired in patients with autonomic neuropathy (mean +/- SE of mean 22 +/- 12 pmol/l) as compared with patients without neuropathy (252 +/- 51 pmol/l). Patients whose diabetes was of only a few years' duration showed a normal PP response to hypoglycaemia, and the response diminished significantly with increasing duration of diabetes. The decreased PP response to hypoglycaemia was significantly correlated with an increased threshold of the sense of vibration, (rs = 0.86). These results suggest that impaired, secretion of PP may serve as an early sign of autonomic neuropathy in diabetes.

Autonomic neuropathy is a common complication in long-term diabetes, about 30% of the patients showing measurable signs of autonomic dysfunction after 10 years duration of disease. The diagnosis is often difficult to establish because clinical symptoms generally occur late in the course of the disease, and may be nonspecific. A number of recently developed quantifiable and reproducible autonomic nerve function tests are reviewed, with emphasis on the physiological basis of the tests and on practical applicability. Finally, diagnostic criteria, based on autonomic nerve function tests, are suggested.

Hormonal, metabolic and cardiovascular responses to insulin induced hypoglycaemia were investigated in seven Type 1 (insulin-dependent) diabetic patients with residual B cell function, eight Type 1 diabetic patients without B cell function and six healthy subjects. No differences were found between the diabetic groups regarding nadir of glucose and rate of recovery to normoglycaemia. The patients with residual B cell function had a glucagon response to hypoglycaemia which was close to that of normal subjects. In patients without B cell function, the glucagon response to hypoglycaemia was present, albeit significantly smaller than in the patients with preserved B cell function (0.025 ng/ml, range 0.007-0.042 versus 0.054 ng/ml, range 0.029-0.087). The group without B cell function had signs of an exaggerated rate of lipolysis and ketogenesis compared with the patients with B cell function and the normal subjects.

In order to elucidate the physiological significance of autonomic neuropathy in juvenile diabetics, cardiovascular, hormonal and metabolic functions have been investigated in three groups of juvenile diabetics: One group had no signs of neuropathy, one group had presumably slight autonomic neuropathy (reduced beat-to-beat variation in heart rate during hyperventilation) and one group had clinically severe autonomic neuropathy, defined by presence of orthostatic hypotension. In all three experimental situations we found sympathetic dysfunction causing cardiovascular and/or hormonal maladjustments in patients with autonomic neuropathy. Regarding metabolic functions we found normal responses to graded exercise and insulin-induced hypoglycemia in patients with autonomic neuropathy in spite of blunted catecholamine responses, suggesting increased sensitivity of glycogen stores and adipose tissue towards the action of catecholamine in patients with autonomic neuropathy.

After induction of hypoglycaemia in 31 Type 1 (insulin-dependent) patients, the 10 patients with the slowest recovery of blood glucose from hypoglycaemia were arbitrarily compared with the 10 patients with the fastest recovery of blood glucose. No differences were found between the two groups regarding response of glucagon to hypoglycaemia, whereas the epinephrine (2-fold), norepinephrine (2.4-fold) and cortisol responses were significantly greater in the group with the slow recovery. The plasma free insulin concentrations were higher (2-fold) in the group with slow recovery from 30 min after stop of insulin and throughout the study. This may be explained by a 3-fold greater amount of insulin binding antibodies in this group compared to the group with fast recovery from hypoglycaemia. An inverse significant correlation was demonstrated between the rates of recovery and the amounts of insulin binding antibodies in all the patients (P less than 0.02). This implicates that enhanced counterregulatory hormone responses in the group with the slow recovery from hypoglycaemia could not compensate for the hypoglycaemic effect of a concomitant higher plasma free insulin concentration. Insulin binding antibodies, acting as a depot of circulating insulin, may be a risk factor of prolonged hypoglycaemia in Type 1 diabetics.

The whole body clearance of noradrenaline (NA) was measured in seven patients pre- and postoperatively. L-3H-NA was infused intravenously for 90 min and steady-state concentrations of L-3H-NA were measured in both arterial and peripheral venous blood. Preoperatively, in the resting supine position the clearance values based on arterial and venous sampling averaged 1.4 and 2.5 l/min, respectively (p less than 0.02). The difference in clearance values was due to peripheral uptake of NA averaging 45%. The plasma appearance rate on NA averaged 2.4 nmol/min before surgery and it increased to 9.5 nmol/min postoperatively (p less than 0.02). The plasma clearance of NA did not change. These results indicate that the calculation of plasma NA clearance based on venous sampling results in values that are too high. Furthermore, such values may be influenced by individual variations in the peripheral uptake of NA, since we found no correlation between clearance values based on venous and arterial sampling. In other experiments we measured the influence of physical exercise in young healthy subjects on the clearance rate of plasma adrenaline (A). The clearance of A, which at rest averaged 1.9 l/min tended to increase at low work loads and to decrease below resting levels at high exercise intensity. The changes were, however, small (+/- 20% of resting values). The regional extraction ratio of NA was 0.5 to 0.6 in the forearm, the liver and the kidney.(ABSTRACT TRUNCATED AT 250 WORDS)

The responses of pancreatic hormones (i.e. glucagon, pancreatic polypeptide, and somatostatin) to insulin-induced hypoglycemia were investigated in 18 insulin-dependent diabetics without residual beta-cell function and in 6 normal subjects. Nine of the diabetics had autonomic neuropathy, and 9 had no neuropathy. After hypoglycemia, no significant increase in any of the 3 pancreatic hormones was found in the diabetics with autonomic neuropathy, whereas significant increments were found in the diabetics without neuropathy and in the normal subjects. These results suggest that autonomic nervous activity is of major importance for pancreatic hormone release during hypoglycemia in man.

Noradrenaline and isoproterenol kinetics using intravenous infusion of L-3H-NA and of 3H-isoproterenol were investigated in eight Type 1 (insulin-dependent) diabetic patients without neuropathy and in eight Type 1 diabetic patients with autonomic neuropathy matched for age, sex and duration of diabetes. Resting plasma noradrenaline and adrenaline concentrations were reduced in patients with autonomic failure (p less than 0.05). The metabolic clearance rate of noradrenaline was similar in both groups of patients, and the appearance rate of noradrenaline in plasma was reduced in patients with autonomic failure (p less than 0.01). The disappearance of L-3H-noradrenaline from plasma after the infusion of L-3H-noradrenaline had been stopped was not different in patients with and without neuropathy. The metabolic clearance of isoproterenol was not influenced by the presence of autonomic failure and mean values were similar to the corresponding values for noradrenaline. Isoproterenol was only taken up by a non-neuronal uptake; this finding may indicate that neuronal uptake is not important for the inactivation of circulating catecholamines. Alternatively, because the non-neuronal uptake of isoproterenol is probably greater than that of noradrenaline, we cannot exclude the possibility that a small decrease in the neuronal uptake of noradrenaline was compensated for by a slightly higher non-neuronal uptake.

To investigate a possible association between the beta-cells and the cells secreting pancreatic polypeptide (PP), the response of PP to insulin-induced hypoglycaemia was investigated in seven insulin-dependent diabetics with and seven without residual beta-cell function, all without signs of autonomic neuropathy. The mean concentrations of PP was significantly greater from 15 to 60 min after symptoms of hypoglycaemia in patients with residual beta-cell function than in patients without (P less than 0.05) despite similar blood glucose concentrations in the two groups. Also the total integrated areas beneath the response curves as well as the incremental integrated areas were significantly greater in patients with beta-cell function (216 +/- 36 pmol/l x min and 188 +/- 34 pmol/l x min, respectively) than in patients without beta-cell function (125 +/- 26 pmol/l x min and 102 +/- 26 pmol/l x min) (P less than 0.05 for both). The mean maximal concentrations of adrenaline (1.53 +/- 0.28 ng/ml v. 1.29 +/- 0.12 ng/ml) and noradrenaline (0.56 +/- 0.16 ng/ml v. 0.45 +/- 0.04 ng/ml) were not statistically different in the two groups. No well established explanation for an association between residual insulin secretion and capacity for PP-response to hypoglycaemia in type 1 diabetics exists.

Plasma adrenaline kinetics (clearance, extraction across the forearm, initial plasma disappearance rate, mean sojourn time, volume of distribution) were studied in sixteen Type 1 (insulin-dependent) diabetic patients during constant i.v. infusion of tritium labelled adrenaline. In patients with (n = 8) and without (n = 8) neuropathy forearm venous plasma noradrenaline and adrenaline concentrations as well as plasma clearance of adrenaline based on arterial sampling (1.7 vs 2.1 l/min) were not significantly different. The initial disappearance time (T 1/2) after the infusion of the tritium labelled adrenaline had been stopped was significantly prolonged in Type 1 diabetic patients with neuropathy compared to those without (after 20 min infusion 2.7 vs 2.2 min, p less than 0.02, after 75 min infusion 3.7 vs 2.9 min, p less than 0.05). The corresponding values for the mean sojourn time of adrenaline in plasma were 6.5 vs 4.7 min (p less than 0.05) after 20 min infusion and 18 vs 10 min (p less than 0.05) after 75 min of infusion. The unchanged plasma clearance and the prolonged initial halftime and mean sojourn time of adrenaline in plasma suggest that adrenaline is distributed in a larger volume in Type 1 diabetic patients with neuropathy as compared to patients without neuropathy (estimated space of distribution 29 vs 20 l). Our results suggest that patients with diabetic neuropathy do not adjust the plasma adrenaline concentration to changes in adrenaline infusion rate as rapidly as those without neuropathy, i.e. the effect of an elevated adrenaline secretion rate may be prolonged in patients with diabetic autonomic neuropathy.

Orthostatic hypotension is one of the most troublesome symptoms in diabetic autonomic neuropathy. Some reports have suggested Pindolol - a beta-adrenoceptor antagonist with intrinsic sympathomimetic activity - to be effective in the treatment of this condition. In order to elucidate the value of this therapy we performed a double-blind placebo controlled cross-over study with Pindolol (15 mg/day). Eight Type 1 (insulin-dependent) diabetic patients with autonomic neuropathy and signs and symptoms of orthostatic hypotension (systolic blood pressure decrease greater than 30 mm Hg when standing) participated in the study. Patients were treated for 10 weeks. Clinical examinations were performed every fortnight and patients registered postural symptoms twice daily on a visual analog scale. No significant changes were seen in blood pressure recordings, heart-rate or visual analog scale registration during treatment with Pindolol compared to placebo. Our study does not support the suggestion that Pindolol is a valuable drug for treatment of diabetic patients with autonomic neuropathy and postural giddiness.

Polymorphonuclear leucocyte (PMN) ingestion of particles coated with lipopolysaccharide (LPS) from Escherichia coli was compared to other PMN functions in seven patients with insulin dependent diabetes mellitus (IDDM) during short-term controlled metabolic changes from normo- to hyperglycemia without ketoacidosis. Factors known to interfere with PMN functions were excluded. PMN ingestion of particles coated with both LPS and bovine serum albumin became reduced from normo- to hyperglycemia. PMN motility was impaired in IDDM, but did not seem to be affected by short-term changes in metabolic control. PMN metabolism did not change from normo-to hyperglycemia. Particle-uptake by diabetic PMN is impaired after short term hyperglycemia in the range normally occurring in diabetics in every-day life.

Haemodynamic variables (plasma volume, heart rate, blood pressure, cardiac output, stroke volume, pulmonary tissue volume, total peripheral vascular resistance, hepato-splanchnic vascular resistance, lower extremity vascular resistance and plasma catecholamines) were measured before and after insulin-induced hypoglycaemia in seven healthy men. Plasma volume decreased significantly at the nadir of glucose (mean decrease 222 +/- 41 ml) and subsequently increased to pre-hypoglycaemic values within 30 min. Cardiac output increased in response to hypoglycaemia (mean increase 2.8 +/- 0.61/min). The early rise in cardiac output was primarily due to an increase in heart rate, but later mainly due to increased stroke volume. Since pulmonary tissue volume was constant, the observed changes in cardiac output are unlikely to be due to a Frank-Starling mechanism but rather to increased sympatho-adrenal activity. Total peripheral vascular resistance as well as lower extremity vascular resistance decreased, whereas hepato-splanchnic vascular resistance was unaffected. Thus insulin-induced hypoglycaemia has marked transient effects on the circulation.

Norepinephrine-induced vasoconstriction, which is mediated by alpha-adrenergic receptors, is accentuated in patients with autonomic neuropathy. In contrast, responses mediated by beta-adrenergic receptors, including vasodilatation and metabolic changes, have not been evaluated in these patients. To study these responses, we administered epinephrine in a graded intravenous infusion (0.5 to 5 micrograms per minute) to seven diabetic patients without neuropathy, seven diabetic patients with autonomic neuropathy, and seven normal subjects. Mean arterial pressure decreased significantly in the patients with autonomic neuropathy (P less than 0.01) but was unchanged in the other groups. Since cardiac output increased to a similar extent in the three groups, the decrease in blood pressure was due to a significantly larger decrease (P less than 0.01) in total peripheral vascular resistance in the patients with autonomic neuropathy. The heart rate increased significantly more during the infusions in the patients with neuropathy than in those without neuropathy. Epinephrine produced a greater increase in blood glucose, the glucose-appearance rate, lactate, glycerol, and free fatty acids in the patients with autonomic neuropathy than in the other groups (P less than 0.05). These findings indicate that several beta-receptor-mediated responses to epinephrine are enhanced in patients with diabetic autonomic neuropathy. The underlying mechanism remains to be elucidated.

The whole body clearance of norepinephrine (NE) was measured in seven patients pre- and postoperatively. L[(3)H]NE was infused intravenously for 90 min and steady-state concentrations of L[(3)H]NE were measured at 75 and 90 min in both arterial and peripheral venous blood. Preoperatively, in the resting supine position, the clearance values based on arterial and venous sampling averaged 1.4 and 2.5 liter/min, respectively (P < 0.02). The difference in clearance values was due to a peripheral uptake of NE averaging 45%. The mean plasma NE increased from 1.70 nmol/liter preoperatively to 5.20 nmol/liter postoperatively (P < 0.02). The plasma appearance rate of NE averaged 2.4 nmol/min before surgery and it increased to 9.5 nmol/min postoperatively (P < 0.02). The plasma clearance of NE averaged 1.4 and 1.6 liter/min pre- and postoperatively, respectively (not significantly different). Our study demonstrates that the calculation of plasma NE clearance based on venous sampling results in values that are too high. Furthermore, such values may be influenced by individual variations in the peripheral uptake of NE, since we found no correlation between clearance values based on venous and arterial sampling. The increase in plasma NE postoperatively was due to an increase in the plasma appearance rate of NE because the clearance rate did not change.

The diagnosis of autonomic neuropathy is often difficult to establish, since clinical symptoms generally appear late in the course of the disease, and may be non-specific. A number of recently developed quantifiable and reproducible autonomic nerve function tests are reviewed, with emphasis on the physiological basis of the tests and on practical applicability. Finally, diagnostic criteria, based on autonomic nerve function tests, are suggested.

Hormonal responses (glucagon, pancreatic polypeptide and somatostatin) to iv glucagon, iv arginine, and ingestion of a mixed meal were investigated in 6 patients with insulin-dependent diabetes secondary to chronic pancreatitis without beta-cell function, in 8 Type I (insulin-dependent) diabetics without beta-cell function, and 8 healthy subjects. No significant differences were found between the two diabetic groups regarding glucagon responses to arginine and meal ingestion. In the patients with diabetes secondary to chronic pancreatitis compared with Type I diabetics and normal controls, the pancreatic polypeptide concentrations were significantly lower and somatostatin concentrations were significantly higher after glucagon, arginine and a mixed meal. Thus, pancreatic glucagon secretion was preserved in patients with insulin-dependent diabetes secondary to chronic pancreatitis, having no residual beta-cell function. These findings suggest that pancreatic glucagon deficiency is not absolute in insulin-dependent diabetes secondary to chronic pancreatitis. A high level of somatostatin may contribute to a lower blood glucose level in patients with chronic pancreatitis.

To investigate the prevalence of diabetic autonomic neuropathy, five simple bedside tests, beat-to-beat variation during quiet respiration, beat-to-beat variation during forced respiration, heart rate and blood pressure response to standing, heart rate response to exercise, and heart rate response to Valsalva's manoeuvre were applied to 75 male insulin-dependent diabetics, mean age 40 years, (range 30-49 years). The subjects were subdivided into three groups according to duration of diabetes, which was between 0 and 40 years. Twenty-eight healthy age-matched male controls were also studied. The prevalence of diabetic autonomic neuropathy in the whole diabetic population indicated by abnormal response in beat-to-beat variation during forced respiration was 27%. Diabetic autonimic neuropathy increased in frequency with duration of disease. Patients with nephropathy or proliferative retinopathy had a significantly higher prevalence of diabetic autonomic neuropathy as indicated by abnormal beat-to-beat variation during forced respirations (p less than 0.01) than patients without these complications.