Increased peripheral venous somatostatin concentration and decreased glucagon response to arginine in patients with insulin dependent diabetes mellitus without residual B-cell function. Increased plasma SRIF in IDDM

The glucagon response to insulin hypoglycaemia is frequently reduced in patients with IDDM. In the present study arginine infusion, thought to act directly on the islet cells, was used to stimulate somatostatin (SRIF) and glucagon in IDDM without residual B-cell function. Thirteen IDDM patients' were compared with 13 sex- and age matched normal controls following an arginine infusion. The plasma SRIF concentrations in the 'IDDM group' and normal controls increased from 24.2 +/- 2.5 to 31.1 +/- 3.9 pmol/l (P less than 0.01) and 19.7 +/- 1.7 to 23.9 +/- 3.4 pmol/l respectively after 10 min (P less than 0.01). The plasma glucagon concentrations increased from 27 +/- 4.7 to 176 +/- 23.1 pmol/l (P less than 0.01) and 36 +/- 5.0 to 302 +/- 31.9 pmol/l (P less than 0.01) respectively after 20 min. Thus, in long standing IDDM without residual B-cell function, increased plasma SRIF concentrations are found and the glucagon response to arginine is reduced. The last observation further explains why these patients are especially vulnerable to hypoglycaemia.     

Rate of fall of blood glucose and physiological responses of counterregulatory hormones,clinical symptoms and cognitive function to hypoglycaemia in Type I diabetes mellitus in the postprandial state

AIMS/HYPOTHESIS: The aim of this study was to establish the effect of a rate of decreasing plasma glucose concentrations on responses to hypoglycaemia, i.e. release of counterregulatory hormones, perception of symptoms, deterioration of cognitive function, and rates of forearm noradrenaline spillover, in the postprandial condition and in the sitting position. METHODS: We studied 11 subjects with Type I (insulin-dependent) diabetes mellitus, twice during clamped insulin-induced hypoglycaemia (2.4 mmol/l) after eating in the sitting position. On one occasion, plasma glucose was decreased at the rate of 0.1+/-0.003 mmol x min(-1) x l(-1) (fast fall), on the other at the rate of 0.03+/-0.001 mmol x min(-1) x l(-1) (slow fall). Subjects underwent a control euglycaemic clamp study as well. RESULTS: In response to fast-fall as compared to slow-fall hypoglycaemia, which was about 30 min longer, cognitive tasks were performed as follows: Trail-Making B, PASAT 2 s, Digit Vigilance Test and Verbal Memory deteriorated more, adrenaline increased less (2.8+/-0.5 vs 3.5+/-0.7 nmol/l, p=0.03), forearm noradrenaline spillover was greater (6.5+/-1.0 vs 5.2+/-0.4 pmol x min(-1) x 100 ml(-1), p=0.04), and symptoms were no different. After recovery from hypoglycaemia, cognitive function was still deteriorated compared to the baseline with no difference between fast and slow-fall hypoglycaemia. The evident response of glucagon to postprandial hypoglycaemia contrasted with the blunted or absent response in the fasting state. CONCLUSION/INTERPRETATION: In the postprandial condition and sitting position, fast-fall hypoglycaemia is more dangerous than slow-fall, because it deteriorates cognitive function more, and activates responses of counterregulatory hormones less than slow-fall hypoglycaemia.     

CHOLINERGIC REGULATION OF PANCREATIC POLYPEPTIDE SECRETION IN CHRONIC RENAL FAILURE

Secretion of pancreatic polypeptide (PP) is regulated mainly by cholinergic mechanisms and we have studied this in patients with chronic renal failure (CRF). Basal serum PP concentrations in 25 patients with CRF (401 +/- 80; 116-2100 pmol/l; mean +/- SEM and range) were significantly higher than in 65 normal subjects (33 +/- 2; 21-120 pmol/l, P less than 0.001). Ingestion of a standard test meal induced significantly larger increases in serum PP in 11 patients with CRF (304 +/- 45; 155-640 pmol/l) than in 11 normal subjects (140 +/- 33; 51-440 pmol/l, P less than 0.005). Insulin-hypoglycaemia (0.1 U/kg i.v.) provoked similar increases in serum PP in five patients with CRF (404 +/- 79; 170-665 pmol/l) as in five normal subjects (449 +/- 92; 180-706 pmol/l). Administration of atropine (1 mg i.v.) did not normalize the elevated basal serum PP concentrations in five patients with CRF. On the other hand, administration of the same dose of atropine 60 min after ingestion of food decreased postprandial serum PP levels to basal values within one hour both in five patients with CRF and in six normal subjects. Sephadex G-50 column chromatography of basal, postprandial and post-atropine sera from three patients with CRF revealed at least three different molecular forms. The PP peak coeluting with the 4200 molecular weight human PP standard comprised more than half of total PP immunoreactivity and was the only peak to be influenced by feeding or atropine. We conclude that in patients with CRF, PP secretion stimulated by cholinergic mechanisms is normal.(ABSTRACT TRUNCATED AT 250 WORDS)     

Increased plasma pancreatic polypeptide (PP) in diabetic ketoacidosis; normalization following treatment

As both hypoglycaemia and hyperglycaemia may modify plasma levels pancreatic polypeptide (PP), we measured plasma PP by a homologous radioimmunoassay in seven diabetics who were admitted to the hospital in overt diabetic ketoacidosis (initial blood glucose 27.1-55.0 mmol/l). None had circulating PP-antibodies. All were treated with continuous infusion of insulin and fluids. Before starting treatment, plasma PP ranged from 2585-136 mmol/l (mean 629 pmol/l). Following treatment plasma PP decreased gradually in all patients. The following morning mean plasma PP was 242 pmol/l, 67 pmol/l when one ureamic patient was excluded. The normal value is less than 100 pmol/l. This study shows that plasma PP is clearly elevated in diabetic ketoacidosis and decreases following treatment.     

Limitations of diet therapy in patients with non-insulin-dependent diabetes mellitus

Sixty-one patients with non-insulin-dependent diabetes mellitus and fasting blood glucose of 12.0 +/- 0.6 mmol/l were studied before and after dietary treatment in an outpatient setting. At the start of the study 33 patients were obese (body mass index greater than 27.0 kg/m2). Twenty patients were newly diagnosed, median known duration of diabetes in the others was 5 years. Beta-cell function was measured by the release of C-peptide after i.v. injection of 1 mg glucagon (area under the curve of C-peptide = AUC-cp), as well as calculated according to the formulae of Matthews. Insulin action was estimated by measurement of fasting blood glucose, insulin and free fatty acids (FFA) concentrations. Non-obese patients showed more severe beta-cell deficiency than the obese ones (AUC-cp 2586 +/- 158 vs. 3294 +/- 277 pmol/l per 15 min), and did not improve in metabolic control during treatment. In the obese patients three response patterns to treatment were observed: weight loss and improvement in metabolic control accompanied primarily with increased beta-cell function or increased insulin action, or worsening of metabolic control. Those with less impaired beta-cell function and shorter known duration of diabetes showed the most favourable response. In conclusion: non-obese type 2 diabetes patients with fasting glucose levels above 10 mmol/l do not improve on dietary treatment alone; in obese type 2 diabetics weight reduction is essential and results in metabolic improvement, irrespective of the preceding fasting blood glucose concentrations. Improved beta-cell function as well as increased insulin action are responsible for this improvement.     

THE EFFECT OF OXYTOCIN INFUSION ON ADENOHYPOPHYSIAL AND ADRENAL CORTICAL RESPONSES TO INSULIN-INDUCED HYPOGLYCAEMIA

The responses of plasma adrenocorticotrophin (ACTH), cortisol, growth hormone (GH) and prolactin to insulin-induced hypoglycaemia were studied in six lean male subjects (age 22-29 years). Intravenous insulin tests were performed with and without oxytocin infusion. Blood sugar nadir occurred at the onset of symptoms (time S) with no significant differences between oxytocin and saline infusion. During the oxytocin infusion mean plasma oxytocin increased from 1.9 pmol/l to 138 pmol/l. Peak increase in plasma ACTH (oxytocin 266 +/- 54 ng/l; saline 281 +/- 43 ng/l, mean +/- SEM) was at S + 10 min while peak plasma cortisol (oxytocin 680 +/- 47 nmol/l: saline 656 +/- 40 nmol/l) was measured at S +/- 60 min, peak GH (oxytocin 96 +/- 17.8 mU/l; saline 106 +/- 18.6 mU/l) at S + 60 min and prolactin (oxytocin 1332 +/- 239 mU/l; saline 1242 +/- 273 mU/l) at S + 30 min. There were no significant differences in plasma concentrations of ACTH, cortisol, GH or prolactin between saline and oxytocin infusion. The results indicate that oxytocin has no effect on plasma ACTH, cortisol, GH and prolactin responses to insulin-induced hypoglycaemia. In particular they fail to support previous studies which suggested an inhibitory role for oxytocin in ACTH secretion.     

Hormonal,metabolic and cardiovascular responses to hypoglycaemia in Type 1 (insulin-dependent) diabetes with and without residual B cell function

Summary 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.     

Effect of porcine gastric inhibitory polypeptide on beta-cell function in type I and type II diabetes mellitus

The effect of highly purified natural porcine GIP on C-peptide release was examined in six type I (insulin-dependent) diabetics (IDD) with residual beta-cell function, six type II non-insulin-dependent) diabetics (NIDD), and six normal subjects. All subjects were normal weight. From -120 minutes to 180 minutes glucose or insulin was infused IV to achieve a constant plasma glucose level of 8 mmol/L. On two separate days GIP (2 pmol/kg/min) or isotonic NaCl at random were infused from 0 to 30 minutes. After 10 minutes of GIP infusion plasma IR-GIP concentrations were in the physiologic postprandial range. At 30 minutes a further increase in IR-GIP to supraphysiologic levels occurred. In all subjects plasma, C-peptide increased more after 10 minutes of GIP infusion (IDD, 0.48 +/- 0.05; NIDD, 0.79 +/- 0.11; normal subjects, 2.27 +/- 0.29 nmol/L) than on the corresponding day with NaCl infusion (IDD, 0.35 +/- 0.03; NIDD, 0.62 +/- 0.08; normal subjects, 1.22 +/- 0.13 nmol/L, P less than .05 for all). The responses of the diabetics were significantly lower than that of the normal subjects (P less than .001 for both groups). No further increase in C-peptide occurred during the remaining 20 minutes of the GIP infusion in the diabetic subjects (IDD, 0.49 +/- 0.05; NIDD, 0.83 +/- 0.10 nmol/L). In the presence of a plasma glucose concentration of 8 mmol/L, physiologic concentrations of porcine GIP caused an immediate but impaired beta-cell response in IDD and NIDD patients.     

A STUDY OF BETA-CELL FUNCTION AFTER GLUCAGON STIMULATION IN THALASSAEMIA MAJOR TREATED BY HIGH TRANSFUSION PROGRAMME

An increased incidence of diabetes mellitus and glucose intolerance has been reported in thalassaemia major treated with a high transfusion programme (HTP). To investigate beta-cell function, serum immunoreactive insulin (IRI), C-peptide (CP) and glucose were measured fasting and at 3, 6 and 10 min after i.v. administration of 1 mg glucagon in 20 thalassaemia patients treated by many transfusions and in nine healthy control subjects. Fasting C-peptide concentrations (mean +/- SEM) were higher in the thalassaemic group (2.15 +/- 0.17 ng/ml) than in the controls (1.41 +/- 0.13 ng/ml). After stimulation with glucagon, C-peptide concentrations were consistently higher (P less than 0.01) by approximately 50% in the thalassaemic than in the control group (5.29 +/- 0.31 vs 3.36 +/- 0.21 ng/ml, at 3 min; 5.22 +/- 0.30 vs 3.53 +/- 0.21 ng/ml at 6 min and 4.69 +/- 0.27 vs 3.30 +/- 0.17 ng/ml after 10 min). Plasma IRI concentrations increased in both groups after glucagon stimulation but were not significantly different. The glucose values were approximately 15% higher at each sampling time in the thalassaemic group than those of the normal subjects. It is concluded that disturbances in carbohydrate metabolism in thalassaemia major treated with HTP are the consequence of hepatic cirrhosis which accompanies secondary haemosiderosis, and possibly iron deposition in the beta-cells of the pancreas.     

Pancreatic polypeptide secretion in diabetic patients with idiopathic haemochromatosis

In order to investigate the endocrine pancreatic dysfunction resulting from iron overload, plasma pancreatic polypeptide (PP) response to a protein-rich meal was studied in 10 healthy controls and 30 insulin-dependent (type I) diabetic patients: ten with idiopathic haemochromatosis (IH), ten with chronic pancreatitis and ten with idiopathic type I diabetes. While fasting plasma PP levels were slightly higher in diabetic with IH (40,8 +/- 7 pmol/l) than those in controls (27,1 +/- 3) on in type I diabetics (31,3 +/- 3) they were similar after the meal (peak level 95 +/- 18, 139 +/- 23, 100 +/- 36 respectively). In contrast the mean PP level was low in diabetics with chronic pancreatitis in the fasting state (15.9 +/- 3.6 pmol/l) and did not rise following the meal. These findings suggest that there is no PP cell injury in diabetics with IH.     

Fasting gallbladder volume, postprandial emptying and cholecystokinin release in gallstone patients and normal subjects

Since abnormal gallbladder emptying may be a contributing factor in the development of gallstone disease, we determined fasting gallbladder volume and postprandial contraction in 20 gallstone patients and 20 normal subjects with the aid of ultrasonography. Moreover, basal plasma cholecystokinin levels and postprandial cholecystokinin (CCK) release were determined. Gallstone patients were divided into strong contractors (13 pts) and weak contractors (below 95% confidence interval for AUC contraction in % during 90 min: 7 pts). Strong contractor patients had significantly larger mean fasting volumes than normal subjects (mean +/- S.E.: 34.9 +/- 6.1 ml and 18.9 +/- 1.6 ml, respectively). This was not true for weak contractor patients (mean fasting volume 23.2 +/- 3.2 ml). Both strong contractor and weak contractor patients had significantly higher mean residual volumes than normal subjects (17.0 +/- 4.1 ml, 18.0 +/- 2.9 ml, and 8.8 +/- 1.1 ml, respectively). Absolute gallbladder emptying was significantly higher for strong contractor patients than for normal subjects, but relative emptying was the same. Opposite patterns of CCK release occurred in gallstone patients and normal subjects. In normal subjects, more CCK release was associated with stronger gallbladder emptying. In contrast, weak contractor gallstone patients had significantly higher CCK release than strong contractor patients. (AUC CCK: 304 +/- 89 pmol/l x 90 min and 106 +/- 29 pmol/l x 90 min, respectively). The present study indicates that strong contractor gallstone patients may have large residual gallbladder volumes due to large starting volumes, whereas weak contractor patients may have large residual volumes due to impaired contraction. Subjects with large fasting and residual volumes may be at increased risk for gallstone disease.(ABSTRACT TRUNCATED AT 250 WORDS)     

Elevated circulating adiponectin in type 1 diabetes is associated with long diabetes duration

OBJECTIVE: To study circulating adiponectin concentrations in relation to diabetes duration and endogenous insulin secretion in patients with type 1 diabetes. PATIENTS: Patients with haemoglobin A1c (HbA1c) < 6% (reference range 3.6-5.4%) were selected for the study. Twenty-two men and 24 women [age 41.3 +/- 13.8 years (mean +/- SD), diabetes duration 4 months to 52 years] participated. Healthy controls (15 women and nine men, age 41.3 +/- 13.0 years) were also included. Overnight fasting serum samples were analysed for adiponectin, HbA1c, C-peptide and lipoproteins. RESULTS: Significant positive associations were found between adiponectin concentrations and diabetes duration in univariate and multiple regression analyses. Serum adiponectin averaged 9.7 +/- 5.3 [median 8.1, interquartile range (IQR) 3.6] mg/l in patients with diabetes duration less than 10 years and 17.8 +/- 10.7 (median 14.7, IQR 7.5) mg/l in patients with longer duration (P = 0.0001). Among the patients, 24 were without detectable (< 100 pmol/l) and 22 with detectable C-peptide levels (185 +/- 91 pmol/l). C-peptide levels in controls averaged 492 +/- 177 pmol/l. HbA1c was 5.7 +/- 0.6% in patients without detectable C-peptide and 5.6 +/- 0.4% in patients with detectable C-peptide (ns). Serum adiponectin was higher in patients without detectable C-peptide than in patients with detectable C-peptide [17.3 +/- 11.1 vs. 10.6 +/- 5.8 mg/l (P < 0.005)] and in the controls [10.1 +/- 2.9 mg/l (P < 0.001 vs. patients without detectable C-peptide)]. CONCLUSIONS: The increase in circulating adiponectin concentrations in patients with type 1 diabetes appears to be strongly associated with long diabetes duration, irrespective of the metabolic control. Among other factors, a putative role for residual beta-cell function in the regulation of circulating adiponectin levels can be considered but we did not find sufficient evidence for this in the present study.     

Influence of metabolic control of insulin-dependent diabetes on plasma nucleotide levels (cAMP, cGMP) during bicycle exercise

Plasma concentrations of cyclic nucleotides (cAMP, cGMP) were measured before and during bicycle exercise in 8 well-controlled (mean pre-exercise blood glucose 5.3 mmol/l; HbA1 8.6%) and 8 moderately controlled (mean pre-exercise blood glucose 12.2 mmol/l; HbA1 10.8%) patients aged 18-32 years with insulin-dependent diabetes mellitus (IDDM) and in a group of non-diabetic control subjects matched for age and sex. Pre-exercise plasma cAMP concentrations and the rise with exercise were similar in all study groups. Significantly lower resting cGMP levels were found in well-controlled IDDM patients (3.5 +/- 0.3 pmol/ml, mean +/- SEM) compared to controls (5.6 +/- 1.1 pmol/ml; p less than 0.05) and moderately controlled IDDM patients (5.6 +/- 1.0 pmol/ml; p less than 0.05). By contrast, plasma cGMP levels increased during exercise in the diabetics but not in the controls. These findings indicate a significant difference in responses of plasma cGMP to exercise between IDDM patients and controls.     

INSULIN-LIKE GROWTH FACTOR-I (IGF-I) AND IGF-I BINDING PROTEIN IN THE FOLLICULAR FLUIDS OF GROWTH HORMONE TREATED PATIENTS

The presence of GH, insulin-like growth factor-I (IGF-I), epidermal growth factor (EGF), oestradiol (E2) and progesterone (PG) were investigated in the fluids obtained from various ovarian follicles of seven patients in whom the induction of super-ovulation was achieved only after GH (0.1 U/kg BW/day) was added to the gonadotrophin therapy. The follicular fluids of six patients responsive to treatment with gonadotrophin alone served as a control. In patients treated with combined therapy, the results demonstrated the presence in the follicular fluids of GH (M +/- SEM: 8.5 +/- 0.6 mU/l), E2 (771 +/- 38 nmol/l), and PG (16.4 +/- 0.7 pmol/l) in significantly higher concentrations compared to that in control follicles (6.2 +/- 0.8 mU/l, 681 +/- 30 nmol/l, and 14.4 +/- 0.6 pmol/l; P = 0.002, 0.012, 0.0001 respectively). Acid-extractable IGF-I (143 +/- 9 ng/ml) and EGF (3.9 +/- 0.3 ng/ml) concentrations were similar to those of control fluids (124 +/- 10 ng/ml and 2.9 +/- 0.7 ng/ml respectively) and were highly correlated with each other (P less than 0.001), suggesting a stimulatory effect of EGF on the local IGF-I production. A correlation between GH and IGF-I (n = 51, r = 0.36), as well as between IGF-I and PG (n = 48, r = 0.77) and E2 (n = 48, r = 0.55) was evident only in the follicular fluid of GH-treated subjects.(ABSTRACT TRUNCATED AT 250 WORDS)     

Abnormalities in fasting circulating proinsulin concentration in mild gestational diabetes

Fasting plasma proinsulin, insulin and glucose concentrations were measured in ten women with mild gestational diabetes and ten controls matched for race, age (32 +/- 6 vs 31 +/- 6 years), body mass index (28 +/- 8 vs 27 +/- 6) and gestational week (24 +/- 4 vs 25 +/- 4 weeks). There was no significant difference in fasting plasma glucose between these gestational diabetics and their controls (median 4.7, range 3.7-6.0 mmol/l vs 4.5, range 3.4-5.3 mmol/l). The fasting proinsulin levels were significantly higher in the gestational diabetics compared with the controls (median 12.2, range less than 4-14.8 pmol/l vs 5.8, range less than 4-12.8 pmol/l, P less than or equal to 0.02, Wilcoxon Summed Rank Test), while the calculated intact insulin levels (immunoreactive insulin minus proinsulin) were significantly lower (median 14.5, range 6.3-81.8 pmol/l vs 51.6, range 11.7-312 pmol/l, P less than or equal to 0.01). The ratio of proinsulin to calculated intact insulin was significantly higher in the gestational diabetics than the controls (median 0.66, range 0.16-2.04 vs 0.12, range 0.03-0.62), P less than or equal to 0.01). These results demonstrate that gestational diabetics, with normal fasting plasma glucose values, have abnormalities in pancreatic beta-cell secretion, which are likely to be important both in the aetiology of gestational diabetes and non-insulin dependent diabetes.     

Residual insulin secretion is not coupled to a maintained glucagon response to hypoglycaemia in long-term type 1 diabetes

OBJECTIVES: To evaluate the influence of residual beta-cell function on glucagon secretion and glucose counter-regulation following hypoglycaemia in type 1 diabetes. DESIGN AND SUBJECTS: The hormonal counter-regulatory responses to standardized insulin-induced hypoglycaemia were investigated, 18 patients with type 1 diabetes of long duration and 12 healthy subjects were investigated. Nine of the diabetic patients (diabetes duration 17 +/- 1 years) had residual insulin secretion, as reflected by persistent urinary C-peptide excretion. The other nine diabetic patients (diabetes duration 21 +/- 1 years) were C-peptide negative. RESULTS: Similar hypoglycaemic nadirs were found in all groups (2.1-2.3 mmol L-1), whereas the recovery of plasma glucose levels was delayed similarly in the diabetic groups. In the control subjects, plasma glucagon increased ( approximately 50%). No significant glucagon response was registered in either of the two diabetic groups. The maximum plasma adrenaline and pancreatic polypeptides (PP) responses to hypoglycaemia were comparable in the two diabetic patient groups; the peak values being lower (P < 0.05) than in the controls. Plasma noradrenaline, growth hormone and cortisol responses to hypoglycaemia were similar in all three groups. CONCLUSION: Residual beta-cell function in patients with long-term type 1 diabetes is not accompanied by preservation of the glucagon response to hypoglycaemia. As the two markers of autonomic function (adrenaline and PP) were similarly reduced in the two diabetic groups, the findings instead favour the concept that the defective glucagon secretory response to hypoglycaemia is because of autonomic nervous dysfunction.     

Modified hyperinsulinaemic, eu- and hypoglycaemic clamp technique using lispro-insulin for insulinoma diagnostic.

Summary:Characterization of metabolically inadequate insulin secretion is essential for insulinoma diagnostics. Hyperinsulinaemic, eu- and hypoglycaemic clamp procedures have been used to suppress endogenous insulin secretion in healthy subjects. The use of exogenous insulin precluded the use of insulin as a parameter to be measured. We now suggest to use exogenous insulin lispro and an insulin-specific ELISA not cross reacting with insulin lispro. Thus, determination of insulin by ELISA in this experimental setting reflects endogenous insulin. A 39-year-old man with a surgically confirmed pancreatic insulinoma was studied under hyperinsulinaemic [lispro insulin 40 mU x m(-2) body surface x min(-1)] clamp conditions. Euglycaemia was achieved (3.8 +/- 0.5 mmol/L) for 1 h and hypoglycaemia (2.36 +/- 0.49 mmol/L) was achieved for another 30 min. Insulin was evaluated by ELISA (cross-reaction with lispro insulin < 0.006%, C-peptide < 0.01%, proinsulin < 0.001%) and by a nonselective RIA (cross-reaction with proinsulin 40%). In control subjects the euglycaemic hyperinsulinaemia suppressed C-peptide to 0.36 +/- 0.03 ng/ml and hypoglycaemic hyperinsulinaemia to 0.29 +/- 0.03 ng/ml. Endogenous insulin was suppressed to 2.8 +/- 0.03 mU/L under euglycaemia and to 2.6 +/- 0.03 mU/L under hypoglycaemia in control subjects. In the insulinoma patient apparently irregular but small changes in both C-peptide (1.43 +/- 0.1 ng/ml) and more pronounced changes in endogenous insulin concentrations 4.41 +/- 0.1 mU/l under euglycaemia and 5.35 +/- 0.3 mU/l under hypoglycaemic conditions, were observed. The basal level of insulin (ELISA insulin 4.6 mU/L) and C-peptide (1.7 ng/ml) were not markedly elevated. Determination of insulin allowed better characterization of irregular pulses because of the shorter half-life of insulin relative to C-peptide. The new modification of sequential eu- and hypoglycaemic clamp procedures should also be useful in pharmacological studies of insulinotropic substances. Direct measurement of peripheral insulin may be more sensitive than C-peptide to detect low levels of autonomous insulin secretion in small insulinomas.     

C-peptide response to oral glucose and its clinical role in elderly people.

C-Peptide response to oral glucose was measured in 45 elderly diabetics, in whom final treatment was established on clinical grounds during a 16-18 months follow-up. The diabetic patients comprised 19 ultimately classified as insulin-dependent (IDD) (group 1) and 26 regarded as non-insulin-dependent (NIDD) (group 2). Fifteen matched controls (group 3) and 15 young controls (group 4) were similarly studied. Fasting C-peptide values were lower in groups 1 and 2 (1.48 +/- 0.39 and 2.14 +/- 0.22 ng/ml; mean +/- SEM, respectively) compared with groups 3 and 4 (2.51 +/- 0.16 and 2.71 +/- 0.20 ng/ml, respectively) (p less than 0.001). Peak C-peptide levels were reached at 30 min in healthy young and at 60 min in healthy elderly. All non-diabetic control subjects showed a peak of at least 6.5 ng/ml and an increment of at least 4 ng/ml. The ratio of C-peptide increment/blood glucose increment (100 delta CP/delta BG) at 60 min derived to assess beta-cell function was at least 90 in all healthy subjects. The ratio was less than 10 in 68% of IDD but in only 27% of NIDD patients (p less than 0.01). The 100 delta CP/delta BG was inversely related to the prevailing fasting blood glucose (FBG) (p less than 0.001). These findings suggest that C-peptide response to oral glucose may be a useful test in certain elderly diabetic patients whose insulin dependence is in question.     

Hexarelin-induced growth hormone response in short stature. Comparison with growth hormone-releasing hormone plus pyridostigmine and arginine plus estrogen.

Hexarelin (HEX) is a synthetic hexapeptide with strong GH-stimulating activity. We evaluated GH response (expressed as maximum value after stimulus [Cmax] and as area under the curve [AUC]) to HEX at the doses of 1 microg/kg i.v. (HEX 1) and 2 microg/kg i.v. (HEX 2), in comparison with the responses to GHRH (1 microg/kg i.v.) + pyridostigmine (PD, 60 mg po) and to arginine (ARG, 0.5 mg/kg i.v.) + ethinylestradiol (EE, 1 mg/day po for 3 days before the stimulation), in 5 subjects with familial short stature (FSS), 11 with constitutional growth delay (CGD), 6 with GH neurosecretory dysfunction (NSD), and 5 with isolated growth hormone deficiency (GHD). Cmax and AUC after HEX 1 were 26.8+/-10.5 ng/ml and 1448+/-514 ng/min x ml in FSS, 23.6+/-14.4 ng/ml and 1146+/-750 ng/min x ml in CGD, 36.9+/-21.5 ng/ml and 2048+/-1288 ng/min x ml in NSD, 9.4+/-5.8 ng/ml and 498+/-200 ng/min x ml in GHD (Cmax and AUC in FSS and CGD, p<0.05 vs GHD). Cmax and AUC after HEX 2 were 37.7+/-16 ng/ml and 1979+/-888 ng/min x ml in FSS, 32.5+/-16.2 ng/ml and 1613+/-237 ng/min x ml in CGD, 39.7+/-20.7 ng/ml and 2366+/-1569 ng/min xml in NSD, 13.4+/-4.2 ng/ml and 645+/-293 ng/min x ml in GHD (Cmax in FSS, CGD and NSD p<0.01 vs GHD; AUC in NSD, p<05 vs GHD). Cmax and AUC after GHRH+/-PD were 46.6+/-8.8 ng/ml and 3294+/-1031 ng/min x ml in FSS, 25.9+/-11.2 ng/ml and 1464+/-735 ng/min x ml in CGD, 38.8+/-21.7 ng/ml and 2428+/-1399 ng/min x ml in NSD, 8.4+/-6.2 ng/ml and 685+/-572 ng/min x ml in GHD (Cmax and AUC in FSS, p<0.001 vs CGD and GHD; Cmax in CGD and NSD, p<0.001 vs GHD). Cmax and AUC after ARG+EE were 21.3+/-4.2 ng/ml and 1432+/-514 ng/min x ml in FSS, 14.8+/-10 ng/ml and 805+/-489 ng/min x ml in CGD, 22.2+/-12.8 ng/ml and 1199+/-309 ng/min x ml in NSD, 4.6+/-2.5 ng/ml and 247+/-191 ng/min x ml in GHD (Cmax and AUC in FSS, CGD and NSD, p<0.01 vs GHD). Specificity was 62% for HEX 1 and 75% for HEX 2, GHRH+PD and ARG+EE. From a diagnostic point of view, HEX 1 + HEX 2 was the association with the largest percentage of false positives (20% in FSS, 27% in CGD and 33% in NSD), HEX 1 +GHRH+PD resulted in 9% in CGD, while the combined use of HEX 1 or HEX 2 with GHRH+PD or ARG+EE and of GHRH+PD with ARG+EE did not show false positive responses. In conclusion: I) the most effective dose of HEX was 2 microg/kg i.v.; 2) HEX did not show more specificity than GHRH+PD and ARG+EE; 3) the association of GHRH+PD with ARG+EE could yield the best results at lower costs, confirming these tests as first-line tools in evaluating GH secretion.     

Pancreatic polypeptide. Metabolism and effect on pancreatic secretion in dogs.

In dogs with gastric and pancreatic fistulas, porcine pancreatic polypeptide (PP) was infused intravenously in doses of 50, 100, 200, 400, and 800 pmol kg-1 hr-1 in the basal state and in doses of 100, 200, and 400 pmol kg-1 hr-1 during stimulation with submaximal doses of secretin (125 ng kg-1 hr-1) plus caerulein (50 ng kg-1 hr-1). Plasma concentrations of PP were measured by radioimmunoassay, and pancreatic bicarbonate and protein outputs were monitored. The half-time for disappearance of PP was 5.5 +/- 1.0 min, the metabolic clearance rate was 25.6 +/- 1.0 ml kg-1, and the volume of distribution was 209 +/- 42 ml kg-1. Basal pancreatic flow and protein output were significantly inhibited by the lowest dose of PP tested, 50 pmol kg-1 hr-1. The lowest dose of PP significantly inhibiting stimulated pancreatic secretion was 100 pmol kg-1 hr-1 for bicarbonate output and 200 pmol kg-1 hr-1 for protein output. The mean +/- SE peak increment in PP concentration in response to a meal of meat, 210 +/- 39 pM, was greater than the mean peak increment with the 400 pmol kg-1 hr-1 dose of exogenous PP, 175 +/- 19 PM. We conclude that exogenous doses of PP that produce smaller increments in PP concentration than those seen after feeding inhibit pancreatic bicarbonate and protein secretion stimulated by secretin and caerulein. This suggests that the amount of PP released by a meal is sufficient to inhibit pancreatic secretion.