Pancreatic alpha-cell function in diabetic hemochromatotic subjects.

To clarify further the etiology of the carbohydrate intolerance in idiopathic hemochromatosis, we investigated the glucose, insulin, C-peptide, and glucagon responses to arginine (0.5 g/kg) infused during 30 min in lean normal subjects; in insulin-requiring subjects with hemochromatosis, genetic diabetes, and total pancreatectomy; and in nondiabetic cirrhotic subjects without portosystemic shunting. Serum insulin, C-peptide, and glucagon responses (30K antibody) were determined by RIA, and glucose level was determined by a glucose oxidase technique. Hemochromatotic and genetic diabetic subjects had similar basal glucose (157 +/- 25 vs. 168 +/- 40 mg/dl) and C-peptide (0.73 +/- 0.42 vs. 0.65 +/- 0.22 ng/ml) values, with subnormal C-peptide peak responses to stimulation (1.05 +/- 0.38 and 1.40 +/- 0.83 vs. 3.95 +/- 0.4 ng/ml in normals; P less than 0.05). No glucagon or C-peptide response to arginine was seen in any pancreatectomized subject. Similar but excessive glucagon levels were present in hemochromatosis, diabetes, and cirrhosis under basal conditions (166 +/- 24, 232 +/- 111, and 263 +/- 116 vs. 76 +/- 15 pg/ml; P less than 0.05) and after arginine stimulation (782 +/- 80, 834 +/- 123, and 902 +/- 275 vs. 489 +/- 81 pg/ml; P less than 0.05) when compared with normals. The excessive glucagon levels found in hemochromatosis, diabetes mellitus, and cirrhosis contrast to the absent response in pancreatectomized subjects and indicate that generalized islet cell destruction is not the major factor in diabetic hemochromatotic subjects.     

PITUITARY AND THYROID INSUFFICIENCY IN THALASSAEMIC HAEMOSIDEROSIS

Thyroid and pituitary function tests using hypothalamic releasing factors were performed in seven patients with thalassaemia and secondary haemosiderosis and in a control group of seven healthy subjects. The TSH level in the thalassaemic patients (18.07 +/- 1.10 microU/ml) was higher than in the controls (1.01 +/- 0.14 microU/ml, P less than 0.001). After TRH administration the TSH values increased less than in controls. Serum thyroxine and FT41 values were lower in the group of patients with thalassaemia (76.7 +/- 7.8 nmol/l and 19.3 +/- 2.2) compared to the controls (116.1 +/- 6.9 nmol/l, P less than 0.005 and 38.6 +/- 3.6, P less than 0.001). The basal prolactin values did not differ significantly between the two groups, but after TRH administration the increment was significantly lower in thalassaemics than in controls (P less than 0.005). The basal LH values were lower in the thalassaemic patients (1.37 +/- 0.24 ng/ml) than in the controls (3.23 +/- 0.50 ng/ml) and did not increase significantly after LHRH administration. The FSH values were also lower in the thalassaemic group (0.46 +/- 0.15 ng/ml) compared to the controls (2.06 +/- 0.08 ng/ml, P less than 0.001), and increased only slightly after LHRH administration. We conclude that in thalassaemia pituitary deficiency exists, mostly of gonadotrophs, but possibly also for the thyrotrophs and the lactotrophs. Latent primary hypothyroidism has also been found in the thalassaemic group. The functional abnormalities found in both endocrine glands are best explained as a consequence of coexisting haemosiderosis.     

The effect of various blood glucose levels on post-glucagon C-peptide secretion in type 2 (non insulin-dependent) diabetes.

We investigated how different plasma glucose concentrations could significantly modify the C-peptide response to glucagon. Twenty poorly-controlled (HbA1c 10.2 +/- 1.5%) non insulin-dependent (NIDDM) subjects (body mass index 27 +/- 1.8), 2 treated with diet alone and 18 with oral hypoglycemic agents were studied. The first day glucagon (1 mg iv) was injected, patients being fasting and untreated. Mean plasma glucose levels were 11.4 +/- 1.2 mM. On a second non consecutive day, after an overnight fast, the same patients were connected to a closed-loop insulin infusion system (Betalike, Genoa), their blood glucose concentrations were stabilized within a normoglycemic range (5-5.5 mM) for 2 h and insulin infusion was stopped. The glucagon test was repeated 30 min later. Blood samples were taken 0, 6, 10, 20 min after glucagon injection. In the second test, basal, and 6, 10 and 20 min post-glucagon glucose levels were significantly lower (p less than 0.001); similarly C-peptide concentrations were significantly reduced both in basal conditions (0.55 +/- 0.04 vs 0.37 +/- 0.04 nM; p less than 0.001) and 6 (0.92 +/- 0.06 vs 0.6 +/- 0.06; p less than 0.001), 10 (0.79 +/- 0.06 vs 0.56 +/- 0.06; p less than 0.001) and 20 min (0.64 +/- 0.05 vs 0.44 +/- 0.04; p less than 0.001) after stimulation. The C-peptide secretion area showed the same trend (49.5 +/- 4.8 vs 32.1 +/- 5.8; p less than 0.001). In conclusion, our data confirms that blood glucose levels modulate the pancreatic insulin secretion; glycemic normalization significantly reduced both basal and post-glucagon C-peptide release.     

A comparison of serum C-peptide response to intravenous glucagon, and urine C-peptide, as indexes of insulin dependence

Serum C-peptide (SCPR) at fasting and after intravenous injection of glucagon was evaluated in diabetic patients with various degrees of insulin dependence, and compared with 24 h urine C-peptide (UCPR). Fasting SCPR did not differ between healthy subjects and sulfonylurea-treated patients (SU) who were considered to have definite non-insulin-dependent diabetes (NIDDM); but was significantly lower in patients with insulin-dependent diabetes (IDDM) (0.24 +/- 0.10 ng/ml in IDDM vs. 1.43 +/- 0.61 ng/ml in SU, P less than 0.001). SCPR reached a peak at 6 min after glucagon injection, except for the IDDM group. The SCPR response at 6 min after 1 mg glucagon injection was significantly lower in the SU (NIDDM) group than in the normal group (2.86 +/- 1.21 v. 4.69 +/- 1.47 ng/ml, P less than 0.001). In the IDDM group, there was no increase of SCPR after glucagon injection. Among diabetic patients, SCPR response to glucagon correlated positively to the amounts of UCPR (P less than 0.001). By analysis of the distribution patterns of SCPR response to intravenous glucagon, SCPR of 1.0 ng/ml and the increment of SCPR of 0.5 ng/ml at 6 min are to be used as cut-off points to differentiate IDDM and NIDDM. These values correspond roughly to the UCPR values below 20 micrograms/day and above 30 micrograms/day, which we previously proposed as indexes to differentiate insulin-dependent and non-insulin-dependent diabetes.     

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

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

Insulin resistance in human liver cirrhosis is not modified by porto-systemic surgical shunt

Cirrhosis of the liver is characterized by glucose intolerance and hyperinsulinaemia. It is considered an insulin resistant state with both a receptor and a post-receptor defect of insulin activity. It would appear that reduced hepatic degradation rather than increased B-cell production is responsible for hyperinsulinaemia. The effect of surgical portosystemic shunt on insulin resistance was studied in 18 cirrhotics with impaired glucose tolerance (12 males, 6 females; mean age 46.9 +/- 0.7 years) by measuring: glucose production (3H-glucose infusion), glucose utilisation (euglycaemic clamp at approximately 100, approximately 1000 and approximately 10,000 microU/1), plasma insulin and C-peptide levels, and liver function indices (serum bilirubin, albumin, ALT, GGT) before and 2 months after surgery. Liver sorbitol clearance was also employed to measure variations in the functional liver plasma flow induced by the shunt. No significant changes were noted in: glucose production (1.94 +/- 0.17 SEM vs 1.96 +/- 0.17 mg/kg/min), glucose utilisation (metabolic clearance rate: 3.32 +/- 0.48 vs 3.42 +/- 0.43 at approximately microU/ml; 9.70 +/- 1.0 vs 9.16 +/- 0.9 at approximately 1000 microU/ml; 10.92 +/- 1.1 vs 11.07 +/- 0.8 ml/kg/min at approximately 10 000 microU/ml), fasting plasma insulin, C-peptide and C-peptide/insulin molar ratio (4.66 +/- 0.47 vs 5.50 +/- 0.54), and the liver function indices. By contrast, there was a significant decrease in functional liver plasma flow (813 +/- 34 vs 604 +/- 34 ml/min, P less than 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)     

Altered C-peptide/insulin molar ratios and glucose turnover rates after stimulation in nondiabetic offsprings of type II diabetic patients

We evaluated the serum glucose/insulin/C-peptide dynamics and C-peptide/insulin molar ratios during sequential standard meal and intravenous (IV) glucagon testing for 240 minutes in eight genetically predisposed but nondiabetic female offsprings of type II diabetic patients and seven weight-matched, normal female controls. Glucose turnover rates and metabolic clearance rates of glucose (MCRG) were also determined isotopically by the D-[3-3H]glucose infusion technique. All the subjects had normal fasting serum glucose and glycosylated hemoglobin (HbA1) values. After meal ingestion, mean serum glucose concentrations were not different except for 120 to 180 minute values, which were significantly higher in the offsprings v controls. After intravenous glucagon infusion, percent maximum increments of glucose were no different. Mean basal immunoreactive insulin (IRI) levels were significantly (P less than 0.02) higher in the nondiabetic offsprings v controls. Following meal ingestion, mean IRI rose to a peak at 40 minutes in both groups, but values were significantly (P less than 0.001) higher in the offsprings v controls. After glucagon administration, the percent maximum increment was significantly (P less than 0.05) lower in the offsprings v controls. Despite exaggerated IRI levels in the offsprings, the mean fasting and stimulated C-peptide levels were identical in both groups throughout the study period. Basal and stimulated C-peptide/IRI molar ratios were quantitatively lower but qualitatively no different in the nondiabetic offsprings v controls throughout the study period. Mean basal hepatic glucose output (HGO) was higher but not statistically different in the offsprings compared with the controls (2.10 +/- 0.28 v 1.65 +/- 0.15 mg/kg X min).(ABSTRACT TRUNCATED AT 250 WORDS)     

Human C-peptide in normal and diabetic subjects

Concentrations of human C-peptide, IRI (immunoreactive insulin) and glucose were determined during oral glucose tolerance test (1.75 g glucose/kg ideal body weight) in 14 normal persons (N), 9 maturity-onset diabetics (DI) and 10 insulin-requiring diabetics (DII) never treated with insulin and in 3 formerly insulin treated diabetics. The mean fasting levels of C-peptide and IRI in the first three groups were: N: 0.37 +/- 0.02 nM and 0.048 +/- 0.009 nM, DI: 0.86 +/- 0.17 nM and 0.11 +/- 0.029 nM, DH: 0.37 +/- 0.04 nM and 0.063 +/- 0.009 nM. One hour after oral glucose ingestion, the respective values increased to: N: 2.53 +/- 0.20 nM and 0.52 +/- 0.077 nM, DI: 2.49 +/- 0.31 nM and 0.49 +/- 0.11 nM, DH: 0.49 +/- 0.05 nM and 0.11 +/- 0.014 nM. Although secreted from the pancreas in equimolar concentrations, the molar ratio of C-peptide to insulin in peripheral blood was about 7 in the fasting state, falling to about 5 in the glucose stimulated condition. Maturity-onset diabetics had higher fasting levels of C-peptide than normal subjects, in agreement with the IRI levels. Three patients previously treated with insulin and having insulin antibodies showed C-peptide responses significantly below the normal range. In one of these patients, the test was repeated 9 months later when the insulin antibodies had disappeared, and the C-peptide response observed at that time was much higher. It is suggested that insulin antibodies cause an impaired IRI - and consequently C-peptide response - by constantly removing insulin from the granules in the B-cell. In normal humans the peripheral C-peptide responses to the oral glucose load showed less relative variation than do the insulin responses. Therefore, a radioimmunoassay for C-peptide in addition to the assay for insulin will provide supplementary information on insulinsecretion.     

Glucagon-glucose (GG) test for the estimation of the insulin reserve in diabetes.

The residual B-cell function was examined by means of the plasma C-peptide response 6 min after a combined injection of glucagon and glucose (GG test) or conventional glucagon test (G test) in four insulin-dependent diabetic patients (IDDM group), in 18 diabetic patients treated with insulin (Insulin group), 31 treated with oral hypoglycemic agents (SU group) and 27 treated with diet only (Diet group) and in 22 borderline cases. By GG test, 6-min C-peptide values of the IDDM group were 0.27 +/- 0.05 nM (n = 4) and were significantly lower than those of the Insulin group (0.89 +/- 0.09 nM, n = 12), the SU group (1.42 +/- 0.10 nM, n = 13), the Diet group (2.47 +/- 0.22 nM, n = 11) and the borderline cases (3.38 +/- 0.22 nM, n = 11). Patients with a 6-min C-peptide concentration below 0.75 nM by GG test appeared to be insulin-requiring patients. In the G test, plasma C-peptide concentrations at 6 min were 0.35 +/- 0.08 nM in the IDDM group (n = 2), 0.72 +/- 0.20 nM in the Insulin group (n = 7), 1.08 +/- 0.09 nM in the SU group (n = 20), 1.40 +/- 0.19 nM in the Diet group (n = 17) and 2.05 +/- 0.21 nM in the borderline cases (n = 12). Some of the Diet group patients showed extremely low C-peptide responses. When comparing the GG test and G test in individual cases, a greater C-peptide response was seen with the GG test in all cases except for IDDM patients.(ABSTRACT TRUNCATED AT 250 WORDS)     

The 75-g oral glucose tolerance test: Effect on splanchnic metabolism of substrates and pancreatic hormone release in healthy man

To determine the effect of the 75 g oral glucose tolerance test on carbohydrate and lipid metabolism, the splanchnic exchange of glucose, lactate, pyruvate, non-esterified fatty acids, beta-hydroxybutyrate and acetoacetate as well as the release of insulin, C-peptide, glucagon and pancreatic polypeptide were evaluated in eight healthy male volunteers in the basal state and for 150 min following glucose ingestion. Oral glucose loading was followed by a rapid rise in splanchnic output of glucose (mean +/- SEM; 154 +/- 12 mmol/150 min), pyruvate (1.2 +/- 1.2 mmol/150 min) and lactate (8.6 +/- 2.0 mmol/150 min), whereas there were reductions in the splanchnic uptake of non-esterified fatty acids (-10.7 +/- 4.4 mmol/150 min) and the splanchnic output of beta-hydroxybutyrate (-4.8 +/- 3.3 mmol/150 min) and acetoacetate (-3.0 +/- 1.2 mmol/150 min). In parallel, splanchnic output of insulin (12.3 +/- 2.7 nmol/150 min), C-peptide (36.1 +/- 5.0 nmol/150 min) and transiently of pancreatic polypeptide rose, whereas that of glucagon fell (-0.58 +/- 0.21 nmol/150 min). Even at 150 min after glucose ingestion, splanchnic output and arterial concentrations of glucose, lactate, insulin and C-peptide were still above their respective basal values while those of non-esterified fatty acids and glucagon were reduced. Taking into account the partial suppression of endogenous glucose production by ingested glucose it is concluded that, in normal postabsortive man, only 49-63% of a 75 g oral glucose load is retained by the splanchnic bed during the first 150 min, the rest being available for non-hepatic tissues.(ABSTRACT TRUNCATED AT 250 WORDS)     

Estimation of B-cell function by the urinary excretion rate of C-peptide in diabetic patients: comparison with C-peptide response to glucagon and to a mixed meal

This study examined the relationship between the C-peptide response to intravenous glucagon and mixed meal stimulation and the 24 h urinary excretion rate of C-peptide and its urinary excretion during the glucagon test in nine control subjects, eighteen Type 1 (insulin-dependent) and twenty-two Type 2 (non-insulin-dependent) diabetic patients. Compared to controls (61.0 +/- 7.1 micrograms), the 24-h urine excretion rate of C-peptide was 8.2 +/- 3.1 micrograms (p less than 0.001) in Type 1 and 89.8 +/- 12.9 micrograms (p = NS) in Type 2 diabetic patients. C-peptide urinary excretion rate during the glucagon test was 6.92 +/- 1.11 micrograms, 0.42 +/- 0.10 microgram (p less than 0.001) and 6.47 +/- 1.13 micrograms (p = NS) respectively. Fasting serum C-peptide values were 1.53 +/- 0.16 ng/ml in controls, 0.42 +/- 0.09 ng/ml in Type 1 (p less than 0.0001) and 2.08 +/- 0.22 ng/ml in Type 2 diabetics (p = NS); C-peptide areas under the curve after glucagon stimulation were, respectively, 241.6 +/- 20.3 ng/ml, 29.2 +/- 5.9 ng/ml (p less than 0.0001) and 170.9 +/- 17.9 ng/ml (p less than 0.03) and after the meal test they were 204.7 +/- 15.6, 68.7 +/- 19.8 ng/ml (p less than 0.0001) and 265.5 +/- 32.9 ng/ml (p = NS).(ABSTRACT TRUNCATED AT 250 WORDS)     

Elevated growth hormone levels and insulin resistance in patients with cirrhosis of the liver

Carbohydrate intolerance is frequently seen in patients with hepatic cirrhosis. To study the role of the counter regulatory hormones, glucagon, cortisol and growth hormone in this disease, these hormones were measured in 11 patients with hepatic cirrhosis and six controls during a 4-hour oral glucose tolerance test (OGTT) and in five normal and cirrhotic subjects during steady-state plasma insulin and glucose concentrations (SSPGI) achieved with the euglycemic clamp technique. Fasting plasma glucose was 103 +/- 4.3 mg/dl in cirrhotics and 88 +/- 3.3 mg/dl in controls (p less than 0.001). Immunoreactive insulin (IRI) was 24.3 microU/ml in cirrhotics and 12.7 +/- 2.2 microU/ml in controls (p less than 0.001); immunoreactive glucagon (IRG) was 263 +/- 30 pg/ml in cirrhotics and 122 +/- 17.5 pg/ml in controls (p less than 0.001); serum growth hormone (GH) was 4.4 +/- 0.9 ng/ml in cirrhotics and 0.5 +/- 0.1 ng/ml in controls (p less than 0.001). During OGTT, the 2-hour glucose concentration was 201 +/- 9.7 mg/dl in cirrhotic subjects and 147 +/- 10.0 mg/dl in controls (p less than 0.001). IRG levels were suppressed by 20% of basal values in patients with cirrhosis, while controls showed 10% suppression after an oral glucose load. At 60 minutes, the serum GH was 14.7 +/- 3.9 ng/ml in cirrhotics and 0.3 +/- 0.1 ng/ml in controls (p less than 0.001). The normal suppressive effect of hyperglycemia on GH secretion in controls was sharply contrasted by a paradoxical elevation of serum GH in the cirrhotic group.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of 12 months rec-GH therapy on bone and collagen turnover and bone mineral density in GH deficient children with thalassaemia major

Children suffering from thalassaemia major are reported to have growth delay and bone alterations even when well transfused and chelated. In the present study we evaluated bone and collagen turnover (bone Gla-protein, BGP; carboxyterminal telopeptide of type I collagen, ICTP; aminoterminal propeptide of type III procollagen, PIIINP, respectively) and bone mineral density (BMD) in 5 pre-pubertal GH deficient thalassaemic children before and during rec-GH treatment (0.6 IU/kg/week). Data were compared with those recorded in an age- and sex-matched control group. Before treatment, serum BGP and ICTP levels were significantly lower (p<0.0001) in children with thalassaemia (9.3+/-0.7 ng/ml and 5.3+/-0.5 ng/ml, respectively) than in healthy controls (18.9+/-0.9 ng/ml and 14.4+/-0.6 ng/ml, respectively), while serum PIIINP levels did not significantly differ in the two groups (6.7+/-0.7 ng/ml vs 6.7+/-0.7 ng/ml). Mean lumbar BMD values of patients (0.62+/-0.05 g/cm2) were significantly lower (p<0.05) than those recorded in healthy controls (0.78+/-0.01 g/cm2), while femoral BMD values were similar in the two groups (patients: 0.70+/-0.08 g/cm2 vs controls: 0.74+/-0.01 g/cm2). One-year GH therapy significantly increased height velocity (from 2.3+/-0.2 cm/year to 6.1+/-0.4 cm/yr, p<0.0001) and IGF-I levels (from 61.6+/-15.4 to 342+/-38.5 ng/ml, p<0.005). Serum BGP (basal: 9.3+/-0.7 ng/ml, 6th month: 10.8+/-0.6 ng/ml, 12th month: 14.9+/-1.4 ng/ml), ICTP (basal: 5.3+/-0.5 ng/ml, 6th month: 7.9+/-0.8 ng/ml, 12th month: 10.9+/-1.7 ng/ml) and PIIINP levels (basal: 6.7+/-0.7 ng/ml, 6th month: 9.9+/-1.0 ng/ml, 12th month: 9.6+/-1.4 ng/ml) significantly increased (p<0.05), while no significant effects were observed on lumbar and femoral BMD values. Although the GH-induced stimulation of bone turnover markedly increased BGP (+60%) and ICTP (+105%) levels, one-year GH therapy was not sufficient to completely normalize these parameters, which remained significantly lower than in healthy controls. In conclusion, our study shows that pre-pubertal GH deficient children with thalassaemia major have reduced bone turnover (both bone formation and resorption) and lumbar BMD values, thus indicating that bone metabolism should be monitored and improved even in well-transfused patients. One-year GH treatment is able to increase, but not normalize, bone turnover, this effect being insufficient to improve BMD values. More prolonged periods of GH therapy are probably requested to positively affect both bone turnover and BMD values in GH deficient thalassaemic patients, as occurs in children and adults with GH deficiency.     

Total pancreatectomy increases the metabolic response to glucagon in humans

To evaluate the impact of glucagon deficiency on the response to glucagon replacement, we infused physiological doses of glucagon (1.25 ng/kg X min) into 9 totally pancreatectomized (PX) diabetic patients (C-peptide, undetectable) 1) for 24 h during their usual diet and insulin regimen and/or 2) for 6 h in a fasted insulin-withdrawn state. During both glucagon infusions, plasma glucagon rose from 46 +/- 2 (+/- SE) pg/ml (0-10% 3500 mol wt glucagon) to 112 +/- 9 pg/ml. In the 24-h study (n = 4), glucagon significantly increased mean 24-h glucose levels (272 +/- 27 mg/dl; P less than 0.05) and glycosuria (29 +/- 5 g/day; P less than 0.01) compared to preinfusion (158 +/- 14 mg/dl and 4 +/- 4 g/day, respectively) and postinfusion (200 +/- 35 mg/dl and 3 +/- 2 g/day) control periods. Blood ketones did not change. The 24-h glucagon infusion significantly lowered the fasting levels of the glucogenic amino acids aspartate (43%; P less than 0.01), threonine (46%; P less than 0.05), serine (46%; P less than 0.02), glycine (47%; P less than 0.01), and methionine (34%; P less than 0.02). Fasting alanine levels decreased from 835 +/- 236 to 393 +/- 66 microM (P less than 0.05). The 6-h glucagon infusion caused a 101 +/- 14 mg/dl maximal plasma glucose increment in PX (n = 8) vs. 33 +/- 11 in 5 insulin-withdrawn type I diabetic patients serving as controls (P = 0.022). Furthermore, when glucagon was infused at a higher rate (3 ng/kg X min) in 12 additional type I diabetic patients, the mean maximal plasma glucose increment (54 +/- 15 mg/dl) was still less than half that in PX, despite a 3-fold higher infusion plasma glucagon level (326 +/- 37 pg/ml). The 6-h glucagon infusion caused a significant decrease in the concentrations of glucogenic amino acids in the glucagon-deficient patients, but not in the type I diabetic patients. We conclude that 1) glucagon replacement in the PX patient markedly alters blood glucose and glucogenic amino acids, but not ketone levels; and 2) the metabolic response to glucagon is considerably more pronounced in PX patients than in type I diabetic patients. These data suggest that glucagon responsiveness is enhanced in the chronic hormone-deficient state.     

Insulin secretion, insulin sensitivity and glucose-mediated glucose disposal in thyrotoxicosis: a minimal model analysis

In order to evaluate simultaneously in thyrotoxic subjects the relative contributions of insulin secretion, insulin-sensitivity (SI) and glucose-mediated (SG) glucose disposal to overall glucose tolerance, seven non-obese patients with thyrotoxicosis were studied by the minimal model analysis of the frequently sampled intravenous glucose tolerance test, before and greater than 1 month after being rendered euthyroid, and compared with eight healthy control subjects. Basal glucose, C-peptide and glucagon levels were similar in all groups but, in the toxic and euthyroid states, basal insulin levels were significantly elevated compared to the control group (11.2 +/- 2.0 and 7.9 +/- 1.1 vs 5.1 +/- 0.6 microU/ml, mean +/- SE, P less than 0.02). FFA levels were raised in the thyrotoxic subjects prior to treatment (0.95 +/- 0.11 vs 0.68 +/- 0.08 and 0.54 +/- 0.08 mmol/l, P less than 0.02). Glucose tolerance (Kg) was reduced in the thyrotoxic subjects compared to the euthyroid state (1.16 +/- 0.12 vs 1.44 +/- 0.13 per min, P less than 0.025) and control group (1.44 +/- 1.0 per min, 0.05 less than P less than 0.1). First phase (phi 1) and second phase (phi 2) insulin release were both significantly elevated in the thyrotoxic and euthyroid states compared to the control group (phi 1 7.10 +/- 1.88 and 5.29 +/- 1.03 vs 1.72 +/- 0.17 microU/mg/min X 10(-2), P less than 0.01; phi 2 18.64 +/- 3.14 and 16.74 +/- 4.48 vs 9.23 +/- 0.74 microU/mg/min X 10(-2) respectively, P less than 0.02). SG was similar in all groups but SI was significantly reduced in the thyrotoxic subjects compared to the control group (2.24 +/- 0.62 vs 5.92 +/- 1.50/min/microU/ml X 10(4), P less than 0.02) and rose post-treatment in the euthyroid subjects (4.23 +/- 1.75/min/microU/ml X 10(4)). In the thyrotoxic subjects before and after treatment, log SI correlated negatively with basal FFA levels (r = -0.57, P less than 0.05) and with phi 2 (r = -0.58, P less than 0.05). The fractional clearance rate of insulin was unaltered by the thyrotoxic state. It is concluded that in thyrotoxicosis the impairment of Kg is due to reduced insulin sensitivity in the presence of enhanced insulin secretion, but glucose-mediated glucose disposal is unaltered by the toxic state.     

Plasma C-peptide response to oral glucose load in hyperthyroidism

Aim of the present study was to evaluate the pancreatic beta cell response to oral glucose load in a group of patients with hyperthyroidism. For this purpose plasma C-peptide at fasting and after a 100 g oral glucose load was measured in 8 newly-diagnosed untreated hyperthyroid patients with fasting normoglycemia, and 8 sex-, age-, and weight-matched healthy controls. As compared to healthy subjects, patients with hyperthyroidism showed higher plasma glucose levels (incremental area 5405 +/- 742 vs 2729 +/- 539 mg/dl x 180 min, p less than 0.05), and slightly reduced plasma C-peptide concentrations (incremental area 166 +/- 12 vs 182 +/- 36 pmol/ml x 180 min, p = NS) following oral glucose load. The ratios between plasma C-peptide and plasma glucose incremental areas were lower in hyperthyroid patients than in controls (3.66 +/- 0.85 vs 10.41 +/- 3.08, p less than 0.05). These data suggest that hyperthyroidism is characterized by a decreased pancreatic beta cell response to oral glucose load.     

Physiological levels of glucagon do not influence lipolysis in abdominal adipose tissue as assessed by microdialysis

To determine whether glucagon stimulates lipolysis in adipose tissue, seven healthy young male volunteers were studied, with indwelling microdialysis catheters placed sc in abdominal adipose tissue. Subjects were studied three times: 1) during euglucagonemia (EG; glucagon infusion rate, 0.5 ng/kg.min); 2) during hyperglucagonemia (HG; (glucagon infusion rate, 1.5 ng/kg.min); and 3) during EG and a concomitant glucose infusion mimicking the glucose profile from the day of HG (EG+G). Somatostatin (450 microg/h) was infused to suppress hormonal secretion, and replacement doses of insulin and GH were administered. Sampling was done every 30 min for 420 min. Baseline circulating values of insulin, C-peptide, glucagon, GH, glycerol, and free fatty acids were comparable in all three conditions. During EG and EG+G, plasma glucagon was maintained at fasting level (20-40 ng/L); whereas, during HG, it increased (110-130 ng/L). Interstitial concentrations of glycerol were similar in the three conditions [30,870 +/- 5,946 (EG) vs. 31,074 +/- 7,092 (HG) vs. 29,451 +/- 6,217 (EG+G) micromol/L.120 min, P = 0.98]. Plasma glycerol (ANOVA, P = 0.5) and free fatty acids (ANOVA, P = 0.3) were comparable during the different glucagon challenges. We conclude that HG per se does not increase interstitial glycerol (and thus lipolysis) in abdominal sc adipose tissue; nor does modest hyperglycemia, during basal insulinemia and glucagonemia, influence indices of abdominal sc lipolysis.     

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.     

Changes in glucagon do not play an essential role in the glucoregulatory responses to mild hyperinsulinemia in dogs

To examine whether an increase in the glucagon concentration is essential for restoring hepatic glucose output following moderate decrements in blood glucose, we used isotope dilution techniques in trained conscious dogs (n = 5) to measure glucose production (Ra) and glucose utilization (Rd) during mild hyperinsulinemia (19 +/- 1 mU/l). In Study A, when insulin was infused to raise plasma insulin (IRI) from 13 +/- 2 to 19 +/- 1 mU/l, basal glucose (93 +/- 3 mg/dl) fell at a rate of 0.37 +/- 0.06 mg/dl/min over 30 min. Ra fell from 2.8 +/- 0.4 mg/kg/min by 0.5 +/- 0.1 mg/kg/min at 20 min (P less than 0.05), but recovered to baseline by 30 min; glucagon (IRG) fell transiently but returned to baseline by 45 min. In Study B, endogenous secretion of IRI and IRG was suppressed by infusion of somatostatin (0.2 microgram/kg/min), while peripheral concentrations were maintained constant by replacing glucagon (0.65 ng/kg/min) and insulin (0.225 mU/kg/min). Steady-state baseline plasma IRI, IRG, glucose and glucose turnover rates were similar to Study A; hyperinsulinemia was then induced as in Study A. Glucose fell by 0.78 +/- 0.19 mg/dl/min over 30 min and, as in Study A, Ra decreased transiently, but recovered to baseline by 30 min. The restoration of Ra occurred in study B despite constant IRG, and preceded later increments in cortisol and catecholamines at 60-90 min. Thus, in both studies A and B, Ra recovered to baseline without an increase in IRG and before the onset of significant hypoglycemia (glucose 83 +/- 1 and 70 +/- 1 mg/dl).(ABSTRACT TRUNCATED AT 250 WORDS)     

Lack of effect of high-dose biosynthetic human C-peptide on pancreatic hormone release in normal subjects

We studied the effect of high doses of biosynthetic human C-peptide on pancreatic hormone secretion in response to oral (75 g) and intravenous [( IV] 0.33 g/kg of D50%) glucose on normal volunteers. The infusion of human C-peptide at a rate of 360 ng/kg/min body weight, increased the plasma C-peptide concentration from a basal level of 0.32 +/- 0.04 pmol/mL to 38.5 +/- 1.8 pmol/ml. Overall, C-peptide had no significant effect on the serum levels of glucose, insulin, proinsulin, glucagon, and pancreatic polypeptide, either under basal conditions or following IV and oral glucose administration. However, small decreases in glucose and insulin concentrations that were not statistically significant were seen during the first hour after C-peptide infusion. The results of the present studies are therefore consistent with the conclusion that even supraphysiologic plasma concentrations of infused C-peptide do not affect basal insulin secretion or overall insulin secretory responses to oral or IV glucose. However, we cannot definitively exclude a small reduction in insulin secretion in the first hour after oral glucose ingestion.