Arginine Infusion Test Research Articles

Oxytocin levels in response to pituitary provocation tests in healthy volunteers.

Oxytocin, secreted into circulation through the posterior pituitary, regulates lactation, weight, and socio-behavioral functioning. Oxytocin deficiency has been suggested in patients with hypopituitarism; however, diagnostic testing for oxytocin deficiency has not been developed. The aim of this study was to investigate known pituitary provocation tests to stimulate plasma oxytocin. Sixty-five healthy volunteers underwent either the hypertonic saline or arginine infusion test, known to stimulate copeptin, or the oral macimorelin test, known to stimulate growth hormone. Plasma oxytocin was measured before and once plasma sodium level ≥ 150 mmol/L for the hypertonic saline, after 60 min for the arginine infusion, and after 45 min for the oral macimorelin test (expected peak of copeptin and growth hormone levels, respectively). Primary outcome was a change from basal to stimulated oxytocin levels using paired t-tests. As expected, copeptin increased in response to hypertonic saline and arginine infusion (P < 0.001), and growth hormone increased to oral macimorelin (P < 0.001). Oxytocin increased in response to hypertonic saline infusion from 0.4 (0.2) to 0.6 pg/mL (0.3) (P = 0.003) but with a high variance. There was no change to arginine infusion (P = 0.4), and a trend to lower stimulated levels to oral macimorelin (P = 0.05). Neither the arginine infusion nor the oral macimorelin test stimulates plasma oxytocin levels, whereas there was an increase with high variance upon hypertonic saline infusion. As a predictable rise in most participants is required for a reliable pituitary provocation test, none of the investigated pituitary provocation tests can be recommended diagnostically to identify patients with an oxytocin deficiency.

Oxytocin Levels in Response to Pituitary Provocation Tests in Healthy Volunteers

Background: Oxytocin, secreted into the circulation through the posterior pituitary, regulates lactation, weight, and socio-behavioral functioning. Oxytocin deficiency has been suggested in patients with hypopituitarism, however, diagnostic testing for oxytocin deficiency has not been developed. Known stimuli used in the diagnosis of pituitary deficiencies - the hypertonic saline and arginine infusion tests stimulating copeptin levels, and the oral macimorelin test stimulating growth hormone levels - have also been shown to stimulate oxytocin secretion in animal models. We hypothesized that these provocation tests would stimulate plasma oxytocin levels in humans. Methods: Basal plasma oxytocin levels were measured for all three tests. Stimulated plasma oxytocin was measured once plasma sodium >150 mmol/l for the hypertonic saline and after 45 minutes for the arginine infusion and the oral macimorelin test, expected peak of copeptin and growth hormone levels, respectively. Primary outcome was change between basal and stimulated oxytocin levels using a paired t-test. Results: Median (IQR) age of all participants was 24 years (22, 28), 51% were female. As expected, copeptin increased in response to hypertonic saline from 4.0 pmol/L [3.3, 6.7] to 34.2 pmol/L [23.2, 45.4] (p-value <0.001) and in response to arginine infusion from 4.6 pmol/L [3.2, 6.2] to 8.3 pmol/L [6.4, 10.8] (p-value <0.001). Growth hormone increased in response to oral macimorelin from 1.6 ng/mL [0.3, 17.2] to 106.0 ng/mL [73.3, 127.2] (p-value <0.001). Oxytocin levels increased in response to hypertonic saline infusion from 0.3 pg/mL [0.3, 0.5] to 0.6 pg/mL [0.4, 0.7] (p-value 0.007), while there was no change in response to arginine infusion (basal 0.4 pg/mL [0.4, 0.6], stimulated 0.4 pg/mL [0.3, 0.6], p-value 0.6), nor to oral macimorelin (basal 38.7 pg/mL [31.1, 66.9], stimulated 34.2 pg/mL [31.2, 48.2], p-value 0.3). Conclusion: We found that hypertonic saline infusion results in doubling of oxytocin levels. Further research will be important to determine whether this test could be used diagnostically to identify patients with oxytocin deficiency. In contrast to animal data, arginine and macimorelin did not stimulate oxytocin.

Pancreatic A-cell function in the partially pancreatectomized Otsuka Long-Evans Tokushima fatty rat, a model of spontaneous non—insulin-dependent diabetes mellitus

We examined whether a 70% pancreatectomy changes the morphofunctionality of pancreatic A cells in a model rat (Otsuka Long-Evans Tokushima Fatty [OLETF]) with non—insulin-dependent diabetes mellitus. Male OLETF rats aged 6 weeks were assigned to two groups: partial pancreatectomy (Px) and sham pancreatectomy (sham). The Px group was divided into three subgroups based on treatment received after surgery, which included treatment with nicotinamide, phlorhizin, or saline. As a control, their diabetes-resistant counterparts, Long-Evans Tokushima Otsuka (LETO) rats, were similarly treated and grouped. Six weeks after surgery, plasma glucagon responses to arginine- and insulin-induced hypoglycemia were examined. In addition, the glucagon content and morphological features of pancreatic A cells in Px-remnant and remnant-equivalent pancreata were investigated 7 weeks after surgery.A sustained nonfasting hyperglycemia was evident in Px OLETF rats, which was ameliorated by administration of nicotinamide. The glucagon content and A-cell mass were not decreased significantly in the remnant pancreas of saline- and phlorhizin-treated Px animals of either strain but increased in nicotinamide-treated animals compared with those in the remnant equivalent of the respective sham rats. The areas under the response curves of plasma glucagon (ΣIRG) during an arginine infusion test and 90 minutes of insulin-induced hypoglycemia were 1,010.7 ± 72.9, 1,083.1 ± 95.3, 1,029.6 ± 65.0, and 1,779.8 ± 226.9 pmol · L −1 · min −7 versus 1,997.0 ± 283.1, 2,217.0 ± 395.0, 1,479.6 ± 78.0, and 3,466.4 ± 174.0 pmol · L −1 · min −1 in phlorhizin-, nicotinamide-, and saline-treated Px OLETF and sham OLETF rats, respectively. A similar trend was observed for differences in the response of pancreatic A cells to both stimuli among various groups of LETO rats. There was no significant difference in ΣIRGs during both tests between OLETF and LETO rats with similar treatments, except during an insulin tolerance test (ITT) in saline-treated Px rats. The magnitude of the plasma glucagon response to both stimuli in the test animals was roughly parallel to the glucagon cotent in the pancreas. These findings suggest that differences in the proliferation and responsiveness of pancreatic A cells between OLETF and LETO rats after a 70% pancreatectomy are not nearly as significant as compared with B cells.

Unique case of growth hormone (GH) deficiency accompanied by clinical anophthalmia, hypoplastic orbits, digital dysplasia, short stature, obesity, and diabetes mellitus

A 43-year-old female was admitted to our hospital for polydipsia and hyperglycemia. She had total blindness and globes were not recognized by inspection, indicating clinical anophthalmia. Physical examination revealed short stature, obesity, prematurely gray hair, shortness of fingers and toes, syndactyly, and multiple dental caries. Laboratory examination showed hyperglycemia, increased glycosilated hemoglobin (HbA1c) and insulin resistance on euglycemic glucose clamp. Blunted growth hormone (GH) secretion was shown in response to insulin-induced hypoglycemia, arginine infusion, and GH-releasing hormone (GHRH) loading test, and in 24 h spontaneous GH profile. Magnetic resonance imaging (MRI) and computed tomography (CT) showed dysostosis of orbit, defect of optic nerve, enlarged suprasellar cistern, and prolonged pituitary stalk. This may be the first report of a unique case with GH deficiency accompanied by clinical anophthalmia, hypoplastic orbits, digital dysplasia, short stature, obesity, and diabetes mellitus. © 1996 Wiley-Liss, Inc.

Serum growth hormone-binding protein is unchanged in adult panhypopituitarism.

The role of GH in regulating GH-binding protein (GHBP) and GH receptor concentrations in humans is not clear. Studies performed mostly in children and on a minor scale in adults are somewhat controversial. The key question as to whether GHBP levels are altered in hypopituitarism before GH treatment is instituted remains unanswered. In this study, we have selected a severely GH-deficient group of adult patients with panhypopituitarism, acquired as a result of surgery and irradiation of hypothalamic-pituitary tumors, to evaluate the GHBP/receptor status by measuring GHBP activity in plasma. Twenty panhypopituitary patients (8 males and 12 females; age range, 20-74 yr) and 20 age (22-68 yr)- and sex-matched normal subjects were studied. GH deficiency was confirmed by insulin-induced hypoglycemia and arginine infusion tests; the peak GH response was less than 2 micrograms/L. Plasma insulin-like growth factor-I levels were below or in the low normal range (mean +/- SD, 88.3 +/- 53.6 micrograms/L) and were significantly different from insulin-like growth factor-I (IGF-I) levels in the normal group (mean +/- SD, 189 +/- 49.8 micrograms/L; P < 0.01). Plasma GHBP activity, measured using a GH-binding/gel chromatography assay, showed similar values in the GH-deficient group (mean +/- SD, 14.1 +/- 3.83%) and the control group (mean +/- SD, 13.7 +/- 3.79%), with no statistically significant difference. Neither the intra- nor intergroup comparison of GHBP levels according to age and sex showed statistically significant differences or age trends. In the light of these data and considering that GHBP activity in plasma probably reflects the GH receptor status in tissues, we may assume that the GH receptor was unaffected by chronic GH deficiency. These findings also support the previously reported concept that the GHBP/receptor level is a relatively fixed determinant of growth, established individually and independently of GH secretory status in early life, perhaps on a genetic basis.

Long term follow-up of Cushing's disease treated with reserpine and pituitary irradiation followed by subtotal adrenalectomy.

Subtotal adrenalectomy was given to 10 adult patients with Cushing's disease, concurrently with or following therapeutic regimen by long term reserpine administration and pituitary irradiation. In the present study, we describe long term follow-up results. Two patients died after the operation due to acute adrenal crisis and pneumonia, respectively. The other 8 patients achieved clinical and biochemical remissions and were followed for long term. Three patients relapsed 9, 14 or 17 years after achieving remission, two patients developed hypopituitarism 12 or 20 years after and one died of cerebral vascular accident at 64 years, 5 years after the remission. The remaining 2 patients maintained remission for 10 or 18 years, respectively. During the remission periods of 0.5 to 20 years with a mean of 10.1 +/- 6.7 years, 6 of 7 patients examined by 1 mg overnight dexamethasone test showed normal suppressibility of plasma cortisol. Provocative tests of plasma GH by l-arginine infusion and/or insulin-induced hypoglycemia were performed in 6 patients in the early remission period. All of 5 patients in the arginine infusion test and 3 of 5 in the insulin-induced hypoglycemia test showed normal responses. Furthermore, to facilitate prediction of long term response or failure to our therapeutic regimen, long term reserpine administration and pituitary irradiation, pretreatment clinical and biochemical characteristics were analyzed retrospectively in 3 divided groups; the present 10 patients treated with reserpine and pituitary irradiation followed by subtotal adrenalectomy, 11 patients achieving long term remission treated by our regimen alone, and 7 patients failed with our regimen alone. There were no significant factors predictive of response to our regimen. These findings suggest that subtotal adrenalectomy does not lead favorable outcome, however, reserpine administration shows usefulness to improve pituitary functions in treating Cushing's disease.

THE SECRETORY DYNAMICS OF GROWTH HORMONE IN PATIENTS WITH CUSHING DISEASE

Growth retardation to complete growth arrest is the hallmark of Cushing syndrome in children. The major mechanism for this has been considered the glucocorticoid-induced resistance of target-tissues to insulin-like growth factor 1 (IGF-1) and other growth factors. The purpose of this study was to examine the growth hormone (GH) secretory dynamics of patients with Cushing disease before and up to 12 months after their cure by transsphenoidal adenomectomy. In fourteen patients, every 20 minutes blood sampling during 24h for determination of plasma GH was performed. These patients also underwent arginine infusion and L-Dopa stimulation tests. Fourteen sex-and pubertal stage- matched normal volunteers were used as controls. Prior to therapy, the patient group had an increased BMI (31.5 ± 5 kg/m2) and markedly decreased plasma 24h GH mean, peak amplitude and peak area values, with pulse frequency similar to that of the controls. GH values after arginine and L-Dopa stimulation were also subnormal in many of these patients with 2 out of 8, and 8 out of 10 failing to show GH responses greater than 7 ng/ml in the respective test. Surprisingly, the same pattern of GH suppression was observed in the patients who were studied 10-11 days, 3 months and 6 to 12 months after their cure, when their BMIs were respectively, relatively stable, 26.9 ± 3.8 kg/m2, and 24.8 ± 3.3 kg/m2. These findings suggest that patients with Cushing disease have marked GH suppression during their illness, which continues for at least a year during their convalescence. We conclude that frank GH deficiency may be another important mechanism for the growth retardation observed in children with Cushing syndrome. In view of the persistent GH suppression after curative removal of the pituitary adenomas, patients should be clinically evaluated for the potential need for GH replacement.

Abnormal glucagon response to arginine and its normalization in obese hyperinsulinaemic patients with glucose intolerance: importance of insulin action on pancreatic Alpha cells

An excessive glucagon secretion to intravenous arginine infusion was found in obese hyperinsulinaemic patients with glucose intolerance. This study was designed to determine whether the glucagon hyperresponsiveness to arginine in these patients would improve by insulin infused at a high enough dose to overcome insulin resistance. By infusing high dose insulin during arginine infusion, the previously exaggerated glucagon response to arginine could be normalized. To normalize the abnormal glucagon response, insulin doses of 4.2 +/- 0.7 and 3.8 +/- 0.5 IU were required during arginine infusion in obese hyperinsulinaemic patients with impaired glucose tolerance and Type 2 (non-insulin-dependent) diabetes mellitus, respectively. This achieved plasma peak insulin levels 3 to 4 times higher than those observed in non-obese healthy subjects. Furthermore, we clarified whether or not the effect of normalizing insulin action and/or glycaemic excursions contributed to normalizing the exaggerated glucagon response to arginine in these patients. Blood glucose was clamped while high dose insulin was infused at the same levels as observed during the arginine infusion test with no insulin infusion. As a result, normalization of the exaggerated plasma glucagon response was achieved, whether hyperglycaemia existed or not. These results clearly demonstrate that, similar to non-obese hypoinsulinaemic Type 1 (insulin-dependent) and Type 2 (non-insulin-dependent) diabetic patients, the exaggerated Alpha-cell response to arginine infusion in obese hyperinsulinaemic patients with glucose intolerance is secondary to the reduction of insulin action on the pancreatic Alpha cell, and that the expression of insulin action plays an important part in normalizing these abnormalities.

Insulin secretion and action in patients with pancreatic cancer

The authors investigated insulin secretory capacity and insulin action in 11 preoperative patients with pancreatic carcinoma and 15 age-matched and weight-matched healthy subjects (C). Five patients were classified as diabetic (D), two as impaired glucose tolerant (IGT), and four as nondiabetic (ND). Postabsorptive serum insulin levels (mean +/- SE, in uU/ml) in D (12 +/- 2), IGT (17 +/- 7), and ND (10 +/- 2) were comparable. After administration of 100 g of oral glucose, peak insulin achieved in D (60 +/- 11) was lower than in IGT (101 +/- 26) and ND (83 +/- 20), whereas peak insulin levels in IGT and ND were significantly (P less than 0.05) higher than in C (45 +/- 6). Comparable insulin response to nonglucose stimuli was documented in all subjects using the slow arginine infusion test with mean serum insulin of 27 +/- 4 in D, 28 +/- 6 in IGT, 34 +/- 10 in ND, and 32 +/- 5 in C. In six patients (P) and six controls, insulin action was assessed by the euglycemic hyperinsulinemic clamp technique, with glucose turnover rates estimated by [3-3H]glucose infusion. Steady-state plasma glucose concentrations were maintained at 92 +/- 3 (P) and 91 +/- 1 mg/dl (C). After insulin infusion at the rate of 1.0 mU/kg/min, comparable high physiologic insulin levels were observed in P (73 to 104 uU/ml) and in C (81 to 103 uU/ml). Postabsorptive rates of endogenous glucose appearance (Ra) were higher in P (2.86 to 3.02 mg/kg/min) than in C (1.50 to 2.80 mg/kg/min). At high physiologic insulin concentrations, negative Ra values were documented in all subjects, and complete suppression of Ra was assumed. Total body glucose use (M) was consistently lower in P (3.90 to 6.40 mg/kg/min) than in C (6.98 to 10.40 mg/kg/min), consistent with a state of insulin resistance. Patients with pancreatic cancer manifest insulin resistance by virtue of a decrease in total body glucose use (M) and decreased insulin response to glucose due to either inherent beta cell dysfunction or decreased islet cell mass. The latter is not identifiable by histologic morphology.

A Study of Anti-Pituitary-Antibodies in Patients with Hypopituitarism and Their Hereditary Background

Recently several types of anti-pituitary-antibodies (APA) have been found in patients with pituitary disorders including hypopituitarism and diabetes insipidus, and in postpartum women. However, the pathophysiological role(s) of APA still remains unknown. In order to elucidate the clinical significance of APA, longitudinal follow-up and family study of APA in patients with hypopituitarism were performed. APA in serum was examined in a total of 11 patients with various types of hypopituitarism (7 of isolated ACTH deficiency, 1 of partial hypopituitarism, 3 of Sheehan's syndrome, 6 males and 5 females). Chronic thyroiditis was associated in 3 out of 7 patients with isolated ACTH deficiency, and empty sella was found in each one patient with isolated ACTH deficiency and partial hypopituitarism, and in 3 patients with Sheehan's syndrome. APA was examined on 2 or 3 occasions at more than a 6 month interval (longitudinal study). In 5 patients, their 16 family members were examined for the presence of APA, and pituitary functions were evaluated in 3 out of 7 family members with positive APA (family study). For pituitary function tests, arginine infusion test, TRH, LH-RH or CRH test and insulin tolerance test were performed. APA reacting to rat pituitary cytoplasmic antigens (pituitary cell antibodies: PCA) and APA reacting to rat GH3 cells and/or mouse AtT20 cells surface antigens (pituitary cell surface antibodies: PCSA) were assayed with indirect immunofluorescence method. At the initial examination, 6 out of 11 patients (55%) showed positive APA. The patients were divided into 3 subgroups according to the longitudinal study: the group with disappearance of initially positive APA (3 patients), the group with altered titers or types of initially positive APA (3 patients), and the group with sustained initially negative APA (4 patients). No effects of replacement therapy on the alterations of APA were observed. In 16 family members of 5 patients (each 1 with partial hypopituitarism and isolated ACTH deficiency syndrome, and 3 with Sheehan's syndrome), APA in their sera were investigated. Seven out of 16 members (44%) showed positive APA. Among 6 first-degree relatives of 16 family members, both or either one of APA and PCSA were positive in 4 (67%). Out of 10 of their second- or third-degree relatives, 3 (30%) were positive for PCA or PCSA. All of 3 relatives with positive APA studied showed mild pituitary hypofunction without any clinical manifestations.(ABSTRACT TRUNCATED AT 400 WORDS)

Hemodynamic and endocrine effects of acute and chronic administration of nifedipine.

Although it is well known that calcium channel blockers can influence contraction of vascular smooth muscle, there is less knowledge on its effect on excitation contraction coupling in the endocrine glands and more specifically on insulin and glucagon release. In this study, nifedipine was administered in doses of 40 to 80 mg/day to 14 patients with essential hypertension, and its hemodynamic effects were evaluated by non-invasive methods, and its effect on glucose metabolism by an arginine infusion test. Nifedipine produced a significant reduction in systolic and diastolic blood pressure, both after the first dose (30/12 mm Hg) and after 8 weeks of administration (19/12 mm Hg). There were no significant changes in cardiac output (5.1 to 4.9 L/min), muscle (2.4 to 3.2 mL/sec/min) or cutaneous basal flow (9.8 to 8.6 mL/100 mL) as measured non-invasively by echocardiogram and by plethysmography. Insulin and glucagon release were evaluated by the arginine infusion test. Nifedipine produced a tendency towards an increase in glucagon release and a reduction in insulin release although these changes did not reach statistical significance. In this group of patients, nifedipine produced a significant reduction in systolic and diastolic pressure, but no significant changes in insulin or glucagon plasma levels.

Growth Hormone Deficiency in Patients With Idiopathic Adrenocorticotropin Deficiency Resolves During Glucocorticoid Replacement

Glucocorticoids (GC) have stimulatory effects on GH secretion in vitro and suppressive effects when administered in pharmacological amounts in vivo. We studied six patients with ACTH deficiency and severely impaired serum GH responses to insulin tolerance tests and arginine infusion tests. All patients underwent the same tests during GC replacement while receiving cortisone acetate in doses ranging from 12.5-25 mg/day. The three patients with idiopathic ACTH deficiency and no evidence of pituitary mass lesions had impaired GH secretion, which returned to normal during GC replacement. In contrast, the three patients with ACTH deficiency and hypothalamo-pituitary mass lesions detected by a computed tomography scan had impaired GH secretion during GC replacement therapy. Our data indicate that in patients with idiopathic ACTH deficiency, an impaired GH response to stimuli reversible during GC replacement therapy may be the functional consequence of the low levels of circulating cortisol. We conclude that physiological serum cortisol levels are necessary for normal serum GH responses to provocative stimuli in man.

Hemodynamic and endocrine effects of acute and chronic administration of nifedipine.

Although it is well known that calcium channel blockers can influence contraction of vascular smooth muscle, there is less knowledge on its effect on excitation contraction coupling in the endocrine glands and more specifically on insulin and glucagon release. In this study, nifedipine was administered in doses of 40 to 80 mg/day to 14 patients with essential hypertension, and its hemodynamic effects were evaluated by non-invasive methods, and its effect on glucose metabolism by an arginine infusion test. Nifedipine produced a significant reduction in systolic and diastolic blood pressure, both after the first dose (30/12 mm Hg) and after 8 weeks of administration (19/12 mm Hg). There were no significant changes in cardiac output (5.1 to 4.9 L/min), muscle (2.4 to 3.2 mL/sec/min) or cutaneous basal flow (9.8 to 8.6 mL/100 mL) as measured non-invasively by echocardiogram and by plethysmography. Insulin and glucagon release were evaluated by the arginine infusion test. Nifedipine produced a tendency toward an increase in glucagon release and a reduction in insulin release although these changes did not reach statistical significance. In this group of patients, nifedipine produced a significant reduction in systolic and diastolic pressure, but no significant changes in insulin or glucagon plasma levels.

Glucose intolerance in thyrotoxic rats: role of insulin, glucagon, and epinephrine.

To elucidate the possible role of insulin, glucagon, and epinephrine on glucose intolerance in thyrotoxicosis, the secretion of insulin and glucagon in vivo (glucose, arginine, and epinephrine infusion tests) and in perfused pancreas and the hepatic action of insulin, glucagon, and epinephrine in perfused liver were investigated in experimental thyrotoxic rats (induced by thyroxine injection, 20 micrograms/kg sc, for 7 days). In thyrotoxic rats, fasting blood glucose (87 +/- 5 mg/dl, mean +/- SD) and plasma insulin (16 +/- 3 microU/ml) were significantly (P less than 0.001) higher than those in controls (74 +/- 5 mg/dl and 8 +/- 1 microU/ml), respectively. In glucose infusion test (0.5 g/kg iv), blood glucose, plasma insulin, and glucagon responses in thyrotoxic rats were not significantly different from those in controls. In arginine infusion test (5 mg/min for 20 min iv), the increments in blood glucose and plasma insulin after arginine in thyrotoxic rats were not significantly different from those in controls. Plasma glucagon response was almost the same in both groups. In epinephrine infusion test (100 micrograms/kg iv), the increments in blood glucose and plasma insulin in thyrotoxic rats were significantly greater than those in controls. In perfused pancreas, insulin and glucagon secretions in response to 16.7 mM glucose or 6.4 mM arginine in the presence of 5.5 mM glucose in thyrotoxic rats were not different from those in controls.(ABSTRACT TRUNCATED AT 250 WORDS)

Peripheral insulin resistance in primary hyperparathyroidism

Carbohydrate metabolism was investigated in 9 patients with symptomatic primary hyperparathyroidism. Before and after parathyroidectomy intravenous and oral glucose tolerance tests, tolbutamide test, arginine infusion test and insulin tolerance test were performed. During intravenous and oral glucose tolerance tests, patients with primary hyperparathyroidism exhibited hyperinsulinemia and impaired glucose tolerance without normalization after surgery. Tolbutamide-induced insulin release did not differ pre- or postoperatively. After restoration of normocalcemia and normophosphatemia we found significantly lower glucose and insulin levels following arginine infusion and a significantly increased hypoglycemic response to parenterally administered insulin, probably indicating partial improvement of glucose tolerance after surgery. Our findings suggest that biochemical abnormalities associated with primary hyperparathyroidism, like hypercalcemia, hypophosphatemia, and elevated parathyroid hormone levels may cause and sustain a form of endogenous insulin resistance, which consequently leads to hyperinsulinemia and to impaired glucose tolerance. Since hyperinsulinemia as well as impaired glucose tolerance seem to be only slowly and partially reversible in symptomatic primary hyperparathyroidism, these data could be considered as an additional argument for early surgical intervention in this disorder.

Effects of total pancreatectomy on the secretion of gut glucagon in humans.

To determine how total pancreatectomy influences the secretion of gut glucagon in man, 15 totally pancreatectomized patients (Px), 14 distally gastrectomized patients (Gx), and 15 healthy subjects were investigated by intravenous arginine infusion test and oral glucose tolerance test. Blood glucose, plasma insulin (IRI), and C-peptide (CPR) levels were determined. Plasma immunoreactive glucagon (IRG) and total glucagon-like immunoreactivity (total GLI) were also measured. Gut glucagon-like immunoreactivity (gut GLI) was calculated to be the difference between total GLI and IRG. In the Px group, arginine infusion did not significantly alter the levels of IRI, CPR, IRG, and gut GLI. Mean basal value of gut GLI in the Px group of 356 +/- 40 pg/ml was significantly higher than 179 +/- 26 pg/ml of the healthy (p less than 0.01) and 182 +/- 24 pg/ml of Gx group (p less than 0.01). Oral glucose loading led to the highest increase of gut GLI in the Px group (p less than 0.01). Thus, extrapancreatic IRG may not be secreted into the plasma in totally pancreatectomized humans in response to arginine stimulation. Complete absence of the pancreas and the deficiency of insulin-effect may lead to a hypersecretion of gut GLI, both in the basal state and after oral glucose loading.

Insulin-like growth factor in pregnancy: studies in a growth hormone-deficient dwarf.

Serum concentrations of insulin-like growth factors I and II (IGF I and IGF II) were measured before, during and after pregnancy in a GH-deficient dwarf. At no time during these periods did the patient secrete GH in response to an arginine infusion or insulin tolerance test. IGF I and IGF II concentrations before pregnancy were low and similar to those of patients deficient only in GH. During the 35th week of gestation, IGF I and IGF II serum concentrations were within the normal range (165 and 127 ng/ml for IGF I and 740 and 860 ng/ml for IGF II). Abnormally low values of IGF I and IGF II were again recorded 36 h postpartum and 35 days later. These data indicate that some material, probably of placental origin, stimulates the secretion of not only IGF I, but IGF II as well. Alternatively, the human placenta may produce IGF. Such secretion can occur without the prior maternal secretion of pituitary GH.

Failure of indomethacin to affect arginine-induced C-peptide and glucagon release in insulin-treated diabetics

Fourteen insulin-treated diabetics were submitted to an arginine infusion test performed with either 11.7 or 5.85 mg kg-1 min-1 arginine monohydrochloride infused during 40 min with or without previous oral administration of a low (75 + 50 mg) or a high (75 mg + 3 mg/kg) dose of indomethacin. Blood glucose, plasma non-esterified fatty acids, insulin, C-peptide and glucagon were determined at regular intervals before, during and after the arginine infusion. These parameters were totally unaffected by the two doses of indomethacin both in the basal state and during the arginine infusions at the two loads tested. Eight subjects had a basal C-peptide level above 0.07 pmol/ml and a mean (+/- SEM) maximal rise of 0.21 +/- 0.04 pmol/ml during the arginine infusion, whereas the remaining six patients had virtually zero values throughout the tests. The arginine-induced plasma glucagon rise was similar for the two rates of arginine infusion; the sum of the increments in plasma glucagon averaged 877 +/- 120 and 647 +/- 92 pg/ml (p greater than 0.1) for the high and low rates of arginine infusion, respectively. The magnitude of the blood glucose rise appeared independent of the amount of arginine infused. Confirming previous reports, we found that the blood glucose rise after arginine was three to four times higher in subjects without C-peptide than in subjects with C-peptide. The mean glucagon response did not differ significantly between subjects with or without C-peptide. Thus, residual B cell function determines the magnitude of the blood glucose rise but not the glucagon response after intravenous arginine.

Hyperglucagonemia in myotonic dystrophy.

To clarify the possible participation of glucagon in glucose intolerance in myotonic dystrophy, six patients with myotonic dystrophy were examined. Three of the six patients had abnormal oral glucose tolerance curves; two had frank diabetic glucose tolerance curves, and the other had a high glucose value 30 min after glucose loading, which fell beyond the normal range (mean +/- 2 SD). The total insulin response to oral glucose, calculated as the insulin area, was significantly exaggerated (P less than 0.01 vs. the control value). In addition to these results, hyperglucagonemia was observed throughout the test in two patients with myotonic dystrophy. In the arginine infusion test, the insulin response was not as exaggerated. Plasma glucagon, however, was significantly higher (P less than 0.05 vs. the control value) 30, 45, and 60 min after arginine infusion, and the mean glucagon area under the curves was significantly greater (P less than 0.05 vs. the control value). None of the myotonic patients showed GH or cortisol excess during an arginine infusion and/or insulin tolerance test. Three patients with myotonic dystrophy who had abnormal glucose tolerance curves showed absolutely or relatively high glucagon levels and exaggerated responses to arginine infusion. These findings suggested that hyperglucagonemia might contribute to the appearance of glucose intolerance in myotonic dystrophy.

Clinical evaluation of hyperglucagonemia in patients with myotonic dystrophy (author's transl)

In order to clarify the possible participation of glucagon in glucose intolerance in myotonic dystrophy, six patients with myotonic dystrophy were examined. Three out of the six patients had an abnormal oral glucose tolerance curve. Two had frank diabetic glucose tolerance curves and the other had a high glucose value at 30 min after glucose loading, which fell beyond the normal range (Mean +/- 2 S.D.). Total insulin response to oral glucose, calculated as insulin area, was significantly exaggerated (p less than 0.01 vs control value). In addition to these results, hyperglucagonemia was observed throughout the test in two patients with myotonic dystrophy. In the arginine infusion test, insulin response was not so exaggerated but plasma glucagon was significantly higher (p less than 0.05 vs control value) at each 30, 45, 60 minutes after arginine infusion, and the mean glucagon area under the curves was significantly greater (p less than 0.05 vs control value). None of the myotonic patients showed growth hormone or cortisol excess during an arginine infusion and/or insulin tolerance test. Three patients with myotonic dystrophy who had abnormal glucose tolerance curves showed absolutely or relatively high glucagon levels and exaggerated response to arginine infusion. These findings suggested that hyperglucagonemia might contribute to the appearance of glucose intolerance in myotonic dystrophy.