Comparative insulinogenic effects of glucose,arginine and glucagon in patients with diabetes mellitus,endocrine disorders and liver disease

Summary In order to compare the insulinogenic effects of glucose, arginine and glucagon, plasma immunoreactive insulin levels following oral glucose loading (50 g), intravenous arginine infusion (30 g for 45 min) and intravenous glucagon injection (1 mg) were determined in patients with diabetes mellitus, various endocrine diseases and chronic hepatitis. In patients with Cushing’s syndrome, plasma insulin responses to all three stimuli were exaggerated, whereas they were low in patients with pheochromocytoma. In other diseases, certain disparities were observed in plasma insulin responses. In patients with mild diabetes mellitus, insulin secretion elicited by glucose seems to be selectively impaired, because arginine and glucagon caused a rise in plasma insulin not significantly different from that in normal subjects. In patients with hyperthyroidism, plasma insulin responses to arginine and glucagon were either absent or limited, although rather a exaggerated response was noted following oral glucose loading. On the contrary, exaggerated responses to arginine and glucagon, and limited response to glucose were observed in hypothyroidism. In patients with chronic hepatitis, the responses of plasma insulin to glucose and arginine were both exaggerated, whereas the response to glucagon was comparable to that in normal subjects. These disparate responses suggest that glucose, arginine and glucagon act on the B-cell via different mechanisms.     

Amino acid modulation of glucose-induced insulin and glucagon release in diabetic patients

In order to determine whether amino acids have a beneficial effect on glucose tolerance in diabetes, the effect of intravenous infusion of mixed amino acids on plasma insulin, glucagon, and blood glucose responses to oral glucose loading was studied in patients with mild to moderate diabetes. Intravenous infusion of mixed amino acids over a period of 30 min which was started 30 min or immediately before oral glucose loading significantly augmented the insulin response but did not improve the blood glucose curve, probably due to excessive glucagon response. However, amino acid infusion over a period of 60 min started immediately before oral glucose loading evoked a sustained rise of plasma insulin associated with a lesser degree of glucagon secretion, thus causing significant improvement of the blood glucose curve.     

The effect of galanin on canine plasma glucose and gastroenteropancreatic hormone responses to oral nutrients and intravenous arginine

Intravenous infusion of galanin into conscious dogs during ingestion of oral glucose or a mixed meal or during iv infusion of arginine resulted in significant blunting of plasma insulin responses and significant increases in plasma glucose levels compared to those in control experiments. Galanin infusions did not significantly alter plasma gastric inhibitory peptide responses to oral glucose or a mixed meal, or plasma gastrin, pancreatic polypeptide, or pancreatic glucagon responses to a mixed meal. Similarly, galanin infusions did not significantly alter pancreatic glucagon responses to iv arginine. In all experimental situations, on cessation of the galanin infusions, prompt elevation of plasma insulin levels occurred. These results suggest that in the conscious dog, galanin administration produces a relatively selective, but readily reversible, inhibition of insulin secretion stimulated by oral nutrients or iv arginine.     

Modulation by verapamil of insulin and glucagon secretion in man

Summary The present investigation was designed to evaluate the effect of acute and protracted verapamil administration on insulin and glucagon secretion in man. For this purpose, 14 normal subjects received two consecutive glucose pulses (5 g i.v. in less than 20 sec or 20 g i.v. in less than 1 min, 7 subjects for each group), 70 or 90 min apart, before and during an infusion of verapamil (160 g/min). Seven additional normal subjects received two consecutive arginine pulses (5 g i.v.), 70 min apart. In 14 inpatients with coronary heart disease, we investigated the effect of protracted verapamil administration. Seven of these subjects underwent two oral glucose tolerance tests (100 g) and the other 7 two arginine tests (30 g) before and after a 10-day treatment with verapamil, 240 mg/die p.o. divided into three doses; the last dose, 80 mg, was given orally 1 h before the performance of the post-treatment test. Verapamil significantly inhibited the acute insulin response (AIR, mean change from 3–10 min) to glucose (5 g), as well as the AIR and AGR (acute glucagon response) to arginine (5 g). By contrast, verapamil failed to alter significantly the AIR to the higher glucose pulse. There was no significant change of oral glucose tolerance after verapamil, nor was there a change in insulin response to oral glucose. By contrast, insulin and glucagon responses to arginine infusion were significantly reduced by the drug.     

Effect of the enteroinsular axis on both the A- and B-cell response to arginine after oral glucose in man

Summary Studies were made on the effect of the enteroinsular axis on amino acid-induced insulin and glucagon secretion during hyperglycaemia in man. The responses of plasma immunoreactive insulin, C-peptide, and immunoreactive glucagon to arginine infusion were investigated in nine healthy subjects after induction of hyperglycaemia by an oral glucose load and by intravenous glucose infusion to produce similar glucose concentrations in the arterialised blood. The plasma immunoreactive insulin and C-peptide levels increased to higher levels after an oral glucose load than after an intravenous infusion of glucose. The incremental areas under the immunoreactive insulin and C-peptide curves during arginine infusion were significantly greater (p<0.01) after oral than after intravenous glucose administration. The plasma immunoreactive glucagon level was suppressed equally after oral and intravenous glucose loads. However, during subsequent arginine infusion, the plasma immunoreactive glucagon level rose more in the presence of hyperglycaemia induced by oral than intravenous glucose. The incremental area under the plasma immunoreactive glucagon curve during arginine infusion was 1.6-fold greater after glucose ingestion than after intravenous glucose infusion. These results suggest that the enteroinsular axis has a stimulatory effect on the responses of pancreatic A and B cells to arginine after oral glucose administration.     

The effect of acetylsalicylic acid on plasma glucose and the response of glucose regulatory hormones to intravenous glucose and arginine in insulin treated diabetics and normal subjects

The effects of oral acetylsalicylic acid (ASA) 3.2 g a day for 5 days on glucose and glucose regulatory hormones were examined in 4 normal subjects, and in 14 insulin requiring diabetic subjects, 9 of whom had significant residual Beta cell function as assessed by C-peptide secretion and 5 of whom did not. In all subjects plasma samples were assayed for glucose, C-peptide, glucagon, growth hormone, and cortisol during sequential intravenous glucose and arginine infusions while the subject was receiving ASA or placebo. The plasma samples from the normal subjects were assayed for insulin.ASA significantly increased early insulin release (p < 0.02) and decreased plasma glucose (p < 0.02) in response to intravenous glucose in the normal subjects. ASA had no effect on glucose or hormone responses to intravenous arginine.The C-peptide positive diabetics had a significantly lower basal plasma glucose while receiving ASA, and this difference persisted throughout the test (p < 0.02). C-peptide levels were similar to control during ASA ingestion. ASA had no significant effect on plasma glucose in the C-peptide negative diabetics.ASA significantly increased fasting plasma glucagon in the normal subjects (p < 0.05) and C-peptide negative diabetics (p < 0.05). There was a significant positive correlation between the changes in plasma glucose and plasma glucagon both basally and 10 min after the commencement of the glucose infusion for the C-peptide negative diabetics but not for the C-peptide positive diabetics or the normal subjects. ASA had no effect on plasma growth hormone or cortisol levels.The reduction of plasma glucose by ASA in man is dependent on continuing β cell function. In the absence of β cell function the stimulatory effect of ASA on glucagon production becomes the major determinant of ASA's effect on plasma glucose. The effects of ASA on pancreatic islet function appears to be the major determinant of its effect on glucose handling.     

Insulin and glucagon secretion in diabetic and non-diabetic patients with circulating islet cell antibodies

Summary Thirty-nine patients (14 non-diabetics, 8 chemical diabetics, and 17 overt diabetics) with circulating islet cell antibodies (ICA) were studied. Insulin and glucagon secretion after oral (100 g) and intravenous glucose loading (200 mg/kg bolus injection followed by an infusion of 20 mg/min over 60 min) and arginine infusion (25 g over 30 minutes) were evaluated in these patients and in non diabetic and diabetic ICA-negative controls. In the non-diabetic groups with or without ICA, insulin and glucagon responses to glucose were similar. Moreover, in ICA positive patients the response of these hormones to arginine infusion was reduced. Similar alterations in insulin and glucagon secretion were observed in the ICA positive and negative patients with chemical or overt diabetes. In particular, fasting hyperglucagonaemia and glucagon hyperresponse to arginine are associated with a lack of insulin secretion in the patients with overt diabetes. Hormonal differences between diabetics with and without ICA could not be detected.This work was previously presented at the 12th Meeting of the European Association for the Study of Diabetes, Helsinki, September 1976 and published in abstract form in Diabetologia12, 422 (1976)     

How does glucose regulate the human pancreatic A cell in vivo?

Summary To investigate the mechanism whereby changes in plasma glucose level alter human pancreatic A-cell activity in vivo, A-cell activity was determined during manipulation of plasma glucose and pancreatic B-cell activity by insulin and glucose infusions. A-cell activity (the acute immunoreactive glucagon response to intravenous arginine, 0–10 min) rose from 482±125 to 968±191 pg · ml^-1 · 10 min^-1 (mean±SEM) when the plasma C-peptide level (a measure of B-cell activity) was suppressed from 2164±365 to 872±162 pg/ml by an insulin infusion at euglycaemia (employing the glucose clamp technique) in six normal subjects. Raising plasma glucose to 6.7 mmol/l during the same insulin infusion returned mean C-peptide (2688±581 pg/ml) and the acute glucagon response to arginine (447±146 pg · ml^-1 · 10 min^-1) close to basal levels. Individual changes in the acute glucagon response to arginine followed the C-peptide changes. The mean change in the acute glucagon response to arginine per unit change in plasma glucose (-191±36) was similar to that seen when plasma glucose was raised to twice basal levels in six different subjects without an insulin infusion (-159±45). This suggests that, when plasma glucose is raised to about twice basal level in vivo, the major factor in suppressing A-cell activity is the concurrent change in B-cell activity rather than direct effects of glucose or circulating insulin on the A cell.     

Plasma alpha-cell glucagon in primary hyperparathyroidism

Plasma glucose, insulin, and alpha-cell glucagon profiles were examined in ten adults with uncomplicated primary hyperparathyroidism before and 8–12 wk after surgical removal of a single parathyroid adenoma. Treatment restored abnormal serum calcium and phosphorus concentrations to a normal range and reduced serum parathyroid hormone levels from 47 ± 4 to 16 ± 4 μ 1 Eq/ml (normal = 0–40). Plasma glucose curves during 100-g oral glucose tolerance, 30 min intravenous glucose (1.5 g/min), or arginine infusions (1.0 g/min) did not differ before and after surgery. However, basal and peak insulin concentrations were higher before treatment during these tests (p < 0.05). Basal glucagon levels were unaffected by hyperparathyroidism (72 ± 7 versus 77 ± 7 pg/ml). Peak 30 min values after arginine provocation were also similar before and after treatment as was maximal suppression of basal glucagon during glucose infusions. Four patients also received 400 g lean beef meals. Glucose and glucagon responses over 240-min periods were nearly identical before and after surgery despite higher insulin levels before treatment.It is concluded that elevated serum parathyroid hormone and plasma insulin concentrations in primary hyperparathyroidism do not relate to abnormalities of plasma alpha-cell glucagon in the basal state or after glucose, arginine, or protein administration.     

Glucagon and insulin secretion in potential diabetes

Summary Insulin and glucagon have been studied in 20 subjects (both of the subjects’ parents were diabetic or in case of only one diabetic parent, the other showed a first degree familiarity of diabetes): 10 showed normal glucose tolerance (‘true prediabetics’) and 10 impaired glucose tolerance (‘genetic chemical diabetes’). Mean insulin response to oral (100 g) and i.v. glucose load (200 mg/kg followed by 20 mg/kg/min for 60 min) and to arginine infusion (25 g in 30 min) was normal in the prediabetics and delayed and higher in the subjects with chemical diabetes as compared to the control group. Glucagon response to arginine was higher, but not significantly, in prediabetics and in subjects with chemical diabetes. In both of these groups glucagon suppression by glucose was not observed. The insulin/glucagon molar ratio was significantly reduced after glucose infusion in these two groups. No correlation was found between insulin and glucagon secretion after arginine or glucose. A possible alteration in the mechanism controlling glucagon secretion even in the earliest phases of diabetes is suggested. This work was supported in part by C.N.R. (Consiglio Nazionale delle Ricerche), Roma, grant # CT 76.01345.04.     

Beta-endorphin and islet hormone release in type-2 diabetes mellitus the effects of normoglycemia, enkephalin, naloxone and somatostatin

The present study was aimed at characterizing the effects of beta-endorphin on plasma glucose, insulin and glucagon plasma levels in subjects with type-2 diabetes mellitus. Infusion of 0.5 mg/h human beta-endorphin produced significant and simultaneous increments in both insulin and glucagon concentrations and decreased plasma glucose levels (-18 +/- 4 mg/dl, 60 min level, p less than 0.01). When the same diabetics were rendered euglycemic by an insulin infusion (1 mU/kg/min), beta-endorphin did not produce the expected decrease in plasma glucose concentrations nor raise plasma insulin levels; only the response of glucagon was preserved. Normal subjects were rendered hyperglycemic by an intravenous glucose infusion to match the plasma glucose levels of diabetic subjects. In this condition, beta-endorphin produced a significant increase of insulin concentrations, whereas glucagon remained suppressed. The intravenous administration of the long-acting met-enkephalin analogue DAMME (0.25 mg) blunted the hormonal responses to the subsequent beta-endorphin infusion in diabetic patients, although the inhibition was short-lived (30-40 min). Naloxone (5 mg), an opiate antagonist, did not produce any significant change in the insulin and glucagon responses to beta-endorphin, while somatostatin (0.25 mg/h) completely abolished the hormonal responses to the opioid.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effect of intermittent physiologic hyperglucagonemia on postprandial plasma glucose levels in normal man

The ability of glucagon to impair glucose tolerance has been questioned by studies involving infusion of exogenous glucagon during a glucose load. Since such hormone administration may not reflect the physiologic pattern of glucagon secretion and may result in hepatic downregulation to glucagon, the present experiments have examined the effects of intermittent andogenous hyperglucagonemia (induced by episodic infusion of arginine) on plasma glucose profiles of normal man following ingestion of mixed meals. In control studies following meal ingestion, plasma glucose, insulin and glucagon increased respectively 15–30 mg/dl, 30–60 uU/ml and 25–50 pg/ml. When meals were accompanied by arginine infusions, plasma glucagon responses were augmented three to fourfold (p < 0.05). Amplitudes of glycemic excursions during infusion of arginine (345 ± 40 mg/dl) were significantly augmented compared to those observed in control studies (286 ± 34 mg/dl, p < 0.02). These results indicate that intermittent increases in plasma glucagon within the physiologic range can adversely affect postprandial glucose profiles in normal man despite concomitant hyperinsulinemia and suggest that such hyperglucagonemia may contribute to impaired postprandial glucose tolerance in diabetic individuals in whom insulin secretion is deficient.     

Physiological concentrations of cholecystokinin stimulate amino acid-induced insulin release in humans

After a meal, hormones released from the gut potentiate insulin release. This study was undertaken to determine if physiological concentrations of plasma cholecystokinin (CCK) stimulate insulin secretion in man. Employing a specific CCK bioassay, postprandial CCK levels were determined in normal subjects. Ingestion of a mixed liquid meal stimulated an increase in circulating CCK from a mean fasting level of 0.9 +/- 0.2 (SEM) pmol/L to a mean peak level of 7.1 +/- 1.1 pmol/L within 10 min of feeding. After 30 min the mean CCK level fell to 3.5 pmol/L and remained elevated for the remainder of the 90-min experiment. Eight subjects underwent 40-min infusions of either arginine (15 g), mixed amino acids (15 g), or glucose (30 g) with or without the simultaneous infusion of CCK-8. Since CCK-8 has full biological potency, this form was chosen for infusion to reproduce total CCK bioactivity in plasma. CCK-8 was infused at rates of 12 or 24 pmol/kg X h, producing steady state plasma CCK levels of 4.5 +/- 0.7 and 8.2 +/- 1.1 pmol/L, respectively, spanning the range of normal postprandial levels. CCK alone had no effect on insulin, glucose, or glucagon levels. Administration of arginine alone stimulated insulin from a mean basal level of 12.8 +/- 1.3 microU/mL to a peak level of 41.3 +/- 5.4 microU/mL. Infusion of CCK at 12 and 24 pmol/kg X h augmented arginine-stimulated insulin levels to peaks of 62.5 +/- 13.9 and 63.0 +/- 4.0 microU/mL, respectively. Moreover, CCK nearly doubled the total amount of insulin secreted during the arginine infusion. A similar potentiation of glucagon release was found with both doses of CCK. In addition, infusion of a mixture of amino acids with and without concomitant CCK infusions revealed that CCK potentiated the insulin release induced by mixed amino acids. In contrast to the potent effect of CCK on amino acid-induced insulin release, infusions of CCK together with glucose caused no enhancement of glucose-stimulated insulin release. These results demonstrate that physiological concentrations of CCK potentiate amino acid (but not glucose)-induced insulin secretion in man. These data suggest, therefore, that CCK may have a role in man as a modulator of insulin release.     

Dose-kinetics of pancreatic glucagon responses to arginine and glucose in subjects with normal and impaired pancreatic B cell function

Summary Pancreatic glucagon responses to different amounts of intravenous arginine and glucose were studied in 10 insulin-dependent diabetics, 14 healthy controls (high insulin responders) and 15 subjects with decreased insulin response to glucose but normal intravenous glucose tolerance (low insulin responders). The dose-kinetics of the glucagon response was studied by using four different arginine doses. The suppressive effect of glucose was evaluated by infusing three glucose doses during a submaximal stimulation with arginine. The diabetics were tested first when under fair metabolic control and then following intensive treatment with insulin to produce near-normalisation of blood glucose. Finally, five subjects underwent insulin-induced hypoglycaemia. The changes in plasma glucagon and blood -amino-nitrogen in response to the four arginine doses were significantly correlated in all groups but the slope of the dose response curve was steeper in the poorly controlled-diabetics than in the non-diabetics. These diabetics displayed higher fasting plasma glucagon values than healthy controls (high insulin responders) (224±4 versus 151±22 pg/ml, p<0.01), higher plasma glucagon responses to arginine and an absence of inhibition by glucose of the arginine-stimulated glucagon release. In strictly controlled diabetic patients, fasting plasma glucagon levels (176±16 pg/ml) were not significantly different from healthy controls, the glucagon response to arginine returned to the normal range, A cell suppressibility by glucose was restored and A cell stimulation by hypoglycaemia reappeared. In the low insulin responders, fasting plasma glucagon was not different from that of high responders (107±12 pg/ml), the slope of the dose response curve to arginine was similar in both groups and the A cells were inhibited by glucose to a similar extent. These results support the concept that islet A cell dysfunction in diabetes is not a primary phenomenon.     

Effect of furosemide on insulin and glucagon responses to arginine in normal subjects

Summary This study aimed at evaluating the influence of furosemide upon insulin and glucagon responses to arginine in healthy subjects. For this purpose, six normal subjects received two consecutive arginine pulses (3 g), 60 min apart, before and after the administration of furosemide (40 mg, IV). The acute insulin response (mean change from 3–10 min) to the second arginine pulse was significantly inhibited by furosemide (mean increase: 14.8 ±3.0 U/ml versus 11.7±2.5 U/ml, p<0.01). By contrast, the acute glucagon response was significantly increased (mean increase: 77±18 pg/ml versus 105±21 pg/ml, p<0.01). No significant changes in plasma glucose levels occurred. In control experiments, in which saline rather than furosemide was administered, the acute insulin and glucagon response to the first arginine pulse did not differ from that observed with the second pulse. The effect of furosemide on insulin and glucagon secretion might be mediated through enhanced release of endogenous prostaglandin E.     

Basal and glucose- and arginine-stimulated serum concentrations of insulin, C-peptide, and glucagon in hyperthyroid patients

The effect of oral glucose and arginine infusion on plasma glucose, glucagon, serum insulin, and C-peptide concentrations was evaluated in 16 patients with hyperthyroid Graves' disease and in ten euthyroid age- and sex-matched normal subjects. Basal plasma glucose concentrations were significantly higher in the hyperthyroid patients, but the plasma glucose response following glucose and arginine administration was similar in the two groups. The insulin response was similar in the hyperthyroid and normal subjects after glucose administration and significantly lower during arginine infusion in the hyperthyroid patients. The serum C-peptide response to both glucose and arginine administration was markedly blunted in the hyperthyroid patients, and the plasma glucagon response to arginine infusion was decreased. These results suggest that pancreatic beta and alpha cell secretory function is impaired in hyperthyroidism as assessed by C-peptide and glucagon secretion following oral glucose administration and arginine infusion. The apparent discrepancy between C-peptide and insulin secretion in the hyperthyroid patients following glucose administration might be due to diminished hepatic extraction of insulin or enhanced metabolism of C-peptide.     

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)     

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

Summary 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.     

Comparison of glucose,fructose, sorbitol,and xylitol utilization in humans during insulin suppression

During fructose, sorbitol, and xylitol perfusions, carbohydrate utilization was studied by continuous indirect calorimetry and compared with glucose utilization during pharmacologic inhibition of endogenous insulin secretion. The experiment was performed in 28 normal volunteers divided into 5 groups (glucose, fructose, sorbitol, xylitol, and saline), each subject being its own control. Insulin suppression was obtained by means of a constant infusion of epinephrine (6 μg/min) and propranolol (0.08 mg/min). After 90 min, during plasma insulin steady state, each sugar or polyol was infused at a rate of 6 mg/kg/min for 120 min. In contrast with a rise in plasma glucose from 161 ± 6 mg/dl to 291 ± 14 mg/dl during glucose infusion, glucose levels remained unchanged during infusion of the glucose substitutes. Carbohydrate oxidation showed a rise of 24, 65, 76, and 44 mg/min during infusions of glucose, fructose, sorbitol, and xylitol, respectively. Lipid oxidation rates decreased by 7, 20, 33, and 23 mg/min during the same infusions. These results indicate that fructose, sorbitol, and xylitol are oxidized at a higher rate than glucose during suppression of endogenous insulin secretion, without any significant rise in glycemia.     

Effect of the somatostatin analog D-Trp8,D-Cys14 on glucose insulin, pancreatic glucagon and growth hormone plasma levels in acromegalics and mild diabetics

The effect of the somatostatin analog (GHRIH-A) D-Trp8, D-Cys14 on plasma levels of growth hormone, pancreatic glucagon, insulin and glucose was studied in four acromegalic patients and in four maturity-onset mild diabetics. Acromegalics received a bolus iv injection of 25 microgram of GHRIH-A, followed by a continuous infusion of 25 microgram in saline over an hour. Mild diabetics were submitted in two different days to two tests: arginine (30 g in 30 min) +/- GHRIH-A (bolus iv injection of 25 microgram followed by an infusion of 25 microgram/h over 120 min) and arginine + saline. GHRIH-A lead to a significant (2 p less than 0.01) fall in GH basal secretion in acromegalics, and significantly reduced the GH response to arginine in maturity-onset diabetics. The inhibitory effect of insulin secretion was less impressive, but significative in both groups. No significant changes in plasma pancreatic glucagon values were noted. In mild diabetics, GHRIH-A infusion induced a small but significant increase in the blood glucose increment due to arginine. Our data suggest that this somatostatin analog may be potentially useful only when GH suppression is the main therapeutic goal to be reached, as in acromegaly and in severe diabetic retinopathy, but not in metabolic control of mild diabetic patients with a good residual insulin secretion.