Xylitol: stimulation of insulin and inhibition of glucagon responses to arginine in man.

The effect of intravenous xylitol infusions on plasma glucagon and insulin responses to intravenous arginine infusions (30 g for 45 min) or arginine "pulses" (4 g for 2 min) was studied in normal subjects. Intravenous infusion of arginine caused biphasic increases in plasma glucagon and insulin in all subjects studied. The increase in plasma glucagon induced by arginine infusion was significantly reduced by xylitol infusions started at 45 min before arginine infusion, irrespective of virtually unchanged blood glucose levels. Plasma insulin response to arginine was exaggerated by xylitol infusion.Repeated arginine pulses given at 30 min intervals evoked uniphasic and almost identical rises of plasma insulin and glucagon with each pulse. Intravenous xylitol infusions significantly blunted plasma glucagon responses and augumented the plasma insulin response to arginine pulses, despite only slight elevations of plasma glucose. These results suggest that xylitol has an inhibitory effect on both basal and arginine-stimulated glucagon secretion, while it enhances insulin secretion.     

Portal and peripheral vein concentrations of insulin and glucagon after arginine infusion in morbidly obese subjects

Five morbidly obese subjects with fasting normoglycemia underwent catheterization of portal and peripheral veins immediately prior to jejunoileal bypass surgery. Levels of immunoreactive insulin (IRI), immunoreactive glucagon (IRG), and glucose were determined in simultaneously obtained serum samples before and after infusion of arginine. Portal levels exceeded peripheral levels by at least 50% with IRI and by 30%–40% with IRG. These results were similar to those reported in nonobese subjects and show that in morbid obesity as well as in nonobese states, peripheral insulin to glucagon molar ratios ($\text{I}\text{G}$) underestimate portal $\text{I}\text{G}$. Although hepatic extraction was not specifically measured, the data suggest that the peripheral levels of insulin and glucagon reported in morbid obesity result from alterations in secretion and not altered extraction.     

Behavior of pancreatic glucagon,insulin, and HGH in liver cirrhosis,after arginine and i.v. glucose

Summary The authors studied the behavior of plasma levels of glucagon, HGH and insulin in a group of cirrhotic patients both in basal conditions and after i.v. arginine and glucose in order to assess their respective importance in the pathogenesis of carbohydrate disorders. After i.v. arginine an increased plasma concentration of pancreatic glucagon was found which reached its highest level at 15 min; i.e. glucose did not suppress the increased plasma glucagon levels. Plasma HGH which is consistently increased is not influenced by i.v. glucose. Plasma insulin was consistently raised during both tests; however, the insulinogenic index after i.v. glucose behaved like that of mild diabetics. The true importance of glucagon in the pathogenesis of carbohydrate intolerance in cirrhotics cannot as yet be determined with certainty; according to the authors, hyperglucagonemia is not the primary factor but only one of the main causes of this intolerance.     

Somatostatin neutralization stimulates glucagon and insulin secretion from the avian pancreas

Using the isolated perfused chicken pancreas, somatostatin antiserum was infused to neutralize the effects of endogenous somatostatin secretion on neighboring endocrine cells. At normal and high glucose concentrations, somatostatin antiserum significantly stimulated both glucagon and insulin secretion. These findings suggest that somatostatin continuously inhibits A and B cell output, and that glucose suppression of glucagon release is partially dependent upon local somatostatin secretion.     

精氨酸刺激试验与胰高血糖素刺激试验对β细胞功能评估的比较

通过对68例2型糖尿病患者进行精氨酸刺激试验(AST)和胰高血糖素刺激试验(GST)，比较其对胰岛β细胞功能的评价，发现精氨酸刺激后C肽于3min达高峰，此峰值与胰高血糖素刺激后6min C肽差异无统计学意义，而且以精氨酸刺激试验3min C肽是否大于0.6nmol／L作为选择治疗方案的参考(与GST结果接近)，与临床符合情况较好。     

Somatostatin,glucagon, and insulin secretion from isolated perfused pancreas of new genetically obese hyperglycemic rats

Insulin, somatostatin, and glucagon release from the perfused pancreas was studied in the newly developed genetically obese hyperglycemic hyperinsulinemic (Wistar fatty) rat. Insulin and somatostatin levels rose significantly compared to those in lean littermate controls during arginine infusion. The glucagon increase, however, was significantly less when total amounts during arginine infusion were calculated. These results show that hypersecretion of insulin and somatostatin in vitro may suppress glucagon release in Wistar fatty rats.     

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.     

Circulating insulin inhibits glucagon secretion induced by arginine in type 1 diabetes

OBJECTIVE: To evaluate if insulin has a suppressive effect on the glucagon secretion stimulated by arginine in type 1 diabetes. RESEARCH DESIGN AND METHODS: The alpha-cell response to an i.v. bolus of arginine (150mgkg(-1)) followed by an infusion of arginine (10mgkg(-1)min(-1)) was studied in random order during either low dose infusion (LDT) or high dose infusion (HDT) of insulin in ten patients with type 1 diabetes. The blood glucose level was clamped at an arterialized level of 5mmoll(-1) by a variable infusion of glucose. Venous C-peptide, glucagon, growth hormone, and insulin were analyzed. RESULTS: The mean plasma concentration of insulin was four times higher during the HDT. The C-peptide level did not differ between the LDT and the HDT. During the LDT in response to arginine the blood glucose level increased from 5.0 to 5.8mmol l(-1) although the glucose infusion was markedly reduced, while no change was seen during the HDT. A significantly smaller increase in the glucagon levels during the HDT was seen (area under the curve of 413+/-45 vs 466+/-44pgml(-1)h(-1), P=0.03) while the growth hormone levels were almost identical. CONCLUSION: This study demonstrates that a high level of circulating insulin exerts an inhibitory effect on the glucagon response to arginine in type 1 diabetes. Thus, the suppressive effect of insulin on the glucagon release from the alpha-cell seems to be general and not only dependent on stimulation by hypoglycemia.     

Metasomatotrophic diabetes and its induction: Basal insulin secretion and insulin release responses to glucose,glucagon, arginine and meals

Summary Growth hormone treatment produced somatotrophic diabetes, with hyperglycaemia, polyuria, glycosuria and elevation in serum non-esterified fatty acids (NEFA) in dogs. Early in this diabetes, fasting serum immunoreactive insulin (IRI) rose 20-fold, the insulin/glucose (I/G) ratio rose 10-fold and in response to glucose infusion, the rise in IRI was twice the normal. In the latter half of the continued growth hormone treatment, the intensity of the diabetes increased, serum IRI declined to the normal level and the I/G ratio became subnormal. Late in the treatment, following glucose infusion, there was no change in serum IRI, no fall in NEFA and further depression of glucose tolerance. In metasomatotrophic diabetes, in which hyperglycaemia, glycosuria and high NEFA level persisted, fasting serum IRI was normal during several months, then became subnormal and the I/G ratio was diminished further. Following glucose IV there was no change in serum IRI, no fall in NEFA and low glucose tolerance. The normally-occurring rises in serum IRI following arginine and glucagon IV and after the ingestion of a meal were absent. These permanently diabetic dogs were responsive to insulin IV. The insulin content of the pancreas was reduced to about 1.2% of the normal after 14 months of this diabetes. From the sequence of change it is concluded that growth hormone induced metasomatotrophic diabetes by causing excessive secretion of insulin under basal and stimulative conditions, leading to permanent loss of function of the beta cells of the pancreatic islets, to such an extent that basal insulin secretion was low and the ability to secrete extra insulin in response to stimuli was lost.     

Purinergic receptors involved in the stimulation of insulin and glucagon secretion

The study of purinergic receptors in the endocrine pancreas is a recent field of investigations. Until recently, ATP has been considered only as an intracellular fuel by most authors. Nevertheless for some years evidence has been obtained that extracellular ATP and/or ADP could act on the B cell membrane to increase insulin secretion. Furthermore it was shown that adenosine could act on the A cell surface to increase glucagon secretion. In both cases the involvement of purinoceptors could be demonstrated using structural analogues which are metabolically stable and not taken up by cells. Also the effects of activators of purinoceptors on B and A cells were suppressed by antagonists. So, it was possible to establish that the purinoceptors involved in the stimulation of insulin and glucagon secretion were different. The B cell is endowed with P2 purinoceptors (for ATP and/or ADP) and the A cell possess P1 purinoceptors (for adenosine). It is of interest to note that B and A cells, which secrete hormones with opposite roles, anabolic and catabolic respectively, have two different types of purinoceptors involved in stimulatory process. The purinergic modulation of B and A cells appears to be of physiological relevance.     

Divergent effect of glucagon antibodies on arginine and glucose-stimulated insulin secretion in the rat

Summary The effects of glucose and arginine on insulin secretion in the presence of glucagon antibodies were investigated in rats in vivo. In contrast to controls, animals given glucagon antibodies showed an inhibition of arginine-stimulated (p < 0.001), but not glucose-stimulated, insulin secretion. That these effects were not due to incomplete neutralisation of endogenous glucagon is evidenced by the presence of large antibody excess throughout the duration of the experiments. Both the glucagonotropic effect of arginine (319 ± 60ng/l, p < 0.01) and the insulinotropic effect of exogenous glucagon (8.3 ± 0.8 g/l, p < 0.001) were demonstrable under our experimental conditions in the absence of exogenous glucagon antibodies. These observations suggest that different mechanisms are involved in the stimulation of insulin release by arginine and by glucose, and that glucagon may play an important physiological role in the mediation and regulation of insulin secretion by secretogogues, such as arginine.     

Somatostatin analogs in medical treatment of acromegaly

Although acromegaly remains a disease primarily addressed by pituitary microsurgery, most patients require secondary treatment for persistent growth hormone (GH) hypersecretion and elevated serum insulin-like growth factor-1 (IGF-1) concentrations following adenomectomy. Persistently abnormal serum GH and IGF-1 can be reduced to normal concentrations in better than half of post-surgery acromegalics using the pharmacologic treatments available at present, the dopamine agonists (DA) and somatostatin (SST) analogs. The long-acting SST analogs octreotide LAR and lanreotide SR have become the mainstay of medical treatment for acromegaly, having largely supplanted DA agents since the introduction of bromocriptine for the suppression of GH secretion in the 1970s. The DA cabergoline may be effective in up to half of patients, however, in particular those patients whose tumors cosecrete prolactin. On the horizon is the GH-receptor antagonist pegvisomant, which is expected to enable the reduction of serum IGF-1 to the normal range in the vast majority of postoperative acromegaly patients, representing a revolutionary development in the medical treatment of this disease. We here review the choices available to the endocrinologist in the pharmacologic treatment of acromegaly, focusing upon the SST analogs.     

Somatostatin stimulates glucagon secretion in ducks

Summary In normal fasting ducks, a somatostatin infusion (800 ng/kg/min for 30 min) elicited a prompt inhibition of insulin secretion, plasma levels falling from 140±20 to 20±6 pg Eq/ml as observed in mammals. — However plasma glucagon-like-immunoreactivity shown to be decreased in mammals by somatostatin was sharply increased from a mean basal level of 1.46±0.13 ng Eq/ml to 6.61±0.77 ng Eq/ml. This effect was not mediated via inhibition of growth hormone secretion since it was also observed in hypophysectomised ducks. Despite the fall in plasma insulin and rise in GLI observed with somatostatin infusion in intact birds, plasma glucose concentrations were lower than with control saline infusion.