Secretion of immunoreactive insulin and glucagon in hamsters bearing a transplantable insuloma.

Glucose, insulin (IRI), pancreatic (IRG) and total (GLI) immunoreactive glucagon were measured in the serum of normal hamsters and of hamsters with an insulin- and glucagon-secreting, transplantable insuloma. The tumor-bearing animals were hypoglycemic, hyperinsulinemic and hyperglucagonemic. The pancreatic islets of tumor-bearing animals secreted less glucagon and insulin in response to arginine or to changes in the glucose concentration of the medium, than did the islets of control hamsters. In addition, the introduction of glucose into the gastro-intestinal tract, which caused a significant rise in the serum GLI concentration of normal hamsters, failed to do so in the tumor-bearing animals. The results suggest that the high levels of serum glucagon and insulin induced by the tumor, suppressed IRI, IRG and GLI secretion in these animals.     

Fetal rat intestinal cells in monolayer culture: a new in vitro system to study the glucagon-like immunoreactive peptides

To establish an in vitro model to investigate the glucagon-related peptides, fetal rat intestinal cells were enzymatically dispersed and placed into culture for up to 7 days. After 1 day in culture, the presence of epithelial-like cells containing glucagon-like immunoreactivity (GLI) was demonstrated using immunocytochemical techniques. The cell peptides were extracted by passage through a cartridge of octadecylsilyl silica and characterized by gel filtration and RIA. Two GLI moieties were detected with apparent mol wts of 11,000-12,000 and 5,000-6,000. The immunoreactive profile obtained for the cells in culture was identical to that of both whole fetal rat intestine and adult rat ileum. The presence of glucagon could not be demonstrated in any of the extracts. The basal levels of GLI and apparent immunoreactive glucagon (IRGa) were 1,457 +/- 381 and 198 +/- 57 pg/dish, respectively, on day 1 of culture. The GLI content of the cells, but not the IRGa, declined with time in culture for up to 5-7 days (P less than 0.03). Addition of insulin to the culture medium (10 or 100 mU/ml) did not influence the decrease in GLI content of the cells, but did inhibit the production of IRGa (P less than 0.05). Addition of 500 mg/dl glucose to the cells in the presence of 20 microU/ml insulin increased the secretion of GLI by 42 +/- 7% over 2 h (P less than 0.05). The stimulation by glucose was not seen in the absence of insulin or with higher insulin concentrations (100 microU/ml), nor did insulin alone (100 microU/ml) have any effect on the release of GLI. Thus, fetal rat intestinal cells in culture produce the GLI peptides, and secrete them in response to glucose. This system may provide a means by which the synthesis and control of secretion of the glucagon-related peptides can be investigated.     

Effect of exogenous insulin and glucagon on exocrine pancreatic secretion in rats in vivo.

BACKGROUND: The physiological roles of the islet hormones insulin and glucagon in the control of exocrine pancreatic secretion is not clear. It is still unknown whether these hormones have a stimulatory or an inhibitory effect on the basal exocrine pancreatic secretion. METHODS: Thirty anesthetized rats were stimulated with doses of insulin and glucagon administered by continuous intravenous infusion. Doses varying from physiological to supraphysiological were used. Different groups of 5 rats were given each of these doses. The volume of pancreatic juice and amylase, lipase and trypsin activity, as well as enzyme output, were measured 0, 20, 40, and 60 min after starting infusion. The insulin, glucagon, and glucose levels were determined in serum at 0, 10, 30, and 60 min. RESULTS: In the insulin group, the secreted volume of pancreatic juice increases with the maximum dose. All insulin doses results in amylase and lipase decreased activity. When submaximum and maximum insulin doses are administered, the trypsin activity also decreases. In the glucagon group, the activity of lipase and trypsin decreases regardless the dose, whereas the amylase activity decreases with submaximum and supramaximum doses. CONCLUSION: Both insulin and glucagon affect the basal exocrine pancreatic secretion in vivo when physiological doses are administered.     

Pancreatic function in the essential fatty acid deficient rat.

The influence of essential fatty acid (EFA) deficiency on pancreatic endocrine and exocrine function was studied in 120-day-old rats. The plasma insulin response was determined after in vivo administration of glucose and arginine. The plasma glucagon response was assessed after infusion of arginine. Islet peptides were examined by immunocytochemistry. The exocrine function of pancreas was studied by amylase secretion in isolated pancreatic acinar cells after stimulation with the cholinergic agonist carbacholine chloride. The EFA-deficient (EFAD) rats showed higher basal plasma insulin concentrations and lower basal glucose levels than control rats (P less than .01 and P less than .01, respectively). The plasma insulin response to glucose was potentiated in the EFAD rats (P less than .001). Both insulin and glucagon responses to arginine were normal. The isolated pancreatic acinar cells showed a low basal amylase secretion, but a normal response to carbacholine chloride. There were no overt morphological changes seen in the pancreas and the immunocytochemical staining pattern of insulin, glucagon, somatostatin, and pancreatic polypeptide cells did not differ from controls. The results of the study show that the secretory function of the endocrine and exocrine pancreas is operational in EFA deficiency. The EFA deficiency was accompanied by a basal hyperinsulinemia and hypoglycemia and an exaggerated insulin response to glucose, the pathophysiology of which has to be further studied.     

Effect of exogenous insulin and glucagon on exocrine pancreatic secretion in rats in vivo

Summary Background. The physiological roles of the islet hormones insulin and glucagon in the control of exocrine pancreatic secretion is not clear. It is still unknown whether these hormones have a stimulatory or an inhibitory effect on the basal exocrine pancreatic secretion. Methods. Thirty anesthetized rats were stimulated with doses of insulin and glucagon administered by continuous intravenous infusion. Doses varying from physiological to supraphysiological were used. Different groups of 5 rats were given each of these doses. The volume of pancreatic juice and amylase, lipase and trypsin activity, as well as enzyme output, were measured 0, 20, 40, and 60 min after starting infusion. The insulin, glucagon, and glucose levels were determined in serum at 0, 10, 30, and 60 min. Results. In the insulin group, the secreted volume of pancreatic juice increases with the maximum dose. All insulin doses results in amylase and lipase decreased activity. When submaximum and maximum insulin doses are administered, the trypsin activity also decreases. In the glucagon group, the activity of lipase and trypsin decreases regardless the dose, whereas the amylase activity decreases with submaximum and supramaximum doses. Conclusion. Both insulin and glucagon affect the basal exocrine pancreatic secretion in vivo when physiological doses are administered.     

The serum glucose response to glucagon suppression with somatostatin,insulin or antiglucagon serum in depancreatized rats

Summary Total immunoreactive glucagon (IRG) and immunoreactive glucagon of A cell origin (IRG_a) were measured in the serum of normal, sham-operated and depancreatized rats, after the administration of three glucagon antagonists: insulin (5–200 mU/rat/h), somatostatin (SRIF; 100 g/kg/h) and antiglucagon serum (AGS, enough to bind three times the calculated total amount of circulating IRG). Since no differences were noted between the responses of normal and sham-operated animals, the values were pooled and used as controls. Pancreatectomy caused a significant increase in serum glucose, IRG_a and total IRG and a significant decrease in serum insulin. AGS and SRIF significantly decreased serum glucose in control, but not in depancreatized rats, even though SRIF caused a significant decrease of IRG_a in all animals. SRIF significantly decreased plasma insulin in control rats, but did not modify total IRG secretion in either group. In control rats the minimum effective hypoglycaemic dose of insulin (5 mU/rat/h) may have decreased serum IRG_a, but not total IRG. At higher doses (20 mU/rat/h) insulin stimulated glucagon secretion. In depancreatized animals, higher doses of insulin (200 mU/rat/h) were needed to lower serum glucose. On the other hand, a dose of 100 U/rat/h was sufficient to lower the serum IRG. We conclude that although hyperglucagonaemia may contribute to the hyperglycaemia of the untreated depancreatized rats, the excessive secretion of glucagon is secondary to insulin insufficiency and that, at least in this animal model, the hypoglycaemic action of insulin is only minimally dependent upon its ability to suppress glucagon secretion.     

Glucagon-like peptides GLP-1 and GLP-2, predicted products of the glucagon gene, are secreted separately from pig small intestine but not pancreas

We developed specific antibodies and RIAs for glucagon-like peptides 1 and 2 (GLP-1 and GLP-2), two predicted products of the glucagon gene, and studied the occurrence, nature, and secretion of immunoreactive GLP-1 and GLP-2 in pig pancreas and small intestine. Immunoreactive GLP-1 and GLP-2 were identified in glucagon-producing cells of the pancreatic islets, and in glicentin-producing cells of the small intestine. Immunoreactive GLP-1 and 2 in intestinal extracts corresponded in molecular size to peptides synthesized according to the predicted structure. By reverse phase HPLC, intestinal and synthetic GLP-1 behaved similarly, whereas synthetic and intestinal GLP-2 differed. Pancreatic extracts contained a large peptide with both GLP-1 and GLP-2 immunoreactivity. Secretion was studied using isolated perfused pig pancreas during arginine stimulation, and isolated perfused pig ileum during either luminal glucose stimulation or vascular administration of the neuropeptide, gastrin-releasing peptide (GRP). Immunoreactive GLP-1 and GLP-2 were secreted in parallel with pancreatic glucagon and intestinal glicentin. The molecular forms of secreted immunoreactive GLP-1 and 2 corresponded to those identified in the tissue extracts.     

Homologous islet amyloid polypeptide: effects on plasma levels of glucagon, insulin and glucose in the mouse.

We examined the effects of a single intravenous injection of homologous islet amyloid polypeptide (IAPP) on the plasma levels of glucagon, insulin and glucose in the freely fed mouse. It was observed that IAPP suppressed basal glucagon levels concomitant with a decrease of the blood glucose concentrations. Basal plasma insulin levels were not affected. IAPP did not appreciably modulate the plasma concentration of glucose, insulin or glucagon after an intravenous glucose load. Further, IAPP inhibited the insulin secretory response to beta 2-adrenoceptor stimulation. IAPP also lowered the plasma glucagon levels following beta 2-adrenoceptor stimulation, whereas no apparent effect on plasma levels of glucose was observed. The data suggest that IAPP suppresses glucagon secretion and lowers blood glucose levels in the freely fed mouse. It might also exhibit a negative feedback inhibition on beta 2-adrenoceptor-induced insulin secretion, but has little influence on glucose-induced insulin release. Since IAPP is co-secreted with insulin, it is not inconceivable, that in the freely fed mouse, IAPP may act to amplify the blood glucose lowering effect of insulin through a direct suppression of glucagon secretion via the islet microcirculation.     

Pancreatic endocrine function in cirrhotic rats

Pancreatic endocrine function in liver cirrhosis was examined in rats both in vivo and in vitro. Experimental liver cirrhosis was induced by subcutaneous injections of 50% carbon tetrachloride in a dose of 2 mL/kg body weight twice a week for 16 weeks. Control rats received a similar dose of olive oil during the same period. In cirrhotic rats, immunoreactive insulin contents in the pancreas were significantly lower, whereas immunoreactive glucagon contents were about threefold higher than those of control rats. In the first part of this study, insulin and glucagon concentrations in both jugular and portal venous blood at basal conditions and after oral glucose loading were simultaneously determined in vivo. Peripheral insulin levels, both before and after glucose loading, were higher, whereas portal insulin concentrations were lower in cirrhotic rats than in the control rats. In contrast, glucagon levels in both the peripheral and portal veins were significantly higher in cirrhotic rats than in control rats. In the second part, isolated perfused pancreata were prepared from cirrhotic and control rats to further characterize the endocrine function of cirrhotic rat pancreas. Insulin secretion in response to 16.7 mmol/L glucose and 100 pmol/L cholecystokinin-octapeptide both were 40% lower in cirrhotic rats than in controls. In contrast, there was no significant difference in arginine-stimulated insulin release between the two groups. However, glucagon secretion in response to 20 mmol/L arginine was 40% higher in cirrhotic rats. If sensitivity is defined as the hormone release proportional to the pancreatic contents, then A and B cells in the cirrhotic rats had normal sensitivity to both glucose and cholecystokinin-octapeptide.(ABSTRACT TRUNCATED AT 250 WORDS)     

The relative importance of nervous system and hormones to the 2-deoxy-D-glucose-induced hyperglycemia in fed rats

We examined the relative contributions of hormones and nervous system to the total 2-deoxy-D-glucose (2-DG)-induced central nervous system-mediated hyperglycemia. 2-DG was injected into the third cerebral ventricle in the following four groups of rats, and hepatic venous plasma glucose, immunoreactive glucagon, immunoreactive insulin, epinephrine, and norepinephrine were measured: 1) intact rats; 2) intact rats receiving somatostatin with insulin infusion through the femoral vein to inhibit glucagon secretion and maintain the basal insulin level; 3) bilateral adrenalectomized (ADX) rats to prevent epinephrine secretion; and 4) ADX rats receiving somatostatin with insulin infusion. Comparing areas under glucose curves among the intact rats, those receiving somatostatin with insulin infusion, ADX rats, and ADX rats receiving somatostatin with insulin infusion, the area under the glucose curve was intact rats greater than intact rats receiving somatostatin with insulin infusion greater than ADX rats receiving somatostatin with insulin infusion greater than ADX rats. These results suggest that there are three distinct sympathetic nervous system responses to 2-DG-induced central nervous system-mediated hyperglycemia. 2-DG-induced hyperglycemia is not dependent on only one of those three systems, it is dependent on all of them. The relative potency of the factors to 2-DG-induced hyperglycemia increases in the following order: direct neural innervation of liver (including suppressive epinephrine action on insulin secretion), glucagon, and direct epinephrine action on liver.     

In vivo in vitro effects of somatostatin and insulin on glucagon release in a human glucagonoma

Inhibition of pancreatic glucagon secretion has been reported to be mediated by glucose, insulin and somatostatin. As no human pancreatic α-cell lines are available to study in vitro the relative importance of insulin and glucose in the control of pancreatic glucagon release, we investigated a patient presenting with a malignant glucagonoma who underwent surgical resection of the tumour. Functional somatostatin receptors were present as octreotide administration decreased basal glucagon and insulin secretion by 52 and 74%, respectively. The removed tumour was immunohistochemically positive for glucagon, chromogranin A and pancreatic polypeptide but negative for insulin, gastrin and somatostatin. The glucagonoma cells were also isolated and cultured in vitro . Incubation experiments revealed that change from high (10 m m ) to low (1 m m ) glucose concentration was unable to stimulate glucagon secretion. A dose-dependent inhibition of glucagon release by insulin was however, observed at low glucose concentration. These findings demonstrate that insulin could inhibit glucagon secretion in vitro in the absence of elevated glucose concentrations. These data suggest, as observed in vivo in vitro in several animal studies, that glucopenia-induced glucagon secretion in humans is not mediated by a direct effect of low glucose on α-cells but possibly by a reduction of insulin-mediated α-cell suppression and/or an indirect neuronal stimulation of glucagon release.     

Glucagon,insulin and somatostatin secretion in response to sympathetic neural activation in streptozotocin-induced diabetic rats. A study with the isolated perfused rat pancreas in vitro

Summary Changes in glucagon, insulin and somatostatin secretion induced by electrical splanchnic nerve stimulation were examined in rats treated with streptozotocin as neonates and as adults. In order to study the direct neural effects we used the isolated perfused rat pancreas with intact left splanchnic nerve in vitro. In normal rats splanchnic nerve stimulation causes significant decreases in insulin (30–40%) and somatostatin (30–50%) secretion at both 16.7 mmol/l and 1 mmol/l glucose concentrations. In the neonatal streptozotocin-diabetic rats splanchnic nerve stimulation at 16.7 mmol/l glucose decreased insulin secretion (14%) further than in the control rats (30%), however, somatostatin secretion did not decrease to the same extent. Similar results were also observed at the low (1 mmol/l) glucose concentration. On the other hand, percent decreases of insulin and somatostatin secretion induced by splanchnic nerve stimulation in the streptozotocin-diabetic rats were similar to the values observed in the normal control rats. The glucagon secretion in response to splanchnic nerve stimulation at 16.7 mmol/l glucose from pancreatic Alpha cells in both types of induced diabetes is exaggerated, and the degree of exaggeration seems to parallel the severity of the hyperglycaemia. However, the splanchnic nerve stimulation-induced glucagon secretion at 1 mmol/l glucose was impaired in the streptozotocin-diabetic rats, but not in the neonatal streptozotocin-diabetic rats. These data suggest that the sensitivity of diabetic Alpha and Delta cells to sympathetic neural activation are blunted, whereas the sensitivity of Beta cells is enhanced in the diabetic animal model.     

The alpha cell response to glucose change during perfusion of anti-insulin serum in pancreas isolated from normal rats

Summary To determine the effect of neutralization of endogenous insulin upon the glucagon response to a rise and fall of glucose concentration, pancreata isolated from normal rats were perfused with either a potent anti-pork insulin guinea pig serum or a nonimmune guinea pig serum for 30 min. During this period glucose concentration was changed from 100 mg/dl to either 130, 180 or 80 mg/dl for 10 min. Antiserum perfusion at 100 mg/dl caused an approximately two-fold increase in glucagon which was not suppressed by an increase in glucose concentration to either 130 or 180 mg/dl, although glucagon secretion was significantly suppressed in the control experiments in which nonimmune serum was perfused. However, the 0.38±0.21 ng/min rise in glucagon secretion in response to a reduction in glucose concentration to 80 mg/dl in the control experiments was not abolished by antiserum perfusion but, instead, was enhanced (2.66±0.60 ng/min). These findings suggest that insulin may be required for glucose-mediated suppression of glucagon in the isolated pancreas of normal rats but not for stimulation of glucagon secretion by mild glucopenia. Alternatively, neutralization of insulin-mediated release-inhibition of glucagon secretion may simply have altered alpha cell responsiveness in a direction that desensitized it nonspecifically to suppression and sensitized it to stimulation.Senior Medical Investigator, Dallas Veterans Administration     

Inhibition of insulin secretion,but normal peripheral insulin sensitivity,in a patient with a malignant endocrine pancreatic tumour producing high amounts of an islet amyloid polypeptide-like molecule

Summary Islet amyloid polypeptide or amylin is a polypeptide secreted mainly from the pancreatic beta cells together with insulin upon stimulation. High levels of islet amyloid polypeptide have also been shown to increase the peripheral insulin resistance and consequently a role for islet amyloid polypeptide in the glucose homeostasis has been suggested. We have studied the glucose homeostasis in a patient with a malignant endocrine pancreatic tumour producing large amounts of an islet amyloid polypeptide-like molecule (about 400 times the upper reference level for islet amyloid polypeptide). This patient developed insulin-requiring diabetes mellitus shortly after the tumour diagnosis. Both intravenous and oral glucose tolerance tests revealed inhibited early responses in insulin and C-peptide release, but the insulin and C-peptide response to glucagon stimulation was less affected. Aneuglycaemic insulin clamp showed normal insulin-mediated glucose disposal. In vitro experiments, where isolated rat pancreatic islets were cultured with serum from the patient, showed a moderately decreased islet glucose oxidation rate and glucose-stimulated insulin release compared to islets cultured with serum from healthy subjects. However, culture of rat islets with normal human serum supplemented with synthetic rat islet amyloid polypeptide did not affect the glucose-stimulated insulin release. In conclusion, the observed effects show that the diabetic state in this patient was associated with an impaired glucose-stimulated insulin release but not with an increased peripheral insulin resistance. Thus, the results suggest that if islet amyloid polypeptide has diabetogenic effects they are more likely to be exerted at the level of insulin secretion than at the level of peripheral insulin sensitivity.     

Stimulation of insulin release by glucose in a transplantable rat islet cell tumor

A subline of an x-ray-induced transplantable rat insulinoma has been studied in vivo and in vitro. Tumors grew rapidly after sc transplantation and were rich in insulin, but contained only small amounts of glucagon and somatostatin. Despite marked basal hyperinsulinemia, iv glucose administration caused a further increase in plasma insulin in tumor-bearing rats. When the pancreas was functionally excluded by ligation of supplying arteries, glucose still elicited a clear insulin response. In vitro, insulin release from perifused tumor fragments was stimulated by the combination of glucose and 3-isobutyl-1-methylxanthine, but not by glucose alone. In contrast, there was a clear stimulation of insulin release by glucose in primary monolayer cultures of tumor cells. This suggests a better functional capacity of the cultured cells compared to that of the tumor fragments. The results indicate that this transplantable rat islet cell tumor is a convenient source of large quantities of functional beta-cells.     

Islet transplantation into rat liver: in vitro secretion of insulin from the isolated perfused liver and in vivo glucagon suppression.

Islet isografts were injected into the portal veins of rats made diabetic with streptozotocin. The isografts normalized not only plasma glucose and insulin levels but also the elevated plasma immunoreactive glucagon level. The in vitro basal insulin secretion and prompt sensitivity to glucose were shown directly by perfusing isolated livers containing transplanted islets. In vitro glucagon secretion to an arginine stimulus could not be demonstrated, although it would have been expected demonstrated, although it would have been expected in normal islets. Thus, it appears that insulin derived from transplanted islets is capable of correcting endogenous hyperglucagonemia and of ameliorating the effects of experimental diabetes while transplanted islet glucagon secretion is relatively suppressed.     

Glucagon secretion in rats with non-insulin-dependent diabetes: an in vivo and in vitro study

Non-insulin-dependent diabetes ( NIDD ) was obtained in adult rats following a neonatal streptozotocin injection. Rats with NIDD exhibited a chronic low-insulin response to glucose in vivo, slightly elevated basal plasma glucose values (less than 2 g/l) and low pancreatic insulin stores (50% of the controls). Glucagon secretion was studied in this model, in vivo and in vitro using the isolated perfused pancreas technique. Normal basal plasma glucagon levels were observed in the fed state and were in accordance with normal basal glucagon release in vitro. The pancreatic glucagon stores were normal in the diabetics. In experiments with the perfused pancreas, the increased glucose concentration suppressed glucagon release as readily in the diabetics as in the controls. Moreover 5.5 mM glucose suppressed glucagon release stimulated by 19 mM arginine to the same extent in both groups. These data indicate that the suppression of A cell function by glucose is normal in rats with NIDD . Theophylline and isoproterenol also produced normal glucagon release in diabetics. By contrast, the glucagon secretion in response to arginine was lower in the diabetics. This was observed either in vivo (arginine infusion) or in vitro in the presence or the absence of glucose in the perfusate. But in the presence of theophylline the response to arginine was normalized in the diabetics. Impairment of A cell function of the diabetics is not limited to recognition of amino-acids, since acetylcholine evoked a lower glucagon response in the diabetics than in the controls. These defects are different from those described in their B cells.     

Peptide YY: intrapancreatic localization and effects on insulin and glucagon secretion in the mouse

We studied the intrapancreatic localization of peptide YY (PYY) and the effects of PYY on insulin and glucagon secretion in the mouse. Immunofluorescence staining of mouse pancreatic tissue showed that PYY occurred within islet cells. These cells were located preferentially at the periphery of the islets. Sequential and simultaneous double immunostaining revealed that most PYY cells also displayed glucagon immunoreactivity; some PYY cells contained immunoreactive pancreatic polypeptide (PP). At the electromicroscopic level, PYY immunoreactivity was demonstrated within the secretory granules of both glucagon cells and of a small granular cell type, which showed structural similarities to PP cells. In in vivo experiments, PYY at dose levels between 0.53 and 8.5 nmol/kg had no influence on basal plasma levels of insulin, glucagon, or glucose. In contrast, insulin secretion stimulated by glucose or the cholinergic agonist carbachol was inhibited by PYY (by 33 and 26%, respectively, at 4.25 nmol/kg). Similarly, carbachol-induced glucagon secretion was inhibited by PYY (by 47% at 4.25 nmol/kg). We conclude that PYY occurs in islet cells of the mouse pancreas, most of which are glucagon cells, and that PYY inhibits stimulated insulin and glucagon secretion in vivo in the mouse.     

Relative contribution of nervous system and hormones to hyperglycemia induced by thyrotropin-releasing hormone in fed rats.

In a continuation of our studies on the mechanism of central nervous system induced hyperglycemia in the rat, we evaluated the relative contribution of a direct neural effect on the liver and of certain hormones to the hyperglycemia induced by administration of thyrotropin-releasing hormone (TRH). The findings were compared with those of a previous investigation using neostigmine or 2-deoxy-D-glucose. In the present study TRH was injected into the third cerebral ventricle of rats, and the concentrations of hepatic venous plasma glucose, immunoreactive glucagon, immunoreactive insulin, epinephrine, and norepinephrine, were measured. Four groups of animals were evaluated: (1) intact rats; (2) rats receiving an infusion of somatostatin with insulin via the femoral vein to inhibit glucagon secretion and to maintain the basal insulin level; (3) rats bilaterally adrenalectomized (ADX) to prevent epinephrine secretion, and (4) ADX rats administered an infusion of somatostatin and insulin. Evaluation of the areas under the glucose curves for the rats receiving somatostatin with insulin, ADX rats, and ADX rats receiving somatostatin with insulin showed values 202, 50, and 79% of those observed in intact animals. These observations suggest that TRH-induced hyperglycemia results from at least two effects: a direct neural effect on the liver including a suppressive effect of epinephrine on insulin secretion (contributing about 79% to the total hyperglycemic effect) and a direct effect of epinephrine on the liver (contributing about 21% to the total hyperglycemic effect).(ABSTRACT TRUNCATED AT 250 WORDS)     

Secretion and hepatic extraction of insulin after weight loss in obese noninsulin-dependent diabetes mellitus

We assessed the effects of weight loss on pancreatic secretion and hepatic extraction of insulin in 11 obese subjects with noninsulin-dependent diabetes mellitus. Weight loss of 15.4 +/- 2.0 kg (mean +/- SE) resulted in decreased fasting insulin [20.2 +/- 2.5 to 9.8 +/- 2.5 microU/mL (145 +/- 18 to 70 +/- 18 pmol/L); P less than 0.02] and C-peptide (850 +/- 80 to 630 +/- 110 pmol/L; P less than 0.05) levels. The plasma glucose response to oral glucose and iv glucagon was improved with unchanged peripheral insulin levels. When plasma glucose levels were matched to those before weight loss, peripheral serum insulin and plasma C-peptide responses to iv glucagon were increased and similar to those in obese nondiabetic subjects studied at euglycemia. The total insulin response (area under the curve) to iv glucagon was reduced 30% (P less than 0.005), while the total C-peptide response area did not change after weight loss. At matched hyperglycemia, the total response area was enhanced 72% for insulin (P less than 0.002) and 64% for C-peptide (P less than 0.001). Incremental (above basal) response areas after weight loss did not change for insulin, but increased 66% for C-peptide (P less than 0.05). The incremental areas were augmented nearly 2-fold (196%) for insulin (P less than 0.01) and 1.7-fold (173%) for C-peptide (P less than 0.01) when assessed at matched hyperglycemia. Both basal (7.3 +/- 0.5 to 14.1 +/- 1.8; P less than 0.01) and total stimulated (6.1 +/- 0.4 to 8.8 +/- 1.4; P less than 0.05) C-peptide to insulin molar ratios increased after weight loss. We conclude that after weight loss in noninsulin-dependent diabetes mellitus, 1) insulin secretion is decreased in the basal state but increased after stimulation; 2) changes in insulin secretion are reflected by peripheral levels of C-peptide but not insulin, due in part to enhanced hepatic insulin extraction; and 3) at matched levels of hyperglycemia insulin secretion is markedly increased and similar to that in obese nondiabetic subjects studied at euglycemia.