Glucagon secretion during the development of insulin-secreting tumors induced by streptozotocin and nicotinamide.

Serial oral glucose tolerance tests in rats treated with streptozotocin and nicotinamide showed that blood glucose levels after glucose loading were suppressed significantly 7 months after treatment as compared to those of earlier stages. Post-glucose plasma insulin levels were significantly elevated at the 9th to 12th month and concomitantly fasting plasma glucagon levels rose significantly. At that time pancreatic islet cell tumors were demonstrated in all of the rats in this experiment. Post-glucose plasma glucagon levels, however, did not show remarkable changes throughout the observation. In spite of hyperinsulinemia, post-glucose plasma glucagon levels of tumor-bearing rats were significantly lower than those of body weight adjusted controls. It is inferred from the study that secretory activity of pancreatic A-cells of tumor-bearing rats is restrained by excess insulin released from islet cell tumors.     

Thyrotropin-releasing hormone and insulin in chemically induced pancreatic islet cell tumors in rats

Thyrotropin-releasing hormone (TRH) and insulin were measured by radioimmunoassay in acetic-acid extracts of 19 pancreatic islet cell tumors induced by streptozotocin and nicotinamide in rats. In addition, gel filtration properties of TRH-immunoreactivity and immunoreactive insulin (IRI) were examined in 5 and 14 tumors, respectively. TRH was demonstrated in 10 of 19 tumors, with a mean of 166 +/- 47 (SEM) pg/mg wet weight, whereas the concentration was less than 3 pg/mg wet weight in the other tumors. In contrast, all tumors contained IRI, with a mean of 11.0 +/- 1.6 micrograms/mg wet weight. Ten tumors in which TRH was demonstrated contained more IRI than those in which TRH was not detected (13.1 +/- 1.8 vs 6.5 +/- 1.7 micrograms/mg wet weight, P less than 0.02). After gel filtration, all TRH immunoreactivity was eluted at the same place as synthetic TRH in the 5 tumors. In addition, gel filtration elutes showed essentially the same pattern of IRI in the 14 tumors, with 3 peaks. The predominant IRI peak comigrated with marker insulin (95.7 +/- 0.8%), another prominent peak occurred coincident with proinsulin standard (3.3 +/- 0.5%), a third peak was present in the void volume (0.28 +/- 0.04%). These distributions of IRI were similar to those in extracts of normal pancreases. The present studies demonstrate TRH immunoreactivity in pancreatic islet cell tumors induced by streptozotocin and nicotinamide in rats. Chemically induced insulinomas can serve as a model for insulin storage which is analogous to islet B cells.     

Interactions between oxytocin, glucagon and glucose in normal and streptozotocin-induced diabetic rats

Oxytocin has been suggested to have glucoregulatory functions in rats, man and other mammals. The hyperglycemic actions of oxytocin are believed to be mediated indirectly through changes in pancreatic function. The present study examined the interaction between glucose and oxytocin in normal and streptozotocin (STZ)-induced diabetic rats, under basal conditions and after injections of oxytocin. Plasma glucose and endogenous oxytocin levels were significantly correlated in cannulated lactating rats (r = 0.44, P less than 0.01). To test the hypothesis that oxytocin was acting to elevate plasma glucose, adult male rats were injected with 10 micrograms/kg oxytocin and killed 60 min later. Oxytocin increased plasma glucose from 6.1 +/- 0.1 to 6.8 +/- 0.2 mM (P less than 0.05), and glucagon from 179 +/- 12 to 259 +/- 32 pg/ml (P less than 0.01, n = 18). There was no significant effect of oxytocin on plasma insulin, although the levels were increased by 30%. A lower dose (1 microgram/kg) of oxytocin had no significant effect on plasma glucose or glucagon. To eliminate putative local inhibitory effects of insulin on glucagon secretion, male rats were made diabetic by i.p. injection of 100 mg/kg STZ, which increased glucose to greater than 18 mM and glucagon to 249 +/- 25 pg/ml (P less than 0.05). In these rats, 10 micrograms/kg oxytocin failed to further increase plasma glucose, but caused a much greater increase in glucagon (to 828 +/- 248 pg/ml) and also increased plasma ACTH. A specific oxytocin analog, Thr4,Gly7-oxytocin, mimicked the effect of oxytocin on glucagon secretion in diabetic rats. The lower dose of oxytocin also increased glucagon levels (to 1300 +/- 250 pg/ml), but the effect was not significant. A 3 h i.v. infusion of 1 nmol/kg per h oxytocin in conscious male rats significantly increased glucagon levels by 30 min in normal and STZ-rats; levels returned to baseline by 30 min after stopping the infusion. Plasma glucose increased in the normal, but not STZ-rats. The relative magnitude of the increase in glucagon was identical for normal and diabetic rats, but the absolute levels of glucagon during the infusion were twice as high in the diabetics. To test whether hypoglycemia could elevate plasma levels of oxytocin, male rats were injected i.p. with insulin and killed from 15-180 min later. Plasma glucose levels dropped to less than 2.5 mM by 15 min. Oxytocin levels increased by 150-200% at 30 min; however, the effect was not statistically significant.(ABSTRACT TRUNCATED AT 400 WORDS)     

Effects of hypersecretion of growth hormone and prolactin on plasma levels of glucagon and insulin in GH3-cell-tumor-bearing rats, and the influence of bromocriptine treatment

Plasma levels of prolactin, growth hormone, glucagon insulin and glucose were measured in non-treated control rats, bromocriptine-treated control rats and GH3-cell-tumor-bearing rats with and without bromocriptine treatment. Bromocriptine treatment increased plasma levels of glucagon, insulin and glucose in control rats. Tumor-bearing rats had increased body weight and increased plasma levels of prolactin, growth hormone, glucagon, insulin and glucose. Bromocriptine treatment reduced body weight and decreased the plasma levels of prolactin, glucagon and insulin, as compared to non-treated tumor-bearing rats. The drug had no effect on plasma levels of growth hormone and glucose. These results indicate that, in GH3-cell-tumor-bearing rats, prolactin, glucagon and insulin are more sensitive to the action of bromocriptine than growth hormone.     

Effect of propranolol on glucose-induced insulin response in rats with insulinomas

This paper describes an inhibitory effect of propranolol on insulin secretion in rats with pancreatic islet cell tumors which have been induced by streptozotocin (65 mg/kg body weight) and nicotinamide (500 mg/kg). Following glucose ingestion (3 g/kg), propranolol (4 mg/kg) was injected into the tumor-bearing rats. Plasma insulin decreased paradoxically despite an increase in blood glucoses. In contrast, propranolol did not suppress insulin secretion in normal rats. The drug was found to have no effect on glucagon secretion in either experimental or control animals during glucose load. This may suggest that the experimentally induced insulinoma in hypersensitive to propranolol for inhibiting insulin secretion.     

Increased body fat in streptozotocin diabetic rats treated with intensive subcutaneous insulin therapy vs. islet transplantation

The continued development of novel insulin treatment is predicated on the hypothesis that strict glycemic control is necessary to prevent the secondary complications of diabetes. Although dramatically successful in reducing selected secondary complications, intensive insulin therapy has consequences. These include hypoglycemia, weight gain, and body fat accumulation. In the present studies we compared a model of intensive insulin therapy in diabetic rats and contrasted weight gain and body fat accumulation with pancreatic islet transplantation. Female Wistar Furth rats (173 g) administered streptozotocin (55 mg x kg(-1), iv) remained diabetic (DB) for four or nine weeks. At week three, a third group was transplanted (TRAN) with islets of Langerhans (3519 +/- 838 150 microm islets); one week later group four began intensive subcutaneous insulin therapy (ISIT; 4 x 0.5-1.0 U regular insulin x day(-1)). Within one week ISIT rats had normalized plasma glucose; levels were not different from age matched controls (CN) or TRAN animals (ISIT 10.6 +/- 1.7, CN 7.2 +/- 0.4, TRAN 7.7 +/- 0.8 mmol x L(-1), P > 0.05). The cumulative occurrence of one episode of hypoglycemia (< 2.8 mmol x L(-1)) occurred in 50% of ISIT rats. At study termination, body weight of ISIT and CN rats did not differ (199 +/- 4 vs. 207 +/- 3, P > 0.05). While carcass protein content was similar for TRAN, ISIT, and CN animals, the body fat of ISIT animals was 24% greater than in CN rats and 21% greater than in TRAN rats (P < 0.05). Correlation of body fat vs. plasma glucose illustrated hypoglycemia contributed to the body fat gain of ISIT rats (n = 8, r = -0.70, P = 0.0535). These studies illustrate a disproportionate gain of body fat from ISIT, an effect not observed with islet transplantation. Thus, the metabolic benefit ascribed to islet transplantation appears related to the absence of hypoglycemia.     

Seasonal glucose uptake in marmots (Marmota flaviventris): the role of pancreatic hormones.

1. Glucose uptake was measured throughout the year in marmots (Marmota flaviventris) by the hyperglycemic clamp technique. During each 2 hr experiment, the plasma glucose level was maintained at 215 mg/dl while blood samples were collected and analysed for glucose, insulin, glucagon, cortisol and catecholamines. 2. Glucose uptake was calculated from the glucose infusion rate, changes in the glucose pool (using a correction factor), and urinary glucose excretion. 3. In autumn, animals peaked in body weight (greater than 4.0 kg) and ceased to feed. Basal plasma insulin levels in autumn were significantly elevated over all other seasons (P less than 0.01) and glucose uptake in autumn was 9.7 +/- 2.4 mg/min which was significantly lower (P less than 0.05) than summer (21.7 +/- 2.4 mg/min) during the steady state phase of the glucose clamp (90-120 min). 4. Plasma glucagon levels declined during the clamp in all seasons but there was no significant difference between seasons. Plasma cortisol and catecholamine (norepinephrine and epinephrine) levels remained unchanged under basal and experimental conditions throughout the seasons. 5. During glucose infusion, beta-hydroxybutyrate levels were suppressed suggesting that lipolysis was reduced during the experiment. 6. These results suggest that the marmot exhibits seasonal changes in glucose uptake; the lowest rate of glucose uptake occurring in the autumn after the animals peak in body weight and cease to feed.     

Suppression of glucose production by GLP-1 independent of islet hormones: a novel extrapancreatic effect

Glucagon-like peptide-1 (GLP-1) is an intestinal hormone that stimulates insulin secretion and decreases glucagon release. It has been hypothesized that GLP-1 also reduces glycemia independent of its effect on islet hormones. Based on preliminary evidence that GLP-1 has independent actions on endogenous glucose production, we undertook a series of experiments that were optimized to address this question. The effect of GLP-1 on glucose appearance (Ra) and glucose disposal (Rd) was measured in eight men during a pancreatic clamp that was performed by infusing octreotide to suppress secretion of islet hormones, while insulin and glucagon were infused at rates adjusted to maintain blood glucose near fasting levels. After stabilization of plasma glucose and equilibration of [3H]glucose tracer, GLP-1 was given intravenously for 60 min. Concentrations of insulin, C-peptide, and glucagon were similar before and during the GLP-1 infusion (115 +/- 14 vs. 113 +/- 11 pM; 0.153 +/- 0.029 vs. 0.156 +/- 0.026 nM; and 64.7 +/- 11.5 vs. 65.8 +/- 13.8 ng/l, respectively). With the initiation of GLP-1, plasma glucose decreased in all eight subjects from steady-state levels of 4.8 +/- 0.2 to a nadir of 4.1 +/- 0.2 mM. This decrease in plasma glucose was accounted for by a significant 17% decrease in Ra, from 22.6 +/- 2.8 to 19.1 +/- 2.8 micromol. kg-1. min-1 (P < 0.04), with no significant change in Rd. These findings indicate that, under fasting conditions, GLP-1 decreases endogenous glucose production independent of its actions on islet hormone secretion.     

Diabetogenic response to streptozotocin varies among obese yellow and among lean agouti (BALB/c x VY)F1 hybrid mice

To test the hypothesis that the elevated insulin levels in obese neoplasia-susceptible yellow Avy/- mice might be a major factor stimulating tumor formation, it is necessary to use normoinsulinemic yellow mice. Although our attempt to obtain normoinsulinemic, euglycemic mice by streptozotocin treatment was unsuccessful, we did observe significant differences in the responsiveness to this treatment among mice of identical genotype. These differences were observed among female yellow Avy/A and agouti A/a (BALB/c x VY)F1 hybrid mice in the responses of body weight gain, plasma glucose, and plasma insulin levels to a single intraperitoneal injection of either 150 or 200 mg/kg streptozotocin (STZ) at 4 weeks of age followed by a 22-week observation period. Among animals treated with the high streptozotocin dose, 80% of the yellow mice gained almost no weight and became grossly hyperglycemic and hypoinsulinemic; however, only 55% of the agouti mice exhibited such a strong response. In the low dose group, 25% of the yellow mice responded with reduced body weight gain, decreased insulin, and elevated glucose levels whereas none of the agouti mice exhibited such responses. More pancreatic islet tissue mass was present in the untreated yellow control mice than among the comparable agouti mice by the end of the study. In both streptozotocin dose groups and in both genotypes, islet tissue mass was reduced to a much greater extent in the more responsive mice than in the less responsive mice. There appeared to be no correlation between islet tissue mass and insulin level. The phenotypic variation in responsiveness to an exogenous agent among test animals of a single inbred or F1 hybrid genotype reported here is not unique to this F1 hybrid since it is seen in most chronic bioassays when relatively low levels of agent are used.     

Carbohydrate intolerance in gonadal dysgenesis: evidence for insulin resistance and hyperglucagonemia

To determine the pathogenesis of carbohydrate intolerance associated with gonadal dysgenesis, plasma glucose, insulin, glucagon, and growth hormone responses to oral glucose and intravenous tolbutamide, arginine and insulin were evaluated in 21 nonobese patients, 7-19 years old. Glucose intolerance was present in 9 of 21 nonobese patients (42.8%). Insulin levels, the area under the insulin curve after oral glucose and intravenous tolbutamide and the insulin to glucose ratio were significantly greater in patients than in controls (p less than 0.005). The decrease in plasma glucose following intravenous tolbutamide was significantly less in patients than in controls (p less than 0.05) despite insulin levels which were greater than in controls (p less than 0.05). After intravenous insulin, plasma glucose fell significantly less in patients than in controls (p less than 0.01). Plasma glucagon levels and the area under the glucagon curve after oral glucose and arginine infusion were significantly greater in patients than in controls (p less than 0.005 and p less than 0.01, respectively). The increase in glucagon after insulin-induced hypoglycemia was significantly less in patients than in controls (p less than 0.025). Fasting and stimulated growth hormone levels and the mean 24-hour growth hormone concentration were similar in patients and controls. These results indicate that glucose intolerance occurs frequently in gonadal dysgenesis and is associated with normal or increased insulin secretory responses. These abnormalities are probably due to insulin resistance and hyperglucagonemia. The decrease in insulin action does not appear to result from excessive growth hormone secretion or treatment with anabolic steroids or estrogen-progesterone medications.     

Effects of orally-administered melatonin and long-term exposure to light and dark on serum indices and gene expression of insulin and glucagon in male Wistar rats

We investigated influence of endogenous and exogenous melatonin on genetic and serologic aspects of secretory function of pancreas in rats. Thirty adult Wistar rats were divided into six groups. To achieve variable levels of endogenous melatonin, 10-day long-term exposure to light and darkness was implemented. Exogenous melatonin was administered orally (10 mg/kg of body weight). Blood glucose and serum levels of insulin, glucagon, and melatonin were measured by ELISA. Gene expression levels of insulin and glucagon were determined using the real time PCR. Results showed increase of blood glucose and decrease in serum levels of insulin after administration of melatonin without any significant difference in serum levels of glucagon. Gene expression levels of insulin in melatonin group were significantly lower than control group, while their glucagon was more. We concluded that oral administration of melatonin leads to increasing blood glucose, due to inhibition of insulin and stimulation of glucagon synthesis.     

Basal insulin, glucagon, and growth hormone replacement

Conclusions drawn from the pancreatic (or islet) clamp technique (suppression of endogenous insulin, glucagon, and growth hormone secretion with somatostatin and replacement of basal hormone levels by intravenous infusion) are critically dependent on the biological appropriateness of the selected doses of the replaced hormones. To assess the appropriateness of representative doses we infused saline alone, insulin (initially 0.20 mU.kg(-1).min(-1)) alone, glucagon (1.0 ng.kg(-1).min(-1)) alone, and growth hormone (3.0 ng.kg(-1).min(-1)) alone intravenously for 4 h in 13 healthy individuals. That dose of insulin raised plasma insulin concentrations approximately threefold, suppressed glucose production, and drove plasma glucose concentrations down to subphysiological levels (65 +/- 3 mg/dl, P < 0.0001 vs. saline), resulting in nearly complete suppression of insulin secretion (P < 0.0001) and stimulation of glucagon (P = 0.0059) and epinephrine (P = 0.0009) secretion. An insulin dose of 0.15 mU.kg(-1).min(-1) caused similar effects, but a dose of 0.10 mU.kg(-1).min(-1) did not. The glucagon and growth hormone infusions did not alter plasma glucose levels or those of glucoregulatory factors. Thus, insulin "replacement" doses of 0.20 and even 0.15 mU.kg(-1).min(-1) are excessive, and conclusions drawn from the pancreatic clamp technique using such doses may need to be reassessed.     

Relationships between glucose, insulin and glucagon during fasting in late gestation in the rat

Plasma glucose, insulin and glucagon were measured in pregnant and age-matched virgin rats in the fed state and after fasting 6, 48 or 120 hours during day 16–21 of gestation. The fed state in pregnancy was characterized by a metabolic setting favoring anabolism. The lower plasma glucose in the fed pregnant rats was associated with higher insulin, slightly lower glucagon and higher insulin/glucose and insulin/glucagon ratios than in virgin rats. During fasting, glucose fell to sustained hypoglycemic levels in the pregnant animals whereas glucose declined but did not achieve hypoglycemia at any point in the virgins. Despite the hypoglycemia, greater levels of plasma insulin persisted in the pregnant throughout the 120 hours of fasting and insulin/glucagon ratios did not differ significantly from the euglycemic virgins. Thus, “accelerated starvation” in pregnancy cannot be ascribed to relative glucagon excess. Rather, the preservation of normal insulin/glucagon ratios despite prevailing hypoglycemia, may provide a mechanism during fasting in pregnancy for restraining maternal protein catabolism in the face of the added fuel demands of the conceptus.     

Amphetamine and chlorpromazine modify cerebral insulin levels in rats

Rats treated with chlorpromazine (CPZ) (1 mg/kg/day i.p.) experienced a marked decline in cerebral insulin levels (0.057 +/- 0.01 ng/g wet weight) with respect to a control group (0.38 +/- 0.05 ng/g wet weight), while rats given D-amphetamine bitartrate (AMPH) chronically (20 mg/kg/day p.o.) showed a rise in cerebral insulin (0.55 +/- 0.04 ng/g wet weight). Combined treatment with both drugs at the same dosages produced lower cerebral insulin levels (0.46 +/- 0.10 ng/g wet weight) than in the AMPH animals. In the groups of rats treated with CPZ and with AMPH + CPZ, there was a slight elevation in serum insulin levels. Serum glucose values did not vary.     

消炎痛对四氧嘧啶引起的大鼠糖尿病的保护作用

本工作观察了预先给予消炎痛对四氧嘧啶引起的糖尿病大鼠血糖、血清胰岛素和胰高血糖素浓度的影响。结果表明:预先皮下注射消炎痛能使糖尿病大鼠血糖浓度明显降低,并且具有明显的量效关系。在消炎痛剂量5,10,15mg/kg时,注射四氧嘧啶48h后血糖浓度由对照组的591.5±38.2mg％分别降低到559.1±53.2,463.2±16.6和266.6±29.9mg％。在注射消炎痛10mg/kg的实验组,血清胰岛素浓度由对照组的10.5±2.7μU/ml增加到31.9±7.0μU/ml,胰高血糖素由对照组的550.0±27.0pg/ml降低到303.1±22.9pg/ml。组织学观察结果表明,消炎痛对四氧嘧啶引起的大鼠胰岛β细胞的损伤具有显著的保护作用。     

Increased glucagon secretion during hyperthermia in a sauna

Plasma glucagon, adrenaline, noradrenaline, insulin and glucose concentrations were measured in 7 healthy young males during hyperthermia in a sauna bath: plasma glucagon levels increased from baseline values of 127.0 +/- 12.9 (SEM) pg X ml-1 to a maximum of 173.6 +/- 16.1 (SEM) pg X ml-1 at the 20th min of exposure. No change in plasma insulin and a slight increase in plasma glucose concentration were seen. Since a concomitant moderate increase in plasma catecholamine levels was also present, the adrenergic stimulus is believed to trigger glucagon release during hyperthermia. Diminished visceral blood flow, known to occur in sauna baths, may cause a decrease in the degradation of plasma glucagon and thus contribute to the elevated plasma glucagon levels.     

Hyperglucagonemia precedes a decline in insulin secretion and causes hyperglycemia in chronically glucose-infused rats

Islet damage from glucose toxicity is implicated in the pathogenesis of type 2 diabetes, but the sequence of events leading to islet cell dysfunction and hyperglycemia remains unclear. To examine the early stages of islet pathology resulting from increased basal glucose loads, normal awake rats were infused with glucose continuously for 10 days. Plasma glucose and markers of islet and liver function were monitored throughout the infusion. After initial hyperglycemia, rats adapted to the infusion and maintained euglycemia for approximately 4 days. Continued infusion led to worsening hyperglycemia in just 5% of rats after 6 days, but 69% after 8 days and 89% after 10 days, despite unchanged basal and stimulated plasma insulin and C-peptide concentrations. In contrast, plasma glucagon concentrations increased fivefold. Endogenous glucose production (EGP) was appropriately suppressed after 4 days (2.8 ± 0.7 vs. 6.1 ± 0.4 mg·kg(-1)·min(-1) on day 0, P < 0.001) but tripled between days 4 and 8 (9.9 ± 1.7 mg·kg(-1)·min(-1), P < 0.01). Surprisingly, the increase in EGP was accompanied by increased mitochondrial phosphoenolpyruvate carboxykinase expression with appropriate suppression of the cytosolic isoform. Infusion of anti-glucagon antibodies normalized plasma glucose to levels identical to those on day 4 and ～300 mg/dl lower than controls. This improved glycemia was associated with a 60% reduction in EGP. These data support the novel concept that glucose toxicity may first manifest as α-cell dysfunction prior to any measurable deficit in insulin secretion. Such hyperglucagonemia could lead to excessive glucose production overwhelming the capacity of the β-cell to maintain glucose homeostasis.     

Effect of subcutaneous pancreatic tissue transplants on streptozotocin-induced diabetes in rats. II. Endocrine and metabolic functions.

The present study examines the effect of subcutaneous pancreatic tissue grafts (SPTG) on endocrine and metabolic functions in streptozotocin (STZ)-induced diabetic rats using radioimmunoassay and biochemical techniques. SPTG survived even after 15 weeks of transplantation and significantly improved the weight of STZ-diabetic rats over a 15-week period. Although blood glucose-, cholesterol-, and glycosylated-haemoglobin (GHb) levels were not significantly lower in STZ-diabetic rats treated with SPTG, the values of these biochemical parameters were lower than those in untreated diabetic rats. Plasma and pancreatic immunoreactive C-peptide (IRCP) levels did not improve after SPTG (IRCP expressed as mean +/- standard deviation were 0.22 +/- 0.07, 0.072 +/- 0.02 and 0.08 +/- 0.03 pg ml-1 in the plasma non-diabetic diabetic and treated rats respectively, while IRCP levels in the pancreas of the non-diabetic, diabetic and treated rats were 433.8 +/- 0.1, 22.9 +/- 0.01 and 10.4 +/- 0.01 pg mg tissue-1 respectively). SPTG, however, improved plasma immunoreactive insulin (IRI) levels in both plasma and pancreas. IRI values in plasma were 54.7 +/- 13.6, 18.0 +/- 5.0 and 22.1 +/- 4.3 microUI ml-1 in non-diabetic, diabetic and treated rats respectively and were 277.3 +/- 37.1, 14.7 +/- 1.8 and 30.3 +/- 15.9 microIU micrograms tissue-1 in the pancreas of non-diabetic, diabetic and treated rats respectively. There was improvement in immunoreactive glucagon (IRG) levels after SPTG. IRG values in the plasma of non-diabetic, diabetic and treated rats were 147.0 +/- 10.7, 408.0 +/- 76.5 and 247.7 +/- 3 pg ml-1 respectively whereas, IRG measured in the pancreas was 1642.25 +/- 424.23, 1899.0 +/- 290.4 and 1714.1 +/- 301.98 pg micrograms tissue-1 in non-diabetic, diabetic and treated rats, respectively. The pancreas:plasma ratio of pancreatic hormones was deranged in untreated diabetes but improved after SPTG. In conclusion, SPTG significantly improved the weight gain, pancreatic insulin content, plasma IRG and pancreas: plasma ratio of IRCP, IRI and IRG. It also reduced blood glucose-, cholesterol-, and glycosylated-hemoglobin levels in STZ-diabetic rats.     

Insulin modulates glucose-dependent insulinotropic polypeptide (GIP) secretion from enteroendocrine K cells in rats

Effects of insulin excess and deficiency on glucose-dependent insulinotropic polypeptide (GIP) was examined in rats following insulinoma transplantation or streptozotocin (STZ) administration. Over 14 days, food intake was increased (p < 0.001) in both groups of rats, with decreased body weight (p < 0.01) in STZ rats. Non-fasting plasma glucose levels were decreased (p < 0.01) and plasma insulin levels increased (p < 0.001) in insulinoma-bearing rats, whereas STZ treatment elevated glucose (p < 0.001) and decreased insulin (p < 0.01). Circulating GIP concentrations were elevated (p < 0.01) in both animal models. At 14 days, oral glucose resulted in a decreased glycaemic excursion (p < 0.05) with concomitant elevations in insulin release (p < 0.001) in insulinoma-bearing rats, whereas STZ-treated rats displayed similar glucose-lowering effects but reduced insulin levels (p < 0.01). GIP concentrations were augmented in STZ rats (p < 0.05) following oral glucose. Plasma glucose and insulin concentrations were not affected by oral fat, but fat-induced GIP secretion was particularly (p < 0.05) increased in insulinoma-bearing rats. Exogenous GIP enhanced (p < 0.05) glucose-lowering in all groups of rats accompanied by insulin releasing (p < 0.001) effects in insulinoma-bearing and control rats. Both rat models exhibited increased (p < 0.001) intestinal weight but decreased intestinal GIP concentrations. These data suggest that circulating insulin has direct and indirect effects on the synthesis and secretion of GIP.