Insulin Secretion In Dogs Research Articles

Decreased Insulin Secretion in Dogs with Chronic Mitral Valve Insufficiency

Glucose metabolism abnormalities secondary to heart failure, including insulin resistance (IR) and impaired fasting glucose, have been gradually recognized as important prognostic factors in disease progression. However, to date, no study has investigated glucose abnormalities in dogs with chronic mitral valve insufficiency (CMVD). Thus, we hypothesized that glucose metabolism abnormalities due to heart failure may develop in dogs with CMVD. A prospective study was performed on 113 client-owned dogs with variable CMVD severities. Serum insulin, glucagon, fructosamine, and glucose concentrations were measured, and insulin resistance was determined using the homeostatic model assessment (HOMA) score. The serum insulin concentration had a significant inverse association with the heart failure severity. However, there was no significant association between the heart failure severity and fructosamine, HOMA score, and fasting blood glucose. Insulin, fructosamine, and HOMA had a significant positive association with body condition scores (BCS), whereas glucose had no association. This study found that insulin secretion in dogs with naturally occurring heart failure due to CMVD might be compromised as the disease worsens.

Basal measures of insulin sensitivity and insulin secretion and simplified glucose tolerance tests in dogs

There is need for simple, inexpensive measures of glucose tolerance, insulin sensitivity, and insulin secretion in dogs. The aim of this study was to estimate the closeness of correlation between fasting and dynamic measures of insulin sensitivity and insulin secretion, the precision of fasting measures, and the agreement between results of standard and simplified glucose tolerance tests in dogs. A retrospective descriptive study using 6 naturally occurring obese and 6 lean dogs was conducted. Data from frequently sampled intravenous glucose tolerance tests (FSIGTTs) in 6 obese and 6 lean client-owned dogs were used to calculate HOMA, QUICKI, fasting glucose and insulin concentrations. Fasting measures of insulin sensitivity and secretion were compared with MINMOD analysis of FSIGTTs using Pearson correlation coefficients, and they were evaluated for precision by the discriminant ratio. Simplified sampling protocols were compared with standard FSIGTTs using Lin's concordance correlation coefficients, limits of agreement, and Pearson correlation coefficients. All fasting measures except fasting plasma glucose concentration were moderately correlated with MINMOD-estimated insulin sensitivity (| r| = 0.62–0.80; P < 0.03), and those that combined fasting insulin and glucose were moderately closely correlated with MINMOD-estimated insulin secretion ( r = 0.60–0.79; P < 0.04). HOMA calculated using the nonlinear formulae had the closest estimated correlation ( r = 0.77 and 0.74) and the best discrimination for insulin sensitivity and insulin secretion (discriminant ratio 4.4 and 3.4, respectively). Simplified sampling protocols with half as many samples collected over 3 h had close agreement with the full sampling protocol. Fasting measures and simplified intravenous glucose tolerance tests reflect insulin sensitivity and insulin secretion derived from frequently sampled glucose tolerance tests with MINMOD analysis in dogs.

ATP-sensitive potassium channel (KATPchannel) expression in the normal canine pancreas and in canine insulinomas

BackgroundPancreatic beta cells express ATP-sensitive potassium (KATP) channels that are needed for normal insulin secretion and are targets for drugs that modulate insulin secretion. The KATP channel is composed of two subunits: a sulfonylurea receptor (SUR 1) and an inward rectifying potassium channel (Kir6.2). KATP channel activity is influenced by the metabolic state of the cell and initiates the ionic events that precede insulin exocytosis. Although drugs that target the KATP channel have the expected effects on insulin secretion in dogs, little is known about molecular aspects of this potassium channel. To learn more about canine beta cell KATP channels, we studied KATP channel expression by the normal canine pancreas and by insulin-secreting tumors of dogs.ResultsPancreatic tissue from normal dogs and tumor tissue from three dogs with histologically-confirmed insulinomas was examined for expression of KATP channel subunits (SUR1 and Kir6.2) using RT-PCR. Normal canine pancreas expressed SUR1 and Kir6.2 subunits of the KATP channel. The partial nucleotide sequences for SUR1 and Kir6.2 obtained from the normal pancreas showed a high degree of homology to published sequences for other mammalian species. SUR1 and Kir6.2 expression was observed in each of the three canine insulinomas examined. Comparison of short sequences from insulinomas with those obtained from normal pancreas did not reveal any mutations in either SUR1 or Kir6.2 in any of the insulinomas.ConclusionCanine pancreatic KATP channels have the same subunit composition as those found in the endocrine pancreases of humans, rats, and mice, suggesting that the canine channel is regulated in a similar fashion as in other species. SUR1 and Kir6.2 expression was found in the three insulinomas examined indicating that unregulated insulin secretion by these tumors does not result from failure to express one or both KATP channel subunits.

ACVIM Abstracts

Type 2 diabetes mellitus occurs in human beings and cats when insulin secretion fails to compensate for obesity-induced insulin resistance. Although obese dogs develop insulin resistance, they are not known to progress to type 2 diabetes, and little is known about the long-term effects of obesity on insulin secretion in dogs. Previous studies of insulin secretion in obese dogs involved dogs with induced, short-term obesity, or were confounded by the inclusion of intact bitches, or used glucose tolerance tests that had insufficient early samples to assess first-phase insulin secretion. The aim of this study was to evaluate glucose tolerance and insulin secretion in dogs with spontaneous obesity.

Meal-induced insulin secretion in dogs is mediated by both branches of the autonomic nervous system.

We investigated the relationship between autonomic activity to the pancreas and insulin secretion in chronically catheterized dogs when food was shown, during eating, and during the early absorptive period. Pancreatic polypeptide (PP) output, pancreatic norepinephrine spillover (PNESO), and arterial epinephrine (Epi) were measured as indexes for parasympathetic and sympathetic nervous activity to the pancreas and for adrenal medullary activity, respectively. The relation between autonomic activity and insulin secretion was confirmed by autonomic blockade. Showing food to dogs initiated a transient increase in insulin secretion without changing PP output or PNESO. Epi did increase, suggesting beta(2)-adrenergic mediation, which was confirmed by beta-adrenoceptor blockade. Eating initiated a second transient insulin response, which was only totally abolished by combined muscarinic and beta-adrenoceptor blockade. During absorption, insulin increased to a plateau. PP output showed the same pattern, suggesting parasympathetic mediation. PNESO decreased by 50%, suggesting withdrawal of inhibitory sympathetic neural tone. We conclude that 1) the insulin response to showing food is mediated by the beta(2)-adrenergic effect of Epi, 2) the insulin response to eating is mediated both by parasympathetic muscarinic stimulation and by the beta(2)-adrenergic effect of Epi, and 3) the insulin response during early absorption is mediated by parasympathetic activation, with possible contribution of withdrawal of sympathetic neural tone.

Effect of C-terminal fragments of glucagon on insulin secretion in dogs

Although the insulinotropic action of glucagon is well known, which parts of the glucagon molecule play an importent role in its action remain to be elucidated. To investigate the direct effect of the C-terminal peptides of glucagon on the endocrine function of the pancreas, glucagon(17–29), (21–29), (23–29), and (25–29) were studied using an in situ local circulation system of the canine pancreas. These glucagon fragments, as well as glucagon(1–29), were infused into the superior pancreaticoduodenal artery (PA) in a dosage of 400 pmol for 10 minutes during 0.5% glucose or 0.5% arginine infusion, and plasma insulin (IRI) and glucagon (IRG) levels in the superior pancreaticoduodenal vein (PV) were determined. During the glucose infusion, plasma IRI increased significantly following the administration of glucagon(23–29), (21–29), (17–29), or (1–29), but not glucagon(25–29). In these experiments, plasma IRG increased significantly following infusion of glucagon(21–29), (17–29), or (1–29). During the arginine infusion, all of the glucagon fragments studied enhanced insulin secretion, whereas plasma IRG was increased following the administration of glucagon(21–29), (17–29), or (1–29). In these experiments with glucose or arginine infusion, blood glucose in the femoral artery (FA) did not change significantly except for glucagon(1–29), which increased the blood glucose level. In addition, the administration of graded doses of glucagon(21–29) [50, 150, and 400 pmol] during the glucose infusion elicited an increase in plasma IRI in a dose-related manner. From the present study, it is concluded that the C-terminal peptides of glucagon enhanced insulin release, and that glucagon(21–29) is the minimum structure among the C-terminal glucagon fragments to stimulate insulin secretion.

Markedly reduced beta-cell function does not result in insulin resistance in islet autografted dogs.

Autotransplantation of islets of Langerhans has resulted in long-term normoglycemia in pancreatectomized dogs. This canine model is useful in evaluating both the progress of islet transplantation and the effect of a reduced islet mass upon the determinants of glucose tolerance: i.e., insulin secretion, insulin sensitivity, and glucose effectiveness. To determine the effect of a reduced islet mass on these factors, we measured the acute insulin response to arginine (AIRa) and glucose (AIRg), the slope of glycemic potentiation of AIRa (SP), insulin sensitivity (Sl), and glucose effectiveness (SG) in control (CN), diabetic (DM), and pancreatectomized dogs rendered normoglycemic with transplanted autografts of islets of Langerhans (TX). Normal fasting plasma glucose (FPG) (TX 4.7 +/- 0.2 mM; CN 4.9 +/- 0.1 mM; P greater than 0.05) was maintained despite a markedly reduced insulin secretion in TX (AIRa 24%, AIRg 15%, and SP 11% of CN). All measures of insulin secretion were significantly correlated (SP vs. AIRg, r = 0.80, P less than 0.0001; AIRa vs. AIRg, r = 0.92, P less than 0.0001) across all animals, but none of the measures of secretion were significantly correlated with either the number of islets transplanted or time posttransplant (P greater than 0.10). Insulin sensitivity was normal in islet autografted dogs (TX: 136 +/- 12 min-1/(nmol/ml); CN: 101 +/- 11 min-1/(nmol/ml), P greater than 0.05) but SG was reduced (TX: 1.93 +/- 0.28 x 100 min-1; CN: 3.53 +/- 0.35 x 100 min-1, P less than 0.05), as determined by the minimal-model method. In diabetic animals (FPG = 16.1 +/- 1.3 mM), insulin secretion was negligible by all measures (P greater than 0.05), and was associated with insulin resistance (Sl = 28 +/- 8 min-1/(nmol/ml)) and reduced SG (1.72 +/- 0.11 x 100 min-1). These studies indicate that across a range of insulin secretion in dogs, the secretagogues arginine and glucose provide similar estimates of beta-cell function. This markedly reduced beta-cell function does not result in insulin resistance when fasting normoglycemia is maintained, but is associated with a decrease in glucose action at basal insulin.

Galanin of the homologous species inhibits insulin secretion in the rat and in the pig

It is known that pig galanin inhibits insulin secretion in dogs, rats and mice. The present study examined whether species-specific, homologous, galanin inhibits insulin secretion. Thus, the effects of rat galanin were examined in the rat, and the effects of pig galanin were examined in the pig, both in vivo and in vitro. In conscious rats, synthetic rat galanin (2 nmol kg-1) abolished the glucose- (0.56 mmol kg-1) induced increase in plasma insulin levels. In vitro, rat galanin (10(-9) to 10(-6) mol l-1) inhibited glucose- (8.3 mmol l-1) stimulated insulin release from isolated rat islets. In anaesthetized pigs, 15 min infusion of synthetic pig galanin (207 pmol min-1) into the pancreatic artery decreased the insulin output with a subsequent recovery. In vitro, pig galanin (10(-6) mol l-1) inhibited glucose- (8.3 mmol l-1) stimulated insulin release from isolated pig islets. We conclude that homologous galanin inhibits insulin secretion in both the rat and the pig.

Absence of effect of heparin on insulin secretion.

Bioartificial pancreatic devices containing isolated islets of Langerhans have been designed, in which the blood of the recipient circulates in contact with an artificial membrane, protecting the islets against immune rejection. This system assumes that heparin, required to prevent blood clotting, does not alter insulin secretion. However, heparin has been reported to inhibit in vitro insulin secretion by rat islets and to suppress in vivo insulin secretion in dogs. Therefore, the following evaluation was made on the effect of different heparin preparations on insulin secretion. (a) Isolated rat islets of Langerhans were perfused or incubated in the absence or presence of 20 micrograms/ml heparin; insulin secretion in response to a stimulation by glucose 20 mM was not altered by the presence of heparin. (b) Insulin secretion by an insulin-secreting cell line (RINm5F) in response to leucine and theophylline was not suppressed by heparin up to 100 micrograms/ml concentration. However, an inhibitory effect was observed at 200 micrograms/ml, which is 100 times higher than the heparin concentration commonly used for therapeutic use. (c) Neither in normal rats nor in dogs did heparin alter portal plasma insulin levels and the increase in plasma insulin following an intravenous injection of glucose. In conclusion, these data do not confirm the formerly observed inhibitory effect of heparin, which can therefore be used for the in vivo evaluation of a bioartificial pancreas.

Insulin secretion in dogs with experimental pancreatitis in response to intrapancreatic injection of glucose

Insulin secretion in dogs with experimental pancreatitis in response to intrapancreatic injection of glucose

NeurotensinおよびXenopsinの膵内分泌におよぼす実験的研究

NeurotensinおよびXenopsinの膵内分泌におよぼす実験的研究

Reversal by methysergide of inhibition of insulin secretion by prostaglandin E in the dog.

These studies were designed to examine whether interrelationships exist between serotonin and prostaglandin E (PGE) during regulation of insulin secretion in dogs in vivo. In our studies serotonin was found to inhibit insulin responses to intravenous glucose. This inhibition was not reversed by complete adrenergic blockade provided through combined phentolamine and propranolol pretreatment. This property of serotonin is similar to that of PGE which also inhibits glucose-induced insulin secretion in vivo independently of adrenergic activity. To investigate whether these effects of serotonin and PGE are related, studies with methysergide (a serotonin antagonist) and indomethacin (a PGE synthesis inhibitor) were performed. Methysergide reversed the effects of both PGE and serotonin. In contrast, indomethacin did not diminish the inhibitory effect of serotonin upon insulin secretion. It is hypothesized that endogenous serotonin may play a role in the inhibitory effect of PGE upon insulin secretion in dogs in vivo.

Dynamics of insulin secretion in dogs with alloxan diabetes

It was shown that hypoinsulinemia in the superior pancratico-duodenal vein and inhibition of the first phase of insulin secretion by the pancreas characteristic of alloxan diabetes of different severity was absent in the femoral vein. The data obtained in the insulin and glucose concentration study in the superior pancreatico-duodenal vein stressed the leading role of the pancreatic factor in the pathogenesis of alloxan diabetes in dogs. Analysis of these parameters in the peripheral femoral vein failed to reflect this statement adequately.

Effect of Ergot Alkaloids on Sulfonylurea-Stimulated Insulin Secretion in Dogs

The insulinogenic response to a standard i.v. dose of a sulfonylurea can be markedly augmented in normal, conscious dogs if they are given 30 min earlier a single i.v. dose of dihydroergotamine (DHE). Since the parent substance ergotamine posssed no such amplifying properties, further experiments were conducted to clarify the essential structural requirements that have to be fulfilled for an ergot alkaloid to act as an amplifier of sulfonylurea-stimulated insulin secretion. Amine alkaloids ergonovine, dihydroergonovone and dihydromethylergonovine had no amplifying potency, but the hydrogenated amino acid alkaloids dihydroergocornine, dihydroergocristine and dihydroergokryptine (Hydergine) were almost as potent amplifiers as was DHE. The data indicate that (a) DHE, Hydergine and by inference all hydrogenated amino acid alkaloids are potent amplifiers of sulfonylurea-stimulated insulin secretion; (b) saturation of the double bond at C9 and C10 of the lysergic acid moiety and the pressence of an amino acid side chain are essential structual requirements for an ergot alkaloid to function as an amplifier of the action of sulfonylureas; and (c) it appears that these compounds are acting chiefly by mechanisms other than alpha-adrenergic and serotonergic receptor blockade, perhaps as regulatory molecules inducing positive cooperative changes in integral proteins of the plasma membrane of beta cells.

The effect of meal feeding and of sham-feeding on insulin secretion in dogs.

After feeding intact conscious dogs 1000 g mashed meat, peripheral venous immunoreactive insulin activity (IRI) increases before any enhancement of amino nitrogen concentration. This course of IRI is paralleled by a decrease of free fatty acids. Meal feeding in dogs, whose pancreatic juice is completely diverted from the gut by a fistula, is followed by a similar IRI increase without a distinct enhancement of amino nitrogen. In oesophagus fistula dogs, sham-feeding meat in 9 out of 15 experiments results in a considerable early IRI increase which is correlated with a small but a significant decrease of blood glucose and free fatty acid concentrations. In these tests there was no amino nitrogen alteration either.

In vivo studies on 5-hydroxytryptamine and insulin secretion in dogs and in man.

5-Hydroxytryptamine (5-HT) effects on the insulin secretion of anaesthetized dogs and of humans were studied. From our investigations the following conclusions can be drawn: 5-HT when injected at a dose of 4.30 mg into the pancreatic artery, elicits a sharp rise of insulin concentration in pancreatico-duodenal vein; on the contrary, 21.50 mg of 5-HT is unable to modify insulin release. The infusion in fasting man of small amounts of 5-HT (∼ 0.50 μg/kg/min) during 1 h, does not alter blood glucose nor plasma insulin levels; a similar infusion, however, increases insulin response after oral glucose load. The results obtained in dogs are in agreement with the idea that 5-HT may modulate insulin release from the pancreas. The results in man suggest that enteramine released by the intestine may increase insulin secretion induced by the ingestion of glucose, through a fine interplay with other gut-factors.

Effect of exogenous bonito insulin on endogenous insulin secretion in dogs.

The secretion of endogenous insulin was investigated through the effect of the infused exogenous bonito insulin on dogs. The systemic infusion of small doses of exogenous bonito insulin (0.3mu/kg) which proved inert on the blood sugar levels, resulted in an inhibition of endogenous insulin secretion. The prolonged infusion of exogenous bonito insulin inhibited both the basal insulin secretion and the biphasic pattern in glucose-induced insulin release. The mean level of endogenous insulin in the pancreatic vein decreased significantly (p<0.05) from 453±97μU/ml (immediately before the sustained infusion of exogenous bonito insulin) to 184±63μU/ml four hours after the start of the infusion. The calculated endogenous insulin output in the group treated with exogenous insulin also decreased significantly (p<0.05).The two phases of glucose-induced insulin secretions in the insulin treated subjects were less marked than those in the control group (p<0.05), and occurred much more rapidly than those in the control.These results suggest that the insulin secretion from the pancreas is affected by the prolonged infusion of exogenous bonito insulin.

Effects of D-glucuronolactone, L-gulonolactone and penitols on insulin secretion in dogs.

Intravenous administration of 0.4g/kg D-glucuronolactone or L-gulonolactone, the precursors of xylitol in the glucuronate-xylulose cycle, produced only small increases in plasma insulin in dogs. The plasma insulin responses were far less than those following the equivalent dose of xylitol, and are presumably explained by the concomitant small rises in plasma glucose. Infusions of ribitol, L-arabitol or D-arabitol (2mg/kg. min) into the pancreatic artery of dogs did not produce any significant increases in plasma insulin concentration in the pancreatic vein, while xylitol and glucose infused in a similar manner always stimulated insulin release. These data appear against the direct involvement of the glucuronate-xylulose cycle or the pentose phosphate pathway in the mechanism of insulin secretion. The mechanism of strong insulin-releasing effect of xylitol in dogs remains unexplained.

Glucose turnover and insulin secretion in dogs with pancreatic allografts.

The endocrine function of pancreaticoduodenal allografts was studied in six dogs and compared with that of normal animals. The grafts were able to prevent the diabetic ketosis that was observed in a control group after total pancreatectomy without following transplantation. — Systemic hyperglycaemia enhanced the insulin release from the transplanted pancreas, as measured by increased IRI levels after intravenous glucose administration. In contrast, the stimulation of insulin secretion by oral glucose loading was less than in normal dogs, while the glucose assimilation was also increased in transplanted animals.-It was speculated that the duodenum might be more susceptible to immunological damage than the pancreas, and that consequently an impairment of the resorption of glucose and of the production of intestinal factors controlling the secretion of insulin may result.-In the near future, pancreatico-duodenal transplantation does not appears to become a therapeutical alternative to the conventional treatment of diabetes mellitus in man.

Effect of bonito insulin on endogenous insulin secretion in dogs.

ARTICLESEffect of bonito insulin on endogenous insulin secretion in dogsH Sando, Y Kanazawa, and T KuzuyaH Sando, Y Kanazawa, and T KuzuyaPublished Online:01 May 1970https://doi.org/10.1152/ajplegacy.1970.218.5.1357MoreSectionsPDF (1 MB)Download PDF ToolsExport citationAdd to favoritesGet permissionsTrack citations ShareShare onFacebookTwitterLinkedInWeChat Previous Back to Top Next Download PDF FiguresReferencesRelatedInformation Cited ByThe endogenous insulin secretion was suppressed during insulin therapy in NIDDM patientsDiabetes Research and Clinical Practice, Vol. 9, No. 2Failure of human insulin to influence endogenous basal insulin secretion in mild diabeticsMetabolism, Vol. 36, No. 4Failure of insulin infusion during euglycemia to influence endogenous basal insulin secretionMetabolism, Vol. 32, No. 6In vitro effect of exogenous insulin on insulin secretion. Studies with glucose, leucine, arginine, aminophylline and tolbutamideActa Diabetologica Latina, Vol. 19, No. 4Feedback Inhibition of Insulin Secretion by Insulin: Relation to the Hyperinsulinemia of ObesityNew England Journal of Medicine, Vol. 306, No. 20Increase in insulin response after treatment of overt maturity-onset diabetes is independent of the mode of treatmentDiabetologia, Vol. 18, No. 1Inhibitory action of rat insulin and synthetic rat C-peptide on insulin secretion in the perfused rat pancreasActa Diabetologica Latina, Vol. 14, No. 5-6Untersuchungen zur Frage einer Autoregulation der InsulinsekretionKlinische Wochenschrift, Vol. 55, No. 10Glucose control of basal insulin secretion in diabetesDiabetologia, Vol. 13, No. 2Electrophysiological evidence for the autoregulation of β-cell secretion by insulinBiochimica et Biophysica Acta (BBA) - General Subjects, Vol. 497, No. 2Suppression of basal insulin secretion by adrenalin in normal man and in patients with insulinomasDiabetologia, Vol. 13, No. 1Die Sekretion des Insulins. Stimulierung und HemmungThe autoregulation of insulin secretion in the isolated pancreatic islets of lean (obOb) and obese-hyperglycemic (obob) miceDiabetologia, Vol. 10, No. 4SUPPRESSION OF INSULIN RELEASE BY FISH-INSULIN-INDUCED HYPOGLYCÆMIA WITH REFERENCE TO THE DIAGNOSIS OF INSULINOMASThe Lancet, Vol. 301, No. 7818 More from this issue > Volume 218Issue 5May 1970Pages 1357-1362 Copyright & PermissionsCopyright © 1970 by American Physiological Societyhttps://doi.org/10.1152/ajplegacy.1970.218.5.1357PubMed5438261History Published online 1 May 1970 Published in print 1 May 1970 Metrics