Differential glycemic effects of morphine in diabetic and normal mice

C57BL/6J ob/ob mice, C57BL/6J+/? lean mice and A/J mice were given injections of 10 mg/kg of morphine or an equal volume of saline, and then blood was sampled by retroorbital sinus puncture. In addition, animals from each strain were exposed to a brief experimental stress ten minutes after the administration of morphine or saline. While morphine produced significant increases in serum glucose in albino mice, morphine lowered blood insulin in both C57BL/6J ob/ob and C57BL/6J+/? mice. Morphine significantly lowered blood insulin in A/J mice, but effects in C57BL/6J mice were not significant. In contrast, morphine attenuated blood glucose and insulin during stress in C57BL/6J ob/ob but did not significantly affect either glucose or insulin during stress in lean C57BL/6J or A/J mice. These results are interpreted in the light of other data suggesting that endogenous opiates modulate the effects of sympathetic nervous system activity in type II diabetes.     

Age-related changes in lipid and carbohydrate metabolism of the genetically obese mouse

Obese mice (C57BL/6J ob/ob) and their lean controls were studied longitudinally from immediately post-weaning until 62 wk of age, at which time the experiment was terminated. The dynamic nature of the metabolic aberrations of the obese mouse syndrome was clearly demonstrated. Obese mice were hyperinsulinemic at all ages yet the concentration of glucose in plasma was elevated only at 5-20 wk and 63 wk of age, but was similar to that of lean mice at 20-60 wk of age. Triacylglycerols accumulated in the liver of obese mice between 5 and 18 wk of age to a level that was 20-fold greater than that found in the age-matched lean control. A decreased concentration of DNA/g of liver was also found in 5-18 wk-old obese mice, indicative of an enlarged hepatocyte. With the exception of 5-wk-old animals, total DNA per liver was increased in obese mice when compared to the lean control throughout the profile. Following the peak in 18-wk-old mice, the hepatic content of triacylglycerols precipitously fell so that at 45 wk of age its concentration in obese mice was similar to that of the lean control. Plasma free fatty acid levels as well as liver glycogen content were comparable in obese mice and their lean controls throughout the profile. In obese mice older than 45 wk of age, the content of triacylglycerols in plasma was significantly lower than that of the age-matched lean control while an accumulation of liver triacylglycerols was again found in obese mice. Myocardial triacylglycerols were elevated in obese mice when compared to the lean control at all ages. The longitudinal metabolic profile of the obese mouse developed in the present study clearly demonstrates the dynamic nature of the deviations in carbohydrate and lipid metabolism in this animal model of human obesity and insulin resistance.     

Effects of streptozotocin on glucose metabolism, insulin response, and adiposity in ob/ob mice.

To determine whether hyperglycemia in the obese hyperglycemic (ob/ob) mouse is related to enhanced activity of the pancreatic beta cell, streptozotocin (175 mg/kg) was injected into lean and ob/ob mice at 8 wk of age. The influence of this injection upon glucose metabolism, adipose cellularity, pancreatic morphology and immunoreactive insulin (IRI) release from isolated pancreatic islets was measured. The plasma glucose levels before and after an oral glucose load were elevated in lean and decreased in ob/ob mice 2 wk after treatment with streptozotocin. By 5 wk after this treatment, a reduced pancreatic islet size, beta cell number and a decreased pancreatic islet IRI release were present in both lean and ob/ob mice. At this time, plasma glucose was still elevated in lean, but depressed in ob/ob mice and the insulin responsiveness in muscle and adipocytes was unchanged. Hyperglycemia abates in the ob/ob mouse as hypersecretion of insulin is diminished, but these observations may not be directly related, since streptozotocin affects key metabolic activities of the livers as well as the pancreatic beta cell. The progression of obesity and status of adipose cellularity are not directly related to hyper-insulinemia, since they are not altered following streptozotocin treatment.     

Effects of an alpha 2-adrenoceptor antagonist on glucose tolerance in the genetically obese mouse (C57BL/6J ob/ob)

This study examines the effects of a relatively selective alpha 2-adrenoceptor antagonist, 8-(L-piperazinyl)imado-[1,2-alpha] pyrazine (compound A), and the preferential alpha 2-agonist clonidine on blood glucose, glucose tolerance, and plasma insulin levels in the C57BL/6J ob/ob mouse and its lean littermate. While clonidine raised blood glucose levels and impaired glucose tolerance, oral administration of compound A resulted in decreased blood glucose levels, as well as improved glucose tolerance in ob/ob mice. Insulin levels in ob/ob mice treated with clonidine were significantly reduced, while compound A raised insulin levels threefold and blocked the effects of clonidine when co-administered to the same animals. Clonidine-induced hyperglycemia in lean littermates was not accompanied by a decrease in insulin levels, while a small but significant increase in insulin levels was observed by compound A administration. Glycogen synthesis in diaphragm of ob/ob mice was enhanced after oral administration of compound A and was accompanied by an increase in plasma insulin levels. Concomitant treatment with a potent somatostatin analog to inhibit insulin release blocked the effects of the alpha 2-adrenoceptor antagonist, compound A. These observations suggest that the alpha 2-antagonist studied, increased plasma insulin levels with an accompanying reduction in blood glucose and an improvement in glucose tolerance in a genetic model of insulin resistance. Differential sensitivity to alpha 2-agonist in these genetically obese mice, ob/ob, was demonstrated by decreased insulin levels due to clonidine administration.     

The effects of exercise and food restriction on obesity and diabetes in young ob/ob mice

Hormone levels and body composition were examined in six-week-old C57BL/6J ob/ob mice following 25 d of limited caloric intake, voluntary exercise, or combined treatment. Pair-feeding obese mice to the daily intakes of lean mice reduced body weight gain, skeletal growth and lean body mass. Although weight gain was the same in the two phenotypes, ob/ob mice had fourfold higher rates of fat deposition. When exercise was combined with pair-feeding, skeletal and lean body growth were reduced even further and weight gain was now less than ad libitum-fed lean controls. Carcass fat accretion, however, continued to be two to three times greater. No single treatment reversed the hyperglycemia or elevated hormone production of obese mice, although slightly lower values of glucose, insulin, glucagon and corticosterone were associated with pair-feeding. When diet was combined with exercise, fasting glycemia and glucagonemia were reduced to equal the values of lean mice but insulin and corticosterone levels remained elevated. The present results show that dieted and exercised ob/ob mice continue to exhibit very high rates of fat deposition even though skeletal and lean growth are severely limited. Since fat accretion is maintained under these conditions, it appears that obese mice are not just storing excess calories as fat, but are actively regulating body fat content to levels about 30 percent higher than lean mice.     

Pancreatic islets of obese hyperglycemic mice (ob/ob).

The development of the obesity-associated hyperglycemic syndrome in ob/ob mice, genetically determined, was observed over time by a combined functional and structural study of pancreatic islets. Islet areas increased with advancing age in ob/ob mice from 2 times at 1 month to 30 times at 6 months of age the size of lean mouse islets. Islet areas apparently increased more than pancreatic insulin content in ob/ob mice. Glucose and insulin tolerance tests were performed to study in vivo responses to glucose and insulin, respectively, in 1-, 3-, and 6-month-old mice. With ob/ob mice, glucose tolerance tests revealed more elevation of plasma glucose than in lean mice, the lean mice revealing more elevated plasma insulin than the obese mice. In insulin tolerance tests, lean mice presented marked hypoglycemia, whereas ob/ob mice revealed slightly higher plasma glucose at 1 month of age but three to four times higher amounts than that of lean mice at 6 months of age. Thus, increasing insulin resistance in ob/ob mice older than 3 months is associated with progressively increasing islet area, which contains proportionally less insulin than that of lean mouse pancreas. The data suggest that insulin resistance in ob/ob mice progressively develops up to 6 months of age and that marked islet hyperplasia is likely in response to sustained hyperglycemia, leading to hyperinsulinemia and eventual marked obesity.     

Changes in glycemia by leptin administration or high- fat feeding in rodent models of obesity/type 2 diabetes suggest a link between resistin expression and control of glucose homeostasis

Resistin is an adipose-derived hormone that has been proposed as a link among obesity, insulin resistance, and diabetes. In agreement with a role of resistin in insulin resistance, the administration of recombinant resistin led to glucose intolerance in mice and impaired insulin action in rat liver. However, the regulation of resistin expression by physiological conditions, hormones, or agents known to modulate insulin sensitivity does not always support the association between resistin and obesity-induced insulin resistance. In the present study we investigated the effects of leptin administration on adipose resistin expression in insulin-resistant and obese ob/ob mice. We show that the expression of resistin mRNA and protein in adipose tissue is lower in ob/ob than in wild-type control mice, in agreement with the reduced adipocyte resistin mRNA level reported in several models of obesity. Leptin administration in ob/ob mice resulted in improvement of insulin sensitivity concomitant with a decrease in resistin gene expression. The lack of effect of leptin on resistin in db/db mice indicated that the leptin inhibitory action on resistin expression requires the long leptin receptor isoform. In addition, we demonstrated that the effect of leptin on resistin expression was centrally mediated. High-fat feeding in C57BL/6J wild-type mice, which is known to induce the development of obesity and insulin resistance, produced an increase in resistin expression. Interestingly, in both ob/ob and high fat-fed mice we obtained a striking positive correlation between glycemia and resistin gene expression. In conclusion, our results demonstrate that leptin decreases resistin expression and suggest that resistin may influence glucose homeostasis.     

Impairment of glucose tolerance in yellow (Avy/A) (BALB/c X VY) F-1 hybrid mice by hyperglycemic peptide(s) from human pituitary glands

A fraction of human pituitary extract containing low molecular weight peptide(s) was found to impair glucose tolerance in obese yellow (Avy/A) (BALB/c X VY) F-1 hybrid female mice. In these mice, purified human GH was not hyperglycemic. Glucose tolerance of untreated yellow mice was somewhat less impaired than that of untreated ob/ob mice, and priming with dexamethasone was not required to elicit impairment of glucose tolerance. The lean agouti (A/a) littermates of the yellow mice did not respond to the hyperglycemic peptide(s), suggesting that an insulin-resistant animal is required for assay of the pituitary hyperglycemic peptide(s). Plasma insulin levels of the obese yellow mice treated with the hyperglycemic peptide(s) were significantly decreased compared to those of saline-treated controls. No decrease in plasma insulin was observed in the similarly treated lean agouti mice. The study demonstrated that the yellow Avy/A (BALB/c X VY) F-1 hybrid mouse is a suitable animal for investigation of the physiological mechanism of action of the pituitary hyperglycemic peptide(s).     

Reversal of type 2 diabetes in mice by products of malaria parasites: I. Effect of inactivated parasites

C57BL/KsJ-db/db and C57BL/KsJ-ob/ob mice are good models for studies on human obesity and type 2 diabetes. We have previously shown that infection with blood-stage malaria or injection of extracts from malaria-parasitized red blood cells induces hypoglycemia in normal mice and normalizes hyperglycemia in mice made moderately diabetic by streptozotocin. In the present study, we show that a single intravenous (IV) injection of Formalin-fixed Plasmodium yoelii YM (FFYM) preparation decreases blood glucose in db/db mice from an initial value of 19 mmol/L to a normal value of 7 mmol/L (P < .0001) for at least 24 hours and reduces food intake. Plasma insulin concentrations in db/db mice were not altered. FFYM was also active in normal and ob/ob mice, an effect associated with an increase in plasma insulin. Although the rate of weight gain in lean ob/+ and lean db/+ was not altered by this treatment, there was a significant reduction in weight gain in db/db and ob/ob mice (P < .001). We suggest that malaria-derived molecules, when fully characterized, may provide structural information for the development of new agents for the management of type 2 diabetes.     

A longitudinal hormonal profile of the genetically obese mouse

Obese mice (C57BL/6J ob/ob) and their lean littermates were studied at various ages from immediately post weaning until 62 weeks of age, at which mortality increased markedly. Several age-related changes were noted. 1) Plasma glucose levels were elevated in obese mice 5-20 weeks and 62 weeks of age, but were similar to those in the lean mice at 20-60 weeks of age. Plasma insulin levels were elevated in obese mice, and there were no age-related differences. 2) Brain serotonin was elevated in obese mice at all ages and increased with age in both obese and lean animals. 3) Pituitary contents of ACTH and beta-endorphin were elevated in young obese mice and increased further as these mice approached their life expectancy. 4) The ratios of ACTH to beta-endorphin immunoreactivities were similar in obese and lean mice, except in obese mice over 50 weeks of age where this ratio was increased. We conclude that: 1) the obese mouse is characterized by hyperinsulinemia and hyperadrenocorticism throughout its life; 2) the insulin resistance of the obese mouse improves at 20 weeks of age, yet deteriorates as its life expectancy is approached; 3) the obese mouse has an elevated brain serotonin content similar to previously described elevations of the putative neurotransmitters dopamine and norepinephrine in these mice; and 4) as the obese mouse approaches its life expectancy, abnormalities may occur in the synthesis, processing, or secretion of ACTH and/or beta-endorphine.     

Effect of adrenalectomy on the metabolism of glucose in obese (C57 B1/6J ob/ob) mice

The genetically obese mouse, C57 B1/6J ob/ob, has been suggested as an appropriate model for the study of obesity associated with diabetes mellitus. Employing glucose ¹⁴C(μl) as a tracer, the data presented here indicate that obese mice are able to clear glucose from the blood compartment at the same rate as their lean littermates. This was demonstrated with or without an associated cold glucose load. The abnormal glucose tolerance curves observed in the obese animals may be a result of secretion of glucose into the blood. Removal of the adrenal glands from the obese mice and their lean littermate does not impair their ability to clear a glucose load from the vascular compartment. The capacity for endogenous glucose secretion of ob/ob mice is severely curtailed by adrenalectomy, in that the glucose tolerance curves of these adrenalectomized animals become similar to those of sham-operated lean littermates. Thus, it appears that a considerable component of the hyperglycemia in ob/ob mice reflects major adrenal involvement that is activated by stress, ie, ether anesthesia and blood sampling. The hyperglycemia in ob/ob mice may reflect glucocorticoid-dependent gluconeogenesis.     

Insulin releasing effects of adrenocorticotropin (ACTH 1-39) and ACTH fragments (1-24 and 18-39) in lean and genetically obese hyperglycaemic (ob/ob) mice

An excessive insulin releasing effect of adrenocorticotropic hormone (ACTH) and ACTH fragments has been considered as a possible factor contributing to the hyperinsulinaemia of genetically obese hyperglycaemic (ob/ob) mice. To investigate this possibility, plasma glucose and insulin responses of 11- to 14-week-old fed lean and ob/ob mice were examined after intraperitoneal administration of ACTH 1-39, ACTH 1-24 and ACTH 18-39, each at a dose of 25 nmol/mouse (50-115 micrograms/mouse). ACTH 1-39 produced a marked and rapid increase of plasma insulin in both lean and ob/ob mice, the effect being much greater in the ob/ob mutant (maximum increases of 5.5 +/- 1.5 and 46.1 +/- 4.1 ng/ml at 10 min in lean and ob/ob mice respectively, P less than 0.001). In lean mice plasma glucose concentrations showed a protracted decreased (maximum decrease of 3.7 +/- 0.5 mmol/l at 120 min), whereas glucose concentrations were increased (maximum increase of 4.2 +/- 1.3 mmol/l at 60 min) in ob/ob mice. ACTH 1-24 produced qualitatively similar but generally smaller effects than ACTH 1-39, while ACTH 18-39 did not significantly affect glucose and insulin concentrations. In 24 h fasted mice, ACTH 1-39 produced similar but generally smaller effects than in fed mice. The results suggest that the effects of ACTH on glucose and insulin homoeostasis are conferred by the N-terminal 1-24 sequence, and ACTH may exert acute effects which contribute to the hyperinsulinaemia and hyperglycaemia of ob/ob mice.     

Increased expression of hypothalamic leptin receptor and adiponectin accompany resistance to dietary-induced obesity and infertility in female C57BL/6J mice

BACKGROUND: Obesity is strongly associated with female infertility, but the mechanisms underlying this relationship are largely unknown. METHODS: We investigated the effect of increasing dietary fat percentage upon body mass, hypothalamic neuropeptide gene expression, adipose hormone secretion and fertility in females of the inbred mouse strains C57BL/6J and DBA/2J. To assess the effect of obesity independent of dietary influence, we also compared these parameters in wild-type female C57BL/6J mice to those congenic for the obesogenic mutations ob/ob and A(y)/a. RESULTS: After 24 weeks, rather than exhibiting an obese, leptin-resistant phenotype like their female DBA/2J counterparts, wild-type female C57BL/6J mice remained lean, fertile and manifested increased hypothalamic LEPR-B expression. Although both mutant genotypes were associated with obesity and subfertility, ob/ob mice demonstrated significantly increased hypothalamic LEPR-B expression, whereas A(y)/a mice had a significant reduction. Interestingly, wild-type female C57BL/6J mice were noted to manifest significantly higher and lower levels of adiponectin and tissue plasminogen activator inhibitor-1 (tPAI-1), respectively, than weight-matched wild-type female DBA/2J mice. CONCLUSIONS: We conclude that (1) resistance to the obese-infertile phenotype in female C57BL/6J mice is associated with increased hypothalamic leptin receptor expression and alterations in adipokine levels consistent with decreased adipose tissue inflammation and (2) that long-standing hyperleptinemic obesity in mice is associated with a downregulation of the hypothalamic leptin receptor.     

Antagonism of ghrelin receptor reduces food intake and body weight gain in mice

BACKGROUND AND AIMS: Ghrelin, an endogenous ligand for growth hormone secretagogue receptor (GHS-R), is an appetite stimulatory signal from the stomach with structural resemblance to motilin. We examined the effects of the gastric peptide ghrelin and GHS-R antagonists on energy balance and glycaemic control in mice. MATERIALS AND METHODS: Body weight, fat mass, glucose, insulin, and gene expression of leptin, adiponectin, and resistin in white adipose tissue (WAT) were measured after repeated administrations of ghrelin under a high fat diet. Gastric ghrelin gene expression was assessed by northern blot analysis. Energy intake and gastric emptying were measured after administration of GHS-R antagonists. Repeated administration of GHS-R antagonist was continued for six days in ob/ob obese mice. RESULTS: Ghrelin induced remarkable adiposity and worsened glycaemic control under a high fat diet. Pair feeding inhibited this effect. Ghrelin elevated leptin mRNA expression and reduced resistin mRNA expression. Gastric ghrelin mRNA expression during fasting was increased by a high fat diet. GHS-R antagonists decreased energy intake in lean mice, in mice with diet induced obesity, and in ob/ob obese mice; it also reduced the rate of gastric emptying. Repeated administration of GHS-R antagonist decreased body weight gain and improved glycaemic control in ob/ob obese mice. CONCLUSIONS: Ghrelin appears to be closely related to excess weight gain, adiposity, and insulin resistance, particularly under a high fat diet and in the dynamic stage. Gastric peptide ghrelin and GHS-R may be promising therapeutic targets not only for anorexia-cachexia but also for obesity and type 2 diabetes, which are becoming increasingly prevalent worldwide.     

Disruption of the striated muscle glycogen-targeting subunit of protein phosphatase 1: influence of the genetic background

A prediabetic phenotype of glucose intolerance, insulin resistance and obesity was observed at approximately 12 months of age in mice homozygous for a null allele of the major skeletal muscle glycogen-targeting subunit G(M) of protein phosphatase 1 (PP1) and derived from a 129/Ola donor strain. In this study, backcrossing of these G(M)-/- mice (termed obese G(M)-/- mice) onto two different genetic backgrounds gave rise to lean, glucose-tolerant, insulin-sensitive G(M)-/- mice (termed lean G(M)-/- mice), indicating that at least one variant gene in the 129/Ola background, not present in the C57BL/6 or 129s2/sV background, is required for the development of the prediabetic phenotype of obese mice. Slightly elevated AMP-activated protein kinase alpha2 activity in the skeletal muscle of lean C57BL/6 mice was also observed to a lesser extent in the obese G(M)-/- mice. Normal or slightly raised in vivo glucose transport in lean C57BL/6 G(M)-/- mice compared with decreased glucose transport in the obese G(M)-/- mice supports the tenet that adequate transport of glucose may be a key factor in preventing the development of the prediabetic phenotype. The pH 6.8/pH 8.6 activity ratio of phosphorylase kinase was increased in lean C57BL/6 G(M)-/- mice compared with controls indicating that phosphorylase kinase is an in vivo substrate of PP1-G(M).     

Effects of adrenalectomy on the obese-hyperglycemic syndrome in mice (gene symbolob)

Summary Mice with the inherited obese-hyperglycemic syndrome (gene symbolob) and their lean litter mates were adrenalectomized and then studied for up to 30–36 weeks with regard to their body weights and the serum glucose and immunoreactive insulin level. Sham operated obese and lean mice were used as controls.-Adrenalectomy did not prevent the excessive weight gain of the obese mice. However, during the first three weeks after adrenalectomy the mean weight increase was some-what smaller than in the sham operated controls. The increase in the body weights of the lean animals was, however, not affected. The most prominent finding after adrenalectomy was a decrease of the serum levels of glucose and insulin in both obese and lean animals.-The results indicate that in the obese mice adrenalectomy decreases the pronounced insulin resistance. It is also suggested that insulin resistance may be dissociated from the development of obesity in these animals.     

Abnormal plasma glucose and insulin responses in heterozygous lean (ob/+) mice

Summary To investigate the effect of the ob gene in the heterozygous condition, plasma glucose and insulin responses of adult heterozygous lean (ob/+) mice were compared with mice of the homozygous lean (+/+) and homozygous obese (ob/ob) genotypes. The ob/+ mice consumed 24% more food than +/+ mice although body weights were similar. Plasma glucose and insulin concentrations were respectively 16% and 176% higher in ob/+ mice than +/+ mice in the freely fed state, and 44% and 88% higher during glucose tolerance tests. In 24 hour fasted ob/+ mice, plasma glucose concentrations were 23% higher than +/+ mice but plasma insulin concentrations were not significantly different. Arginine produced a greater insulin response (172%) and a greater fall in glycaemia (200%) in ob/ + mice. A significant difference in the hypoglycaemic effect of insulin in ob/+ and +/+ mice was not observed. These results demonstrate an effect of the ob gene on glucose homeostasis in heterozygous lean (ob/+) mice. The abnormalities were qualitatively similar but considerably less severe than those in ob/ob mice, suggesting that ob/+ mice might prove useful to study factors predisposing to inappropriate hyperglycaemia.     

Urinary organic acid profiles in obese (ob/ob) mice: indications for the impaired omega-oxidation of fatty acids.

As a means of generating an hypothesis to explain genetic obesity of the C57BL/6J ob/ob mouse, we used gas chromatography-mass spectrometry to compare the urinary organic acid profiles of obese (ob/ob) and lean (+/?) mice on both a chow and a chemically simplified diet. More than 60 peaks were found and quantified; 45 peaks were identified. No acid was excreted in greater amounts by lean mice and none was excreted exclusively by either lean or obese mice. When normalized to body weight (obese mice being 40% heavier) and to creatinine excretion (30% greater in obese mice), however, only the daily excretion of malate, 2-hydroxyglutarate, aconitate, 3-hydroxy-3-methylglutarate, oxalate, ethylmalonate, and 4-hydroxyphenylacetate were significantly greater in obese mice. When allowed to eat only an all-fat (Crisco) diet for 4 days, the excretion of adipate rose 10-fold in lean mice, but only threefold in obese mice. Adipate excretion by Zucker rats also increased on the Crisco diet, but was indistinguishable between lean and fatty rats, suggesting that omega-oxidation might be impaired in obese mice but not in fatty rats. This suggestion complements an earlier proposal that a comparative increase in ethylmalonate excretion, which was also characteristic of fatty Zucker rats, might be explained by an increased concentration of butyryl-CoA due to inadequate beta-oxidation. An impairment of omega-oxidation in the obese mouse may also explain why urinary 3-hydroxy-3-methylglutarate, which is derived from short chain products of beta-oxidation, is increased in obese mice but not in fatty rats.(ABSTRACT TRUNCATED AT 250 WORDS)     

In vitro studies on insulin secretion in the genetically obese mouse

Summary Pancreatic insulin content and insulin secretion, from the pancreas of obese mice fed ad lib (ob/ob), obese mice maintained on a restricted diet (ob/ob RD) and lean mice has been studied using incubated pieces of pancreas in vitro and in a perifusion system. The ob/ob mice pancreas contained approximately twice as much insulin as the lean mice pancreas, whereas the ob/ob RD mice had a normal insulin content. Increasing the glucose concentration had a marked and prolonged stimulating effect on insulin secretion in the pancreas of the ob/ob and ob/ob RD mouse, but not in the lean mouse. Leucine stimulated insulin secretion in all three groups of animals both in the absence and presence of glucose in a biphasic manner; in the presence of glucose the insulin secreted from the pancreas of the ob/ob and ob/ob RD mice was abnormally high. Arginine stimulated insulin secretion from the lean mouse pancreas in the absence of glucose, whereas in the obese mouse pancreas stimulation was observed only in the presence of glucose, and the effect increased with increasing glucose concentration. The large amounts of insulin which can be secreted by the pancreas of the ob/ob and ob/ob RD mice under stimulation suggest that an abnormal response of the pancreas to biological stimuli of insulin secretion could be a primary defect in these animals.     

Islet amyloid polypeptide and insulin relationship in a longitudinal study of the genetically obese (ob/ob) mouse

Obese mice (Ume? ob/ob) and their lean litter-mates were investigated from 7 to 52 weeks of age with respect to the plasma concentration of islet amyloid polypeptide (IAPP) and insulin. Plasma levels of IAPP were highly elevated in the ob/ob mice and remained unchanged until age 33 weeks, after which a sudden significant increase occurred at age 40 weeks. The plasma concentration of insulin gradually increased from start to end and reached extremely high levels. In the lean mice, there were no age-related differences in plasma levels of IAPP and insulin, being of the same magnitude as in normal NMRI mice. The plasma IAPP/insulin molar ratio was similar in lean and obese mice until age 14 weeks. At 21 weeks, the ratio in the ob/ob mice had decreased dramatically and remained markedly (sixfold) lower than in the lean mice until the end of the study. The IAPP concentration in the pancreata of 21-week-old ob/ob mice was 25-fold higher than that in the lean mice. Immunohistochemically, a majority of the ob/ob mice displayed enlarged and more numerous pancreatic islets, compared with the lean mice, and the IAPP- and insulin-labeling intensity was equal for all animals. At the electron-microscopic level, there was an increase in the number of IAPP- and insulin-immunoreactive gold particles per whole granule area as well as per core granule area. We conclude that the dramatically increased IAPP levels in severely hyperinsulinemic ob/ob mice may be of importance for the development of insulin resistance. Further, the disproportionate secretion of IAPP and insulin in the adult obese mouse might indicate a disturbed negative feedback effect of IAPP on insulin secretory mechanisms, resulting in very high plasma insulin levels.