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PubMed2004

Impaired pancreatic growth, beta cell mass, and beta cell function in E2F1 (-/- )mice.

We evaluated the effects of E2F1 on glucose homeostasis using E2F1(-/-) mice. E2F1(-/-) mice show an overall reduction in pancreatic size as the result of impaired postnatal pancreatic growth. Furthermore, these animals have dysfunctional beta cells, linked to impaired PDX-1 activity. Because of the disproportionate small pancreas and dysfunctional islets, E2F1(-/-) mice secrete insufficient amounts of insulin in response to a glucose load, resulting in glucose intolerance. Despite this glucose intolerance, E2F1(-/-) mice do not develop overt diabetes mellitus because they have insulin hypersensitivity, which is secondary to a diminished adipose tissue mass and altered adipocytokine levels, which compensates for the defect in insulin secretion. These data demonstrate that factors controlling cell proliferation, such as E2F1, determine pancreatic growth and function, subsequently affecting metabolic homeostasis.

Adaptor Proteins, Signal Transducing↗
PubMed1986

Renin secretion by the spontaneously diabetic rat.

Renal function studies and measurements of in vivo plasma renin activity (PRA), kidney renin content, and renin secretion by isolated, perfused kidneys were performed in spontaneously diabetic and nondiabetic BioBreeding/Worcester (BB/W) rats. Diabetic animals evidenced hyperglycemia, glycosuria, and plasma volume expansion. After dietary sodium deprivation, plasma volume fell to levels equivalent to those of sodium-deprived, nondiabetic rats. Dietary sodium deprivation evoked a larger proportional increase in PRA among diabetic than nondiabetic animals, although PRA before sodium restriction was equivalent in the two groups. Basal renin release (RR) was higher from isolated, perfused kidneys from diabetic rats than from nondiabetic kidneys. Diabetic kidneys, moreover, displayed increased kidney renin content (KRC). By contrast, while isoproterenol (10(-5) M) stimulated a nearly fivefold increment in RR from nondiabetic, perfused kidneys, a negligible effect was observed in diabetic kidneys. The dose-response curve of renin secretion (as a proportion of total renal content) in response to isoproterenol was shifted downward. Hence, while KRC and spontaneous RR by isolated, perfused kidneys were increased, the increment in PRA with salt depletion and the renin-secretory response to isoproterenol in vitro were impaired. We propose that specific defects in renin secretion, in particular, the response to beta-adrenergic stimulation, may be operative in diabetes.

Animals↗
PubMed2001

Retinopathy of Great Pyrenees dogs: fluorescein angiography, light microscopy and transmitting and scanning electron microscopy.

OBJECTIVE: Investigation of the pathogenesis of Great Pyrenees retinopathy. ANIMALS: One male and two female puppies of parents who were affected with Great Pyrenees retinopathy and one 4-year-old affected adult male Great Pyrenees dog. PROCEDURE: The puppies were examined daily from 7 weeks of age by indirect ophthalmoscopy and their fundi were photographed until the lesions were static. Fluorescein angiography was completed at 7 weeks of age, within 24 h of detection of ophthalmoscopic lesions, and then weekly. The eyes of a 4-year-old and two 20-week-old puppies were examined with light microscopy, and transmitting and scanning electron microscopy. RESULTS: Blocked choroidal fluorescence was detected at 7 weeks of age. The blocked fluorescence enlarged, when the characteristic serous retinal detachments developed at 11 weeks of age. The detachments enlarged in size and number until the puppies were approximately 20 weeks old. Fluorescein pooling confirmed the presence of transient retinal pigment epithelial detachments. Leakage of dye into serous retinal detachments was not detected in this study. Light microscopy and transmitting and scanning electron microscopy confirmed the presence of multifocal serous retinal detachments with focal retinal degeneration that extended to the inner nuclear layer in a 4-year-old dog. The retinal detachments were accompanied by hypertrophy, hyperplasia, increased pigmentation, and vacuolation of the retinal pigment epithelium. CONCLUSIONS AND CLINICAL RELEVANCE: Great Pyrenees retinopathy is manifested by multifocal serous retinal and retinal pigment epithelial detachments. These detachments are similar to those noted with central serous retinopathy of humans. The sudden development of multifocal retinal and retinal pigment epithelial detachments, and the serous nature of these detachments, supports a theory that they develop secondary to focal secretion and absorption defects in retinal pigment epithelial cells. Given the age of the puppies when the blocked choroidal fluorescence was noted and maturation of the dog retina at 8 weeks postpartum, this retinopathy is considered to be a retinal pigment epithelial dysplasia. This unique inherited retinopathy offers an opportunity to study retinal pigment epithelial secretion.

Animals↗
PubMed1997

PlcR1 and PlcR2 are putative calcium-binding proteins required for secretion of the hemolytic phospholipase C of Pseudomonas aeruginosa.

The plcHR operon of Pseudomonas aeruginosa includes the structural gene for the hemolytic phospholipase C,plcH (previously known as plcS), and two overlapping, in-phase, genes designated plcR1 and plcR2. Hemolytic and phospholipase C (PLC) activities produced by Escherichia coli and P. aeruginosa T7 expression systems were measured in strains carrying both plcH and plcR genes and in strains carrying each gene separately. When plcH was expressed by itself in the E. coli T7 system, the area of the hemolytic zone on blood agar was less than twice the area of growth. By contrast, when plcR was coexpressed with plcH in this system, the area of the hemolytic zone was approximately 10 times that of the area of the growth on blood agar. Native polyacrylamide gel electrophoretic analyses of PlcH activity expressed in either the E. coli or the P. aeruginosa T7 system carrying plcH alone, or along with the plcR genes, suggest that PlcR either posttranslationally alters the physical or biochemical nature of PlcH or releases PlcH from a complex in the cell so that it can be secreted. The hypothesis that PlcR is involved in the secretion of PlcH is supported by the observation that the ratio of extracellular to cell-associated PlcH activity produced by P. aeruginosa strains containing an in-frame deletion in the chromosomal plcR genes is significantly reduced in comparison with this ratio seen with the wild-type parental strain. This defect in the secretion of PlcH can be complemented by the plcR genes in trans. Additional data suggest that PlcR does not directly affect the secretion of the nonhemolytic phospholipase C (PlcN). PlcR is highly similar to a calcium-binding protein (CAB) from Streptomyces erythraeus. PlcR and CAB contain typical motifs (EF hands) characteristic of eucaryotic calcium-binding proteins, including calmodulin. P. aeruginosa naturally produces membrane vesicles (MVs) containing extracellular proteins including PLC. MVs from the PAO1WT strain contained at least 10-fold more PLC specific activity than those isolated from a strain carrying a deletion of plcR (PAO1 deltaR). Immunogold electron microscopy of PAO1WT and PAO1 deltaR whole cells revealed a distribution of PlcH in these strains consistent with the hypothesis that PlcR is required for the secretion of PlcH.

Calcium-Binding Proteins↗
PubMed1995

Insulin secretion, insulin action, and hepatic glucose production in identical twins discordant for non-insulin-dependent diabetes mellitus.

12 identical twin pairs discordant for non-insulin-dependent diabetes mellitus (NIDDM) were studied for insulin sensitivity (euglycemic insulin clamp, 40 mU/m2 per min), hepatic glucose production (HGP, [3-3H]glucose infusion), and insulin secretion (oral glucose tolerance test and hyperglycemic [12 mM] clamp, including glucagon administration). Five of the nondiabetic twins had normal and seven had impaired glucose tolerance. 13 matched, healthy subjects without a family history of diabetes were included as control subjects. The NIDDM twins were more obese compared with their non-diabetic co-twins. The nondiabetic twins were insulin resistant and had a delayed insulin and C-peptide response during oral glucose tolerance tests compared with controls. Furthermore, the nondiabetic twins had a decreased first-phase insulin response and a decreased maximal insulin secretion capacity during hyperglycemic clamping and intravenous glucagon administration. Nondiabetic twins and controls had similar rates of HGP. Compared with both nondiabetic twins and controls, the NIDDM twins had an elevated basal rate of HGP, a further decreased insulin sensitivity, and a further impaired insulin secretion pattern as determined by all tests. In conclusion, defects of both in vivo insulin secretion and insulin action are present in non- and possibly prediabetic twins who possess the necessary NIDDM susceptibility genes. However, all defects of both insulin secretion and glucose metabolism are expressed quantitatively more severely in their identical co-twins with overt NIDDM.

Age of Onset↗
PubMed2002

Molecular etiologies of MODY and other early-onset forms of diabetes.

Maturity-onset diabetes of the young (MODY) are monogenic forms of type 2 diabetes that are characterized by an early disease onset, autosomal-dominant inheritance, and defects in insulin secretion. Genetic studies have identified mutations in at least eight genes associated with different forms of MODY. The majority of the MODY subtypes are caused by mutations in transcription factors that include hepatocyte nuclear factor (HNF)-4 alpha, HNF-1 alpha, PDX-1, HNF-1 beta, and NEURO-DI/BETA-2. In addition, genetic defects in the glucokinase gene, the glucose sensor of the pancreatic beta cells, and the insulin gene also lead to impaired glucose tolerance. Biochemical and genetic studies have demonstrated that the MODY genes are functionally related and form an integrated transcriptional network that is important for many metabolic pathways.

Age of Onset↗
PubMed1998

T cell receptor-initiated calcium release is uncoupled from capacitative calcium entry in Itk-deficient T cells.

Itk, a Tec family tyrosine kinase, plays an important but as yet undefined role in T cell receptor (TCR) signaling. Here we show that T cells from Itk-deficient mice have a TCR-proximal signaling defect, resulting in defective interleukin 2 secretion. Upon TCR stimulation, Itk-/- T cells release normal amounts of calcium from intracellular stores, but fail to open plasma membrane calcium channels. Since thapsigargin-induced store depletion triggers normal calcium entry in Itk-/- T cells, an impaired biochemical link between store depletion and channel opening is unlikely to be responsible for this defect. Biochemical studies indicate that TCR-induced inositol 1,4,5 tris-phosphate (IP3) generation and phospholipase C gamma1 tyrosine phosphorylation are substantially reduced in Itk-/- T cells. In contrast, TCR-zeta and ZAP-70 are phosphorylated normally, suggesting that Itk functions downstream of, or in parallel to, ZAP-70 to facilitate TCR-induced IP3 production. These findings support a model in which quantitative differences in cytosolic IP3 trigger distinct responses, and in which only high concentrations of IP3 trigger the influx of extracellular calcium.

Animals↗
PubMed1988

Characteristics of desensitization of insulin secretion in fully in vitro systems.

This report has investigated desensitization of pancreatic B cell secretion, or diminution of the insulin response to chronic stimulation. Freshly isolated rat islets were continuously challenged with various secretagogues over 24 h either in batch incubation or in a computer-controlled, flow-through perifusion system. At various glucose concentrations, secretion rose to a peak level in the third hour, then dropped to a new desensitized secretory level which was 25% or less than that of the maximum rate. The amount of insulin secreted was glucose dependent although secretory kinetics were independent of the amount of hormone secreted. At all glucose concentrations the reduction in islet insulin content was not great enough to account for the observed degree of desensitization. Furthermore at hour 20, islets responded vigorously to an alternate stimulus, indicating insulin stores and islet secretory machinery were still capable of being stimulated. Addition of 3-isobutyl-1-methylxanthine or forskolin did not prevent glucose-induced desensitization. Insulin secretion desensitized similarly to nonglucose (alpha-ketoisocaproic acid) and nonfuel (phorbol ester) stimuli. Glucose potentiation of a terminal KIC response, although demonstrable after 20 h of chronic glucose, was diminished somewhat compared to that after 3 h of chronic glucose. Delaying glucose stimulation by 6 h reduced insulin secretion, yet desensitization persisted. Although insulin secretion entrained to a glucose signal which oscillated from 1.3-12.7 mM in sine wave pulses of 90-min frequency, desensitization was not prevented. Thus, desensitization occurred in response to glucose, nonglucose, and nonfuel stimuli and despite delayed or oscillating signals. We conclude that exhaustion of a finite insulin compartment is not the underlying defect in desensitized secretion and suggest that metabolic feedback or recruitment of multiple heterogeneous compartments may explain this phenomenon.

1-Methyl-3-isobutylxanthine↗
PubMed2002

Monogenic forms of obesity and diabetes mellitus.

Great progress has been made in identifying several genes and in understanding the molecular pathogenesis of inherited syndromes of obesity and diabetes mellitus (DM). In humans, mutations in leptin, leptin receptor, proopiomelanocortin (POMC), melanocortin-4 receptor (MC4R) and prohormone convertase 1 (PC1) have been described in patients with severe obesity. Most of these obesity disorders, with the exception of the MC4R mutations, exhibit recessive inheritance and a distinct phenotype with varying degrees of hypothalamic dysfunction, and they unravel the critical role of the central leptin and melanocortin pathways in human appetite control and energy homeostasis. Maturity onset diabetes of the young (MODY) is a genetically and clinically heterogeneous subtype of type 2 DM with early onset autosomal dominant inheritance and a primary defect in insulin secretion. To date, six MODY genes have been identified, the glucokinase gene and five beta cell-specific transcription factor genes, hepatocyte nuclear factor-1alpha (HNF-1alpha), HNF-1beta, HNF-4alpha, insulin promoter factor-1 (IPF-1) and NeuroD1/BETA2. Mitochondrial DNA mutations cause another form of DM with an insulin secretory defect that is commonly associated with neurosensory hearing impairment, and has strict maternal inheritance. At the other end of the spectrum are the inherited syndromes of insulin resistance that are caused by mutations in the insulin receptor gene and in the adipocyte-specific transcription factor PPARgamma. The advances in our knowledge of the phenotypic manifestations and underlying molecular mechanisms of genetic syndromes of obesity and DM raise expectations for molecular diagnosis, as well as for more etiological therapies and better prevention of the continuously increasing prevalence of obesity and DM in our modern societies.

Animals↗
PubMed1987

[Growth hormone secretion following administration of growth hormone releasing hormone in constitutional short stature and idiopathic growth hormone deficiency].

A stimulation test using 1 microgram growth-hormone-releasing factor (GRF 1-29 X NH2)/kg bodyweight was performed in children with familial short stature and in children with constitutional delay of growth and development. The GH secretion induced by this means was not different in these groups, but there was a difference in the response between normal children and children with idiopathic growth hormone deficiency (GHD). GH secretion after GRF administration was significantly lower in the GHD group than in the other groups. However, 6 of 24 patients with GHD responded to the test with a normal increase in GH (greater than 10 ng/ml), and 11 with an intermediate response (2-10 ng/ml). Thus, the test does not differentiate individual patients with defective growth hormone secretion from normal short children.

Adolescent↗
PubMed2002

Knockout models are useful tools to dissect the pathophysiology and genetics of insulin resistance.

OBJECTIVE: The development of type 2 diabetes is linked to insulin resistance coupled with a failure of pancreatic beta-cells to compensate by adequate insulin secretion. DESIGN: Here, we review studies obtained from genetically engineered mice that provide novel insights into the pathophysiology of insulin resistance. RESULTS: Knockout models with monogenic impairment in insulin action have highlighted the potential role for insulin signalling molecules in insulin resistance at a tissue-specific level. Polygenic models have strengthened the idea that minor defects in insulin secretion and insulin action, when combined, can lead to diabetes, emphasizing the importance of interactions of different genetic loci in the production of diabetes. Knockout models with tissue-specific alterations in glucose or lipid metabolism have dissected the individual contributions of insulin-responsive organs to glucose homeostasis. They have demonstrated the central role of fat as an endocrine tissue in the maintenance of insulin sensitivity and the development of insulin resistance. Finally, these models have shown the potential role of impaired insulin action in pancreatic beta-cells and brain in the development of insulin deficiency and obesity.

Adipose Tissue↗
PubMed1990

Defect in the tissue cellular immune response: experimental visceral leishmaniasis in euthymic C57BL/6 ep/ep mice.

In BALB/c mice, successful defense against visceral leishmaniasis is T cell dependent, expressed by tissue granuloma formation, and probably mediated by macrophages activated by cytokines, including gamma interferon (IFN-gamma). C57BL/6 ep/ep (pale ear) mice, which reportedly exhibit impaired IFN-gamma production, were challenged with Leishmania donovani to determine the outcome of infection in a euthymic host with an apparent defect in lymphokine secretion. In BALB/c and normal C57BL/6 mice, L. donovani liver burdens peaked at 2 weeks and were largely eliminated by 4 weeks. In contrast, in pale ear mice, infection progressed until after 4 weeks and persisted at high levels at 8 weeks. The failure to resolve hepatic infections was not related to deficiencies in (i) Thy-1+, L3T4+, or Lyt-2+ T cells; (ii) IFN-gamma secretion; (iii) liver tissue Ia expression; (iv) macrophage antimicrobial capacity; or (v) antileishmanial antibody production. However, despite the anticipated influx of mononuclear cells into livers, these cells were not properly focused on the parasitized Kupffer cells, the inflammatory infiltrate receded prematurely, and mature granulomas failed to develop. These results suggest that there is a cellular immune defect at the tissue level and emphasize the critical role of granuloma formation in successful resolution of systemic intracellular infections.

Animals↗
PubMed1996

Effects of a change in the pattern of insulin delivery on carbohydrate tolerance in diabetic and nondiabetic humans in the presence of differing degrees of insulin resistance.

While it is well established that people with non-insulin dependent diabetes mellitus have defects in both insulin secretion and action, the relative contribution of each to glucose intolerance is not known. Therefore, nondiabetic (lean and obese) and non-insulin dependent diabetes mellitus subjects were studied on two occasions. On each occasion, insulin secretion was inhibited with somatostatin and glucose was infused in a pattern and amount that mimicked the systemic delivery rate normally observed after ingestion of 50 g of glucose. Insulin also was infused so as to mimic postprandial insulin profiles observed in separate groups of diabetic and nondiabetic subjects after food ingestion. Glucose turnover was measured using the isotope dilution method. A delayed pattern of insulin delivery (i.e., a "diabetic" insulin profile) led to higher (P < 0.05) glucose concentrations in all groups; however, the effects were transient, resulting in only a modest increase in the integrated glycemic responses. An isolated defect in insulin action had little effect on peak glucose concentration; however, it prolonged the duration of hyperglycemia, leading to a 2.5-4.2-fold increase (P < 0.05) in the integrated glycemic response. A combined defect in the pattern of insulin secretion and action was additive rather than synergistic. Both defects caused hyperglycemia by altering suppression of endogenous glucose release and stimulation of glucose disposal. Whereas obese diabetic and nondiabetic subjects had comparable defects in glucose clearance, non-insulin dependent diabetes mellitus subjects also had defects in hepatic insulin action. Thus, abnormalities in the pattern of insulin secretion and action alone or in combination impair glucose tolerance. An isolated defect in insulin action has a more pronounced and prolonged effect than does an isolated change in the pattern of insulin secretion. Hepatic and extrahepatic insulin resistance results in marked and sustained hyperglycemia.

Blood Glucose↗
PubMed2002

Requirement of flhA for swarming differentiation, flagellin export, and secretion of virulence-associated proteins in Bacillus thuringiensis.

Bacillus thuringiensis is being used worldwide as a biopesticide, although increasing evidence suggests that it is emerging as an opportunistic human pathogen. While phospholipases, hemolysins, and enterotoxins are claimed to be responsible for B. thuringiensis virulence, there is no direct evidence to indicate that the flagellum-driven motility plays a role in parasite-host interactions. This report describes the characterization of a mini-Tn10 mutant of B. thuringiensis that is defective in flagellum filament assembly and in swimming and swarming motility as well as in the production of hemolysin BL and phosphatidylcholine-preferring phospholipase C. The mutant strain was determined to carry the transposon insertion in flhA, a flagellar class II gene encoding a protein of the flagellar type III export apparatus. Interestingly, the flhA mutant of B. thuringiensis synthesized flagellin but was impaired in flagellin export. Moreover, a protein similar to the anti-sigma factor FlgM that acts in regulating flagellar class III gene transcription was not detectable in B. thuringiensis, thus suggesting that the flagellar gene expression hierarchy of B. thuringiensis differs from that described for Bacillus subtilis. The flhA mutant of B. thuringiensis was also defective in the secretion of hemolysin BL and phosphatidylcholine-preferring phospholipase C, although both of these virulence factors were synthesized by the mutant. Since complementation of the mutant with a plasmid harboring the flhA gene restored swimming and swarming motility as well as secretion of toxins, the overall results indicate that motility and virulence in B. thuringiensis may be coordinately regulated by flhA, which appears to play a crucial role in the export of flagellar as well as nonflagellar proteins.

Bacillus thuringiensis↗
PubMed1991

The effects of overeating on insulin secretion in normal mice.

This study was performed to examine the effect of overeating on in vivo and in vitro insulin secretion in normal mice. Six week old male CRJ-ICR mice were maintained on a cookie and chocolate mashed diet (C.C. diet) until 30 weeks of age; control mice received an ordinary mouse chow. The mice on the C.C. diet (C.C. mice) consumed 125-130% of the daily caloric intake of control mice throughout the study. C.C. mice developed mild hyperglycemia with relative obesity from 16 weeks of age. Fed blood glucose levels at 30 weeks of age for C.C. mice were 158.3 +/- 6.7 mg/dl as opposed to 127.2 +/- 3.1 mg/dl for controls (p less than 0.01). In experimental mice at 18 weeks of age, plasma insulin response after intraperitoneal glucose load (2 mg/g BW) and insulin secretion at 30 mM glucose from the perfused pancreas were similar to those in control mice. However, at 30 weeks of age, insulin secretion at 30 mM glucose from perfused pancreas in C.C. mice was significantly suppressed compared with that of control mice (p less than 0.02). Conversely, in vivo insulin secretory response to intraperitoneal glucose load was significantly increased in C.C. mice (p less than 0.05). There were no differences in insulin secretion at 15 mM glucose from perfused pancreas. These results indicate that impairment of beta-cell secretory capacity develops in impaired glucose tolerant mice with obesity, while in vivo studies show a high insulin response to glucose. This alteration of beta-cell function may be the initial change during the development of the hyperglycemia-induced defect in insulin secretion.

Aging↗
PubMed2002

[Nature history and genetics of type 2 diabetes].

The nature history of type 2 diabetes is characterized by the interaction between beta-cells function and insulin sensitivity. Normal glucose tolerance could be maintained when there is a balance between insulin sensitivity and beta-cells function. For most of type 2 diabetic patients, both defects in insulin secretion as well as insulin action are needed for the development of diabetes. In addition, there is abundant evidence indicating the importance of genetic factors in the development of type 2 diabetes, including data from the twin studies, family studies, studies among different ethnic groups living in the same environment and admixture studies. In the last two decades, that genetic defects affecting both beta-cells function and insulin sensitivity has been identified. But those defects can only explain a very small portion of etiology of type 2 diabetes, and the gene defects contributing to the cause of most type 2 diabetes are still at large. We have learned, from the past experience that type 2 diabetes is a very heterogeneous and complex disease. The complexity of type 2 diabetes is related to factors such as genetic heterogeneity, interactions between genes, and the modulating role played by the environment.

Animals↗
PubMed1998

Genetic, metabolic and clinical characteristics of maturity onset diabetes of the young.

Maturity onset diabetes of the young (MODY) is a genetically and clinically heterogeneous subtype of non-insulin-dependent diabetes mellitus (NIDDM) characterised by early onset, autosomal dominant inheritance and a primary defect in insulin secretion. To date, three MODY genes have been identified on chromosomes 20q (MODY1/hepatic nuclear factor (HNF)-4alpha), 7p (MODY2/glucokinase) and 12q (MODY3/HNF-1alpha). Mutations in MODY2/glucokinase result in mild chronic hyperglycaemia as a result of reduced pancreatic beta-cell responsiveness to glucose, and decreased net accumulation of hepatic glycogen and increased hepatic gluconeogenesis after meals. In contrast, MODY1 and MODY3 are characterised by severe insulin secretory defects, and by major hyperglycaemia associated with microvascular complications. The role of the three known MODY genes in susceptibility to the more common late-onset NIDDM remain uncertain. Genetic studies seem to exclude a role as major susceptibility genes, but leave unresolved whether they may have a minor role in a polygenic context or an important role in particular populations.

Adolescent↗
PubMed1980

Depression of leucine and isoproterenol induced insulin secretions in the spontaneously diabetic New Zealand white rabbit.

Rabbits were studied from a closed colony of NZW rabbits which exhibits a 19% occurrance of spontaneous diabetes mellitus. Six overtly diabetic rabbits and eight rabbits with normal glucose disposal were tested with intravenous glucose challenge (500 mg/kg), L-leucine administration (125 mg/kg), and 30 minute infusions with isoproterenol (10 microgram/kg/min.). These agents were shown to be ineffective insulin secretogogues in the overtly diabetic group when compared to the highly significant IRI response observed in colony rabbits with normal glucose disposal. The data indicate that the defect in IRI secretion observed in the spontaneously diabetic NZW rabbits is not confined to stimulation by glucose, but represents an abnormal IRI release mechanism which appears to lack secretogogue specificity.

Animals↗