Plasma glucagon responses to insulin-induced hypoglycemia and arginine in spontaneous non-insulin-dependent diabetes mellitus (NIDDM) rats, Otsuka Long Evans Tokushima Fatty (OLETF) strain

Abstract

Plasma glucagon responses to insulin-induced hypoglycemia and arginine in spontaneous non-insulin-dependent diabetes mellitus (NIDDM) rats, Otsuka Long Evans Tokushima Fatty (OLETF) strain. Acta Endocrinol 1993;129:585-93. ISSN 0001-5598Pancreatic A-cell function in the newly developed Otsuka Long Evans Tokushima Fatty (OLETF) strain of non-insulin-dependent diabetes mellitus (NIDDM) rats was examined in relation to the morphological changes in their islets and the plasma glucagon responses to insulin-induced hypoglycemia and an arginine test by chronological studies in seven male OLETF and seven male non-diabetic control Long Evans Tokushima Otsuka (LETO) rats each at 10, 16 and 24 weeks of age and eight male OLETF rats that were placed in a cage with a wheel for exercising from 5 to 24 weeks of age. The hormonal contents and morphological features of the pancreas of these rats were examined. After iv injection of insulin, the plasma glucagon level rose significantly from the basal level in OLETF rats at 10 weeks old, but little if at all in those of 16 and 24 weeks old. The pancreatic A cells of LETO rats of all age groups responded equally well to glucopenia. The areas under the response curves of plasma glucagon (\ m=sum\ \ g=D\ I RG)during the 90 min of insulin-induced hypoglycemia were 14496\m=+-\7860vs 9588\m=+-\3930,2257\m=+-\3018vs 9235\m=+-\5447(p<0.05) and 826\m=+-\985vs 9707\m=+-\2510(p<0.01) ng\m=.\mi n\m=-\1\m=.\l \m=-\1 in OLETF rats vs LETO rats of 10, 16 and 24 weeks old, respectively. The plasma glucagon responses during the arginine test were higher in OLETF rats than in LETO rats at 10 and 16 weeks but not at 24 weeks of age. Exercise-trained OLETF rats of 24 weeks old had normal ability to secrete glucagon from the pancreas in response to glycopenia (\m=sum\\g=D\IRG:8645 \m=+-\2467 ng\m=.\min \ m= -\ 1 \ m=. \ l \ m=-\ 1) . There were no significant differences in the insulin and glucagon contents of the pancreas of young and old OLETF rats. Morphological studies on the pancreas of sedentary OLETF rats of 24 weeks old revealed enlarged, multilobulate, fibrotic islets in which A cells did not occupy a peripheral position but were widely dispersed, whereas in sections of the islets from exercise-trained rats the microstructure and locations of A and B cells appeared normal. These results demonstrated that the pancreatic A-cell response to glucopenia was impaired in old sedentary OLETF rats, probably due to an abnormal A-cell-B-cell morphofunctional relationship.The normal A-cell response to changes in glucose concentration is known to be lost in type I diabetes, i.e. the glucagon response to insulin-induced hypoglycemia and the suppression of glucagon secretion by hyperglycemia (1). However, the exact mechanism responsible for this defect is still unknown because of conflicting results and an inadequate understanding of the mechan¬ isms of the A-cell response to fluctuations of glucose concentration in non-diabetic islets. Previous studies have suggested several possible mechanisms ofthe A-cell...

The cholecystokinin-A receptor mediates inhibition of food intake yet is not essential for the maintenance of body weight

“…Comparison between the CCK-AR -/-mice and the OLETF rats reveals several important differences. The OLETF rats have increased body weight, are prone to diabetes mellitus, and develop pancreatic islet fibrosis with age relative to wild-type strains (31,(44)(45)(46). In contrast, we have shown that the CCK-AR -/-mice maintain normal weight, normal blood glucose levels, and have pancreatic islet morphology that is indistinguishable from wild-type controls.…”

“…of central mediators (e.g., serotonin, neuropeptide Y, orexins, corticotropin-releasing hormone), as well as a number of peripheral peptides (e.g., leptin, gastrin-releasing peptide, and glucagon-like peptide 1) (54,55,(57)(58)(59). A line of rats, Otsuka Long-Evans Tokushima Fatty (OLETF), which was initially developed as a model of non-insulin-dependent diabetes mellitus (31,44), has recently been shown to lack CCK-A receptors because of a spontaneous deletion in the corresponding receptor gene (29,30). Comparison between the CCK-AR -/-mice and the OLETF rats reveals several important differences.…”

“…Additional studies were performed to determine whether abnormalities in pancreatic morphology (i.e., islet fibrosis), which have been observed in OLETF rats (31,(44)(45)(46), are also present in CCK-AR -/-mice. Representative pancreatic sections from CCK-AR -/-and wild-type mice, ranging in age between 7 and 17 weeks, are compared in Fig.…”

Downregulation of the skeletal muscle pyruvate dehydrogenase complex in the Otsuka Long-Evans Tokushima Fatty rat both before and after the onset of diabetes mellitus

“…Male OLETF rats own innate polyphagia with rapid body weight gain and accumulation of intra-abdominal fats, leading to the development of hyperlipidemia and insulin resistance from twelve weeks of age (Kawano et al, 1992;Sato et al, 1995). The cumulative incidence of diabetes in male OLETF rats reaches 80-100% at twenty-four weeks of age (Ishida et al, 1993).…”

Histopathological and biochemical studies on pancreatic fibrosis in WBN/Kob rats

“…WBN/Kob rats [15,23], OLETF rats [4], and Aly mice [14] are known to develop pancreatitis spontaneously, and experimental pancreatitis can be induced by ethanol feeding [24] or arginine injection [6] in rats or mice. These conditions have thus been utilized as models for human pancreatitis.…”