Beta-islet cell tumors of the pancreas: results of a study on 1,067 cases.
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Pyruvate carboxylase (PC) activity is enhanced in the islets of obese rats, but it is reduced in the islets of type 2 diabetic rats, suggesting the importance of PC in beta-cell adaptation to insulin resistance as well as the possibility that PC reduction might lead to hyperglycemia. However, the causality is currently unknown. We used obese Agouti mice (AyL) as a model to show enhanced beta-cell adaptation, and type 2 diabetic db/db mice as a model to show severe beta-cell failure. After comparison of the two models, a less severe type 2 diabetic Agouti-K (AyK) mouse model was used to show the changes in islet PC activity during the development of type 2 diabetes mellitus (T2DM). AyK mice were separated into two groups: mildly (AyK-M, blood glucose <250 mg/dl) and severely (AyK-S, blood glucose >250 mg/dl) hyperglycemic. Islet PC activity, but not protein level, was increased 1.7-fold in AyK-M mice; in AyK-S mice, islet PC activity and protein level were reduced. All other changes including insulin secretion and islet morphology in AyK-M mice were similar to those observed in AyL mice, but they were worse in AyK-S mice where these parameters closely matched those in db/db mice. In 2-day treated islets, PC activity was inhibited by high glucose but not by palmitate. Our findings suggest that islet PC might play a role in the development of T2DM where reduction of PC activity might be a consequence of mild hyperglycemia and a cause for severe hyperglycemia.
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This study was designed to delineate the nature of β-cell dysfunction in a model of genetically determined nonobese diabetes, the Goto-Kakizaki (GK) rat. Pancreatic β-cell function was analyzed immediately after weaning and 5 weeks thereafter, comparing animals with or without insulin treatment during the interval. In 3.5-week-old GK rats, fasting plasma glucose was mildly elevated with normoinsulinemia, and the islet insulin content was reduced by 33%. When incubated with 3–30 mm glucose in vitro, the GK rat islets showed reduced glucose sensitivity, i.e. the EC50 values were 19.5 and 15.9 mm, and the Hill constants for the positive cooperativity 2.1 and 4.2, in the islets of GK and the control rats, respectively. On the other hand, the maximum response to glucose was not attenuated when reduced islet insulin content was considered. In 8.5-week-old GK rats, hyperglycemia worsened and glucose-stimulated insulin release by the islets more severely impaired. A daily insulin injection from the 3.5–8.5 weeks of age significantly lowered plasma glucose in the GK rat, accompanied by a marked suppression of both basal (with 3 mm glucose) and glucose (6–30 mm)-stimulated insulin release by the islets. In the GK rat, β-cell dysfunction develops by the age of 3.5 weeks, and insulin treatment during the subsequent 5 weeks accelerates its progression.
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Pancreatic Islets
Insulin oscillation
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Thyroxine treatment induced experimental hyperthyroidism in ob/ob mice, inhibited glucose-induced insulin secretion from the isolated perfused ob/ob mouse pancreas, and reduced total pancreas insulin content. In contrast, glucose-induced insulin release from incubated pancreatic islets and insulin content of pancreatic islets from ob/ob mice isolated by freehand microdissection were not reduced after thyroxine treatment when expressed per microgram dry islet. Histological examination of the ob/ob mouse pancreas revealed islets without degenerative lesions of islet cells. Granularity of beta cells was well preserved. The average number of pancreatic islets was unchanged. However, the beta cell area was significantly decreased in relation to the total pancreatic parenchyma after thyroxine treatment. This implies that insulin release and content per pancreatic islet was half of that of the controls. ATP content of islets was slightly reduced. Glucose oxidation and glucose utilization by islets from treated mice were slightly increased. Thyroxine treatment of the animals did not abolish the stimulation of 45Ca2+ uptake by glucose, but it did suppress the potentiating effect of fasting on the stimulatory effect of glucose on 45Ca2+ uptake. The metabolic characteristics of islets from experimentally hyperthyroid mice are those of all hyperthyroid tissues. The results provide no evidence for the view that the effects of thyroxine treatment may be due to disturbed metabolic function or energy deprivation of pancreatic islets. Inhibition of insulin secretion from the pancreas after thyroxine administration is apparently due to a reduction in pancreas insulin content and a diminished pancreatic islet volume. Reduced pancreatic islet volume represents most probably a reduction of individual islet cell volume.
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Changes in Somatostatin Concentration in Pancreas and Other Tissues of Streptozotocin Diabetic Rats*
Changes in immunoreactive somatostatin were examined in islets, whole pancreas, stomach, and hypothalamus of streptozotocin-diabetic rats. There was no change in islet somatostatin content at 2 days after the administration of streptozotocin, but thereafter, somatostatin progressively increased in the diabetic animals by 45% at 2 weeks, 230% at 6 weeks, and 500% by 6 months. By contrast, islet glucagon rose acutely and maintained a constant 2-fold elevation irrespective of the duration of the diabetes. Morphometric analysis of the somatostatin- and glucagon-producing cells in the islets revealed an apparent augmentation of both cell types. The concentration of somatostatin per total pancreas was also increased in the diabetic animals, suggesting that the islet increase was part of a true increase in pancreatic somatostatin. Pancreatic glucagon was unchanged despite the islet increase. The increase in pancreatic somatostatin was paralleled by an elevation in gastric somatostatin concentration, implying a common mechanism in response to streptozotocin for the somatostatin cells in these two sites. There was no change in hypothalamic somatostatin concentration. Islet somatostatin was also increased in alloxan-diabetic rats. suggesting that streptozotocin does not stimulate the D cells directly.
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We have recently shown that the diabetic syndrome in Psammomys obesus is characterized by severe depletion of islet immunoreactive insulin (IRI) stores together with a marked increase in the islet proinsulin to insulin ratio. In the present in vitro studies, we show marked enhancement of proinsulin biosynthesis in islets from diabetic P. obesus (approximately 8-fold compared to nondiabetic islets). Proinsulin to insulin conversion and insulin degradation do not differ significantly between diabetic and nondiabetic islets. The rate of IRI secretion at a stimulatory concentration of glucose (16.7 mM) is comparable in diabetic and nondiabetic animals, but at a nonstimulatory glucose concentration (0 mM), islets obtained from diabetic animals show significant IRI release. beta-Cells from diabetic P. obesus also exhibited increased secretion of newly synthesized proinsulin and conversion intermediates under stimulatory conditions. Moreover, a novel secretory compartment, highly enriched in newly synthesized C peptide, characterized the beta-cells of diabetic animals. Our data suggest that the marked insulin depletion observed in diabetic islets is probably due to a hyperglycemia-driven increase in secretory demand that is not met by the enhanced biosynthetic capacity of these islets. This leads to relative enrichment of the depleted diabetic islets with immature secretory granules of a higher proinsulin content.
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Immunoreactive neurotensin (IR-NT) content in 2 N acetic acid extracts of pancreas was measured in genetically diabetic (C57BL/KsJ db/db and ob/ob) and obese (C57BL/6J ob/ob and db/db) mice and normal littermate controls from 5 to 24 wk of age to determine the relationship of any changes to the development of metabolic abnormalities. Pancreatic IR-NT in obese mice showed no consistent change compared with lean littermate controls. In contrast, diabetic mice demonstrated an increase in pancreatic IR-NT that occurred at 6–8 wk of age, and maximal about the time of islet B-cell failure (8–10 wk), and persisted over the study period. Pancreatic IR-NT eluted in two peaks on reverse phase high-pressure liquid chromatography, one of which exhibited a retention time similar to that of synthetic NT. These findings suggest that pancreatic IR-NT concentration is regulated by insulin, with elevated levels occurring in association with insulin deficiency and its metabolic consequences but not with insulin resistance. Taken together with the previous demonstration that NT influences pancreatic islet hormone secretion, the present findings support a possible role of endogenous NT in islet hormone regulation.
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Abstract Although galanin has been shown to be present in pancreatic islet cells, there is no literature available on the pattern of distribution and the effect of galanin in the pancreas of diabetic animals or human models. The aim of this study was to examine whether galanin immunoreactivity changes after the onset of diabetes mellitus in the rat model. The present study used immunohistochemical techniques to examine the pattern of distribution of galanin–like immunoreactive cells in the pancreas of rats with streptozotocin‐induced diabetes. The effect of galanin on insulin secretion from intact rat pancreatic tissue fragments was also investigated using a radioimmunoassay technique. Numerous galanin–like immunoreactive cells were observed in both the peripheral and central regions of the islet of Langerhans of normal rat pancreas. By contrast, the islets of diabetic rat pancreas contained significantly (P < 0.0001) fewer galanin–like immunoreactive cells than nondiabetic rats. Galanin was colocalized with insulin in the islets of normal and diabetic rats. Galanin had an inhibitory effect on insulin secretion from the isolated pancreatic tissue fragments of normal and diabetic rats at all concentrations (10 −12 to 10 −6 M) employed. Galanin at 10 −9 M caused a significant (P < 0.02) decrease in insulin secretion from normal rat pancreatic tissue fragments compared to basal. These observations indicate that galanin may play a significant role in the regulation of insulin secretion.
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Hyperinsulinemic and hypoglycemic rats with islet cell tumors induced by streptozotocin were shown to have significantly decreased immunoreactive insulin and somatostatin concentration (expressed as per g wet weight (w. wt)) and content (expressed as per whole pancreas) in the pancreas surrounding the tumor as compared to those of age and weight adjusted controls. The pancreatic glucagon concentration of the former was significantly lower than that of the latter but no significant difference between glucagon content in the two groups was observed. Thus, inverse relationships were demonstrated between circulating insulin and somatostatin as well as insulin in the pancreas. It is suggested that a large amount of insulin in plasma results in a decrease in pancreatic insulin and somatostatin.
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Genetically diabetic mice (C57BL/KsJ-db/db) were used as a model to study the development of defects of insulin secretion in relation to common metabolic indicators (body weight, serum glucose and insulin, and islet insluin contant). Consistent with the idea of a protective effect of oestrogen on the pancreatic beta-cell, the female diabetic mice survived longer than the males. In males, while serum insulin decreased in the later stages of the disease, serum glucose increased progressively with age. Perfusion of the diabetic pancreases revealed a rise and subsequent fall with age of the basal insulin released at 3 mM glucose. Despite previous reports of beta-cell hyperplasia, progressive impairment of the insulin response to 20 mM glucose, or to 20 mM glucose and 1 mM 3-isobutyl-1-methylxanthine, was seen with increasing age in experiments with perfused pancreas or microdissected islets. Islet content of insulin also decreased progressively with age in the diabetic animals.
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The β-cell function, total islet volume, and number were studied in 1- to 18-month-old mice, together with the extractable pancreatic insulin and glucagon. The β-cell function, determined as the total amount of insulin released in response to glucose from the in vitro perfused pancreas showed an agerelated increase, without any differences in the kinetics of insulin secretion between young and old mice. The total islet number and area in each individual pancreas was determined planimetrically after selective staining of the islets by perfusing the pancreas with dithizone. The islet area increased from 5.4 ± 1.7 mm2 at 1 month to 16.3 ± 2.1 mm2 at 18 months, whereas the number of islets remained virtually unchanged (1072 ± 51). Pancreatic insulin increased with age by nearly 500%, in contrast to a 35% reduction in pancretic glucagon. There was a strong relationship between body weight and total pancreatic DNA (P = 4.7 ×10-8), islet area (P = 3.2 × 10-7), insulin secretory capacity (P = 7 × 10-4), and total pancreatic insulin (P = 1.9 × 10-5), but no relationship between body weight and islet number. The insulin secretory capacity increased proportionally to the increase in islet area (P = 9.9 Times; 10-3). The islet area and total pancreatic insulin were closely related (P = 2.8 × 10-12), as were pancreatic insulin and the insulin secretory capacity (P = 3.3 × 10-11). There was a negative relationship between pancreatic glucagon and islet area (P = 0.005) and between pancreatic glucagon and insulin (P = 0.01). The close relationship between pancreatic insulin and islet area, shown to be an expression of islet volume, makes it possible to estimate the volume of the endocrine pancreas after standard RIA of pancreatic insulin. The combined morphometric and physiological analysis is unique in studying islet cell function relative to the volume of the endocrine pancreas.
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