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Anne Dutour

The physiopathology of non-insulin-dependent diabetes mellitus (NIDDM) is still a hot issue in endocrinology. The disease is associated with a defect in insulin secretion as well as markedly impaired glucose uptake in response to insulin. Katz et al. (Nature, 377, 151–155) have disrupted the murine GLUT4 gene in an effort to build up a new model of tissue-specific (i.e. mainly muscular) insulin resistance. Strikingly, they show that knockout mice lacking GLUT4 transporter do not develop diabetes.

Glucose transport is one of the main components maintaining glucose homeostasis. Glucose uptake is mediated by a family of different specific transporters ensuring facilitated glucose diffusion through the membrane. GLUT1 is ubiquitous and found mainly in erythrocytes, placenta and the blood–brain barrier. Because of its low Km, it supplies in concert with GLUT3 the constant level of glucose needed by the brain. GLUT2, expressed preferentially in the liver and in the pancreas,

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A. Zerbib, G. Ribes, R. Gross, R. Puech and M. M. Loubatières-Mariani

Abstract.

Insulin and pancreatic somatostatin secretions were studied after stimulation with an arginine infusion (5 mmol/1) in isolated perfused pancreata of adult streptozotocin-diabetic rats. In the presence of 2.8 mmol/l glucose, arginine clearly stimulated insulin and somatostatin secretions in diabetic rats, whereas it was ineffective in normal rats. Thus, not only the B-cells, but also the D-cells of the pancreas from streptozotocindiabetic rats are hypersensitive to arginine. The infusion of insulin (4 U/l) did not modify this hypersensitivity of the D-cells to arginine in pancreata of streptozotocindiabetic rats.

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Dag Hofsø, Thor Ueland, Helle Hager, Trond Jenssen, Jens Bollerslev, Kristin Godang, Pål Aukrust, Jo Røislien and Jøran Hjelmesæth

Objective

To explore inflammatory mediators in morbidly obese (MO) subjects with various categories of glucose tolerance and to study the changes in these mediators after an oral glucose load.

Design

Cross-sectional and experimental study.

Methods

A total of 144 MO subjects were classified into three categories: normal glucose tolerance (NGT); pre-diabetes; and new onset diabetes mellitus (NODM) were included, as were 27 normal weight normoglycemic controls. Serum osteoprotegerin (OPG), visfatin, leptin, adiponectin, interleukin-1 receptor antagonist (IL-1Ra), and C-reactive protein (CRP) were analyzed during an oral glucose tolerance test (OGTT).

Results

Fasting levels of leptin and IL-1Ra were consistently higher in obese persons (P<0.001 and P<0.05). MO subjects with NGT had higher CRP levels (P<0.001) and lower adiponectin levels (P<0.05) compared to controls. Yet when compared with MO subjects with NODM, those with NGT had lower CRP levels and higher adiponectin levels (both P<0.05). Baseline OPG and visfatin levels did not differ between the groups (P=0.326 and P=0.198). During OGTT, OPG levels decreased (P<0.001) and visfatin levels increased transiently (P=0.018). The response in OPG and visfatin did not differ between the groups (P=0.690 and P=0.170). There were minor changes in adiponectin and leptin levels.

Conclusions

Morbid obesity and glucose intolerance were associated with lower adiponectin levels and higher CRP levels, thus supporting a relationship between obesity, glucose homeostasis, and inflammation. Oral glucose suppressed OPG levels and transiently enhanced visfatin levels independent of obesity and glucose tolerance status, indicating that glucose may be involved in the acute regulation of these proteins.

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R. Gross and P. Mialhe

Abstract. Duck isolated perfused pancreas was used to assess glucose, adrenergic mediated effects and pancreatic function interrelationships. A moderate physiological 50% increase in glucose level, corresponding closely to the difference observed between 24-h-fasted and fed animals, induced a significant decrease of pancreatic glucagon not due to a rise in somatostatin secretion. The great responsiveness of the A cell was still found after glucagon stimulation by catecholamines or β adrenergic agonism. Insulin was irresponsive to the glucose load we used, suggesting that glucose-induced glucagon suppression was also insulin independent. As far as the D cell was concerned, glucose had no effect on pancreatic somatostatin output; however, an interesting finding was that β adrenergic agonism has a permissive effect on D cell responsiveness to the nutriment.

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Jak Jervell

Insulin is a polypeptide, in which two chains, the A and B-chains, are linked by disulphide bridges. In addition there is an internal disulphide bridge in the A-chain. Insulin is found in all animals with backbones right down to the primitive myxine glutinosa. All insulin varieties have biological activity in mammals although the antigenic properties may be species specific. Since insulin was discovered in 1926 bovine and porcine insulin has been used in the treatment of human diabetic patients. In the Nordic countries porcine insulin has been used by most patients. During the last decade this has become highly purified and has few antigenic contaminants.

The amino-acid sequence in the insulin made in the human pancreas differs very little from pork insulin. The N-terminal amino acid in the B-chain is alanine in pork insulin and threonine in human insulin. The difference between human and bovine insulin is somewhat greater. Threonine

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Yan Hui Ma, Jian Wang, Gail G Rodd, Janice L Bolaffi and Gerold M Grodsky

Ma YH, Wang J, Rodd GG, Bolaffi JL, Grodsky GM. Differences in insulin secretion between the rat and mouse: role of cAMP. Eur J Endocrinol 1995;132:370–6. ISSN 0804–4643

Although information regarding insulin secretion usually is considered equivalent when generated in the mouse or the rat, it is established that the kinetics of insulin secretion from mouse and rat pancreatic beta cells differ. The mechanisms underlining these differences are not understood. The in vitro perfused pancreas and isolated islets of the mouse or rat were employed in this study to investigate the role of cyclic adenosine monophosphate (cAMP), a major positive modulator of betacell function, as one differentiating signal for the uniquely different insulin release from the beta cells of these commonly used rodents. Glucose-stimulated first-phase insulin release from the perfused pancreas of the rat was higher than the mouse when calculated per gram of pancreas or as fractional secretion, but this phase was identical in the two species when results were adjusted for total body weight. Whether related to insulin content, pancreatic weight or body weight, the rat pancreas responded to glucose with a progressively increasing second-phase insulin release compared to the mouse pancreas, which secreted a flat second-phase of lesser magnitude. Isolated islets from rat and mouse were comparable in insulin content whereas the basal cAMP level of mouse islets was less than half that of the rat. At submaximal stimulation with glucose or glucose + IBMX or forskolin, mouse islets exhibited lower cAMP levels to a given stimulus than the rat. In rat islets cAMP levels increased to approximately 1000 fmol per islet, although insulin secretion maximized by 100–150 fmol. Insulin release at the same 100–150fmol cAMP per mouse islet was one-third that of the rat and secretion had not maximized in mouse islets at 800 fmol. Despite their similar insulin contents, mouse islets consistently secreted less insulin for a given level of cAMP per islet than the rat. The lower capacity of mouse islets to achieve comparable cAMP levels was not the result of increased catabolic rate because the "half-time" disappearance of islet cAMP after a stimulus was similar (~1 min) for both species. It is concluded that, compared to the mouse, beta cells of the rat pancreas elicit a more pronounced secondphase insulin secretion that is due, at least in part, to a greater production of, and sensitivity to, cAMP.

Gerold M Grodsky, Metabolic Research Unit, University of California, H5W 1157, Box 0540, 3rd and Parnassus Avenue, San Francisco, CA 94143, USA

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S Alex, LE Braverman, SL Fang, B Norvell, S Robinson, C Franz and C Longcope

Chronic feeding of dehydroepiandrosterone (DHEA) and its sulfated metabolite, dehydroepiandrosterone sulfate (DHEAS), has previously been reported to decrease hyperglycemia, obesity, cancer, and autoantibody generation in a number of animal models and to increase muscle mass and physiological and psychological well-being in elderly humans, although these latter studies remain controversial. The present study was carried out to determine whether large amounts of DHEAS given orally would prevent the occurrence of spontaneous and iodine-induced autoimmune lymphocytic thyroiditis (LT) and/or spontaneous insulin-dependent diabetes mellitus (DM) in male and female BB/Wor rats. DHEAS was administered by gavage (44 mg/rat/day) or in the chow (133 mg/rat/day) to LT- and DM-prone rats from 30 to 120 days of life; some of these rats also received iodine in the drinking water to enhance the incidence and intensity of LT. Onset of DM requiring protamine zinc insulin and its maintenance dose were assessed. Rats were killed at 90 or 120 days of age and blood, thyroid, adrenals, pancreases, testes, and ovaries were removed. Serum glucose, DHEA, DHEAS, thyroxine (T4), tri-iodothyronine (T3) and thyrotropin (TSH) concentrations were measured in all rats in both experiments. Serum DHEAS concentrations were 10-fold higher in the rats given the steroid by gavage or in the diet compared with levels in control rats. DHEAS administered over a prolonged period of time had no significant effect on body weight, incidence and severity of DM, incidence and intensity of spontaneous and iodine-induced LT, and thyroid, pancreas and testes weights but did significantly decrease adrenal and ovarian weights. Serum T4, T3, and TSH concentrations were similar in control and DHEAS-treated rats. In conclusion, DHEAS did not prevent the occurrence of iodine-induced or spontaneous autoimmune LT or spontaneous DM in the BB/Wor rat, at variance with its reported immunosuppressive effects in other animal models.

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M. Jonung, Y. Berlatzky, M.-H. Chen, R. Munda, I. G. Banks, K. Brackett, R. F. Murphy and S. N. Joffe

Abstract. There is increasing interest in pancreatic transplantation for patients with diabetes. In experimental models, endocrine function is usually monitored by determination of insulin and glucose levels in plasma. In this study following a segmental pancreatic autotransplant to the iliac fossa in dogs, a combined analysis of three pancreatic islet hormones, insulin, pancreatic polypeptide (PP) and glucagon was undertaken by radioimmunoassay of plasma. These were measured under basal conditions and following provocation with a standard meal, arginine, secretin and bombesin infusions. Immunohistochemical and electron microscopic examination of transplanted tissue was also performed.

Circulating insulin and glucose levels in the surviving dogs with transplants reflected normoglycaemia with a normal tolerance to iv glucose and immunohistochemical detection of endocrine cells producing insulin, PP and glucagon. Secretory granules were found in A and B cells by electron microscopy. The normal circulating glucagon immunoreactivity could have originated in gastric antral A cells as well as in pancreatic tissue. It was not possible, however, to stimulate the autotransplanted pancreas to release detectable PP into the circulation.

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S. Efendić and R. Luft

ABSTRACT

Somatostatin, the recently discovered growth hormone release-inhibiting hormone in the hypothalamus, also inhibited glucose induced insulin release from the isolated perfused rat pancreas. The lowest effective dose of somatostatin was 1 ng/ml of perfusate. By increasing the dose to 100 ng/ml an almost complete inhibition of basal as well as stimulated insulin release was obtained. The inhibition of glucose stimulated insulin release mediated by somatostatin might be of competitive nature since somatostatin seemed to dislocate the glucose-insulin dose-response curve to the right.

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Steen Larsen, Jannik Hilsted, Else K. Philipsen, Bente Tronier, Meta Damkjær Nielsen and Helge Worning

Abstract.

Insulin was withdrawn from 7 patients with Type I (insulin-dependent) diabetes and 4 patients with insulin-dependent diabetes secondary to chronic pancreatitis, both groups without residual beta-cell function. Median plasma glucagon concentrations rose slightly, but significantly after withdrawal of insulin in Type I diabetic patients (from 14 (range: 11-16) to 19 (14-25) pmol/l by 6 h), but not in the patients with secondary diabetes. This was accompanied by a significantly higher increase in blood glucose concentration from 5.1 (4.9-5.7) to 15.2 (12.9-18.1) mmol/1 by 6 h in Type I diabetic patients compared with patients with secondary diabetes (from 4.9 (4.3-6.7) to 13.1 (10.9-13.5) mmol/l) (p<0.01). Beta-hydroxybutyrate increased to a similar extent in the two groups, whereas no significant increases were found in glycerol and lactate in any of the groups. Increased secretion of glucagon is not essential for the development of hyperglycemia and ketonemia in patients with diabetes secondary to chronic pancreatitis, but may augment the degree of hyperglycemia in Type I diabetic patients compared with patients having secondary diabetes.