Studies on the prediction and development of diabetes in offspring of diabetic Chinese Hamsters

Summary Two hundred and fifty-three hamsters born between January and September 1968 have been continuously tested biweekly for urine glucose and ketones from 15 days of age through September 1969. They comprise 67 litters out of 28 females sired by 19 males from 7 inbred lines. — All 46 hamsters from two severe ketotic diabetic parents have become diabetic (consistent 4+ Tes-Tape rating). Twenty-five of the 46 have developed ketonuria (consistent 4 + Ketostix rating). — While 100% of the litters from ketotic diabetics became diabetic within 8 months, the incidence of diabetes from ketotic diabetic to nonketotic diabetic matings was 59%; ketotic diabetic to trace glucosuric 41%; and ketotic diabetic to nondiabetic 24%. — Diabetes developed earlier in progeny from ketotic diabetics than in those from milder diabetics. At 3 weeks, pups from ketotic diabetics were 26% trace glucosuric, 26% diabetic, 2% ketotic and by 2 months 85% diabetic. At 3 weeks, descendents from ketotic diabetics mated to nonketotic diabetics were 16% trace glucosuric, 2% diabetic and by 2 months only 36% diabetic. — Animals from severely ketotic diabetic Chinese hamsters are ideally suited for prediabetes research since they are predictable and rapidly become diabetic as proof of their earlier prediabetic state. Progeny from less severe diabetic parents are not predictable since only 59% developed diabetes and the incidence varied from litter to litter from the same parents. Further, nondiabetic parents have produced diabetic offspring. The data suggest that the inheritance of diabetes in chinese hamsters is complex since it cannot be explained by a single recessive gene.

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Untersuchungen über die Voraussage und die Entwicklung des Diabetes bei Nachkommen diabetischer chinesischer Hamster

Zusammenfassung 253 zwischen Januar und September geborene chinesische Hamster wurden ab dem 15. Lebenstag und bis September 1969 in zweiwöchigen Abständen auf das Vorliegen von Zucker und Ketonkörper im Urin untersucht. Es handelte sich um Tiere aus 67 Würfen von 28 Weibchen und 19 Männchen aus 7 verschiedenen Inzuchtlinien. Alle 46 Nachkommen schwer ketotisch diabetischer Eltern entwickelten einen Diabetes, der bei 25 Tieren auch von Ketonurie begleitet war. Innerhalb der ersten 8 Lebensmonate wurde ein Diabetes festgestellt bei 100% der Nachkommen ketotisch-diabetischer Eltern, bei 59% der Nachkommen eines ketotisch-diabetischen und eines nicht ketotisch-diabetischen Elternteils, bei 41% der Nachkommen eines ketotischen und eines nur spurenweise glykosurischen Tieres und bei 24% der Nachkommen eines ketotischen und eines nicht diabetischen Elternteils. Bei den Nachkommen ketotisch-diabetischer Eltern trat der Diabetes früher auf als bei denen von Eltern mit milderen Formen des Syndroms. 3 Wochen nach der Geburt zeigten 26% der Nachkommen ketotisch-diabetischer Eltern spuren-weise Glykosurie, 26% waren diabetisch und 2% ketonurisch. Zwei Monate nach der Geburt waren 85% der Tiere diabetisch. Bei 3 Wochen alten Nachkommen eines ketotisch diabetischen und eines nicht ketotisch-diabetischen Elternteils waren die entsprechenden Werte 16% für spurenweise Glykosurie, 2% für Diabetes, und im Alter von 2 Monaten waren nur 36% der Tiere diabetisch. — Auf Grund dieser Ergebnisse wird geschlossen, daß sich Nachkommen ketotisch-diabetischer chinesischer Hamster geradezu ideal für die Untersuchung des prädiabetischen Syndroms eignen, da sie alle diabetisch werden und damit der endgültige Beweis für das Bestehen eines prädiabetischen Zustandes in kurzer Zeit erbracht werden kann. Bei Nachkommen weniger schwer diabetischer Eltern kann eine sichere Voraussage nicht gemacht werden, da nur 95% der Tiere einen Diabetes entwickeln und auch dieser prozentsatz von Wurf zu Wurf der gleichen Eltern stark schwanken kann. Da außerdem auch Nachkommen nichtdiabetischer Eltern Diabetes entwickeln können, scheint es daß die Heredität des diabetischen Syndroms des chinesischen Hamsters komplexer Natur ist und nicht auf Grund des Einflusses eines einzelnen rezessiven Gens erklärt werden kann.

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Prévisibilité et développement du diabète dans la progéniture de hamsters chinois diabétiques

Résumé Le glucose et les corps cétoniques urinaires de 253 hamsters nés entre janvier et septembre 1968 ont été mesurés toutes les deux semaines à partir de l'âge de 15 jours jusqu'en septembre 1969. Ces animaux proviennent de 67 nichées produites par 28 femelles mariées à 19 mâles de 7 lignées consanguines. — Tous les 46 hamsters provenant de parents diabétiques avec cétose sévère sont devenus diabétiques (continuellement 4+ au Tes-Tape). 25 parmi ces 46 animaux ont développé une cétonurie (continuellement 4 + au Ketostix). — Alors que 100% des animaux de parents diabétiques avec cétose sont devenus diabétiques en 8 mois, on trouve une incidence de diabète de 59% chez des animaux provenant de croisements entre animaux diabétiques cétosiques et non-cétosiques; cette incidence est de 41% chez les animaux provenant de parents cétosiques diabétiques mais avec des animaux ayant des traces de glycosurie; elle est de 24% chez ceux provenant de croisements d'animaux diabétiques cétosiques avec des non-diabétiques. — Le diabète apparaît plus tôt dans la progéniture d'animaux diabétiques avec cétose que chez celle issue d'animaux avec diabète léger. A l'âge de 3 semaines, parmi les petits de parents ayant un diabète cétosique, 26% montraient des traces de glycosurie, 26% étaient diabétiques et 2% étaient cétosiques. A l'âge de 2 mois, 85% sont devenus diabétiques. A l'âge de 3 semaines, les petits issus de mariages entre parents avec diabète cétosique et noncétosique ont présenté des traces de glycosurie dans 16% des cas et un diabète dans 2% des cas. Seulement 36% étaient diabétiques à l'âge de 2 mois. — Les animaux de hamsters chinois avec diabète cétosique sévère se prêtent de façon idéale à des recherches sur le prédiabète, parce que l'apparition de la maladie est prévisible et que, de plus, ces animaux deviennent rapidement diabétiques confirmant ainsi leur état prédiabétique antérieur. Chez la progéniture de parents ayant un diabète moins sévère, son apparition est imprévisible du fait que 59% seulement ont dévélopé un diabète et que la fréquence de la maladie varie de nichée à nichée issues de mêmes parents. Par ailleurs, on sait que des parents non-diabétiques ont eu des petits diabétiques. Ces données suggèrent que la transmission du diabète chez le hamster chinois est complexe puisqu'elle ne peut pas être expliquée par la présence d'un seul gène récessif.

     

Ultrastructural changes in A-cells exposed to diabetic hyperglycaemia. Observations made on pancreas of chinese hamsters

Summary Pancreatic A-cells of chinese hamsters with diabetes of varying severity and duration were examined by electron microscopy. Two predominant changes were observed: 1. Lysosomal digestion of secretory granules (granulolysis, crinophagy) occurred in practically all A-cells of diabetic animals but was rarely observed in those of normoglycemic controls. This is considered a response of A-cells to the cessation of glucagon release secondary to hyperglycemia. 2. In relatively degranulated A-cells of ketotic diabetic animals, dilatation of the cisternae of the RER was seen together with accumulation of pale, flocculent material, possibly reflecting persisting or enhanced glucagon synthesis. In addition, numerous maturing secretory granules were seen in the cisternae of the Golgi complex. Since these apparently contradictory phenomena may be seen in the same cell, it is suggested that granulolysis may not only result from decreased hormone release secondary to hyperglycemia but that different and independent stimulatory signals may exist for glucagon synthesis, for glucagon release, and for the initiation of granulolysis.Supported in part by the Fonds national suisse de la Recherche scientifique (Grants. No. 4848.3 and 3.154.69).     

Decreased cyclic AMP and Insulin responses to glucose in pancreatic islets of diabetic chinese hamsters

Summary The dose as well as the time kinetics of insulin and adenosine-3,5-monophosphate (cyclic AMP) responses to glucose were compared in pancreatic islets isolated from normal and diabetic Chinese hamsters. The insulin content in diabetic islets was about one-half that in normal islets. Insulin release in diabetic islets incubated for 10 min with glucose 60–1000 mg/l00 ml was from one-third to one-half that in normal islets. Glucose 1000 mg/l00 ml stimulated three-fold increases in insulin release without increasing the accumulation of [³H] cyclic AMP in either normal or diabetic islets prelabelled with [³H] adenine. However, in the presence of 1.0 mM of the phosphodiesterase inhibitor, 3-isobutyl-1-methylxanthine (IBMX), glucose 150 mg/l00 ml elicited significant increases of insulin release (+ 134%) and [³H] cyclic AMP accumulation in islets (+ 44%) and incubation medium (+ 48%) of islets of normal but not diabetic hamsters. Also, in perifusion experiments with 0.1 mM IBMX, glucose 500 mg/l00 ml produced threefold greater increases in insulin release and two-fold greater increases in efflux of cyclic AMP in normal than diabetic islets. By contrast with the lesser effects of glucose in diabetic islets, 1.0 mM IBMX increased islet and medium cyclic AMP, as well as insulin release, similarly in normal and diabetic islets. It is suggested that the impairment of glucose induced insulin release in islets of the diabetic Chinese hamster may be due to a defective interaction of glucose with the adenylate cyclase-cyclic AMP system in the pancreatic B cell.This work was presented in part at a meeting of the European Association for the Study of Diabetes, Sept. 1975, Munich, Germanyon leave from the Department of Endocrinology, Karolinska Hospital, Stockholm     

Use of a glucose controlled insulin infusion system (artificial beta cell) to control diabetes during surgery

Summary An artificial beta cell has been used to achieve and maintain a preset plasma glucose concentration in five diabetic patients undergoing surgery. These subjects were compared to control groups of normal subjects receiving either saline or glucose, and diabetics receiving glucose intraoperatively. Hyperglycaemia during surgery was seen in normals (mean plasma glucose ± SEM: 185±16 mg/dl) and, to a greater degree, diabetics (247±36 mg/dl) receiving glucose. Insulin and C-peptide levels did not increase during 2 hours of operation in any of the control groups, suggesting beta cell suppression during surgery. As C-peptide levels declined similarly in normal subjects whether they received saline or glucose, the hyperglycaemia seems to be due to an inability to use exogenous glucose. This is confirmed by a correlation of maximal plasma glucose to glucose infusion rate (r = 0.78, p<0.01). The artificial beta cell was able to achieve the same plasma glucose after 2 hours of operation (128±21 mg/dl) as normal subjects receiving saline (110±7 mg/dl). The artificial beta cell proved to be a safe, convenient and effective way of monitoring and controlling the hyperglycaemia seen in diabetic patients undergoing surgery.     

Mechanism of the hyperketonaemic effect of prolonged exercise in insulin-deprived Type 1 (insulin-dependent) diabetic patients

Summary The effects of moderate exercise of 2-h duration on the concentration and turnover rate of total ketone bodies were assessed in 7 acutely insulin-deprived Type 1 (insulin-dependent) diabetic patients with an isotope tracer technique using a constant infusion of ¹⁴C--hydroxybutyrate. These results were compared to those obtained in 13 normal control subjects in whom a similar range of hyperketonaemia (1–6mmol/l) was induced by fasting. In all subjects, the concentration and the rate of production of ketone bodies followed a biphasic pattern with an initial fall lasting for about 20 min followed by a secondary rise. When integrated over the entire working period, the exercise-induced changes in ketone turnover were markedly dependent on the initial ketone body concentrations in both groups: at low ketonaemia (1 mmol/l), exercise increased the rate of production and disposal of ketones. These effects were progressively attenuated as basal ketonaemia rose and were reversed to an inhibitory action in markedly ketotic subjects (>4 mmol/l). Despite the finding that, at high ketosis, exercise inhibited ketogenesis to a similar degree in control subjects and diabetic patients, the changes in concentration recorded at the end of exercise were different in the 2 groups: ketonaemia was reduced in fasted control subjects and increased in the diabetic patients. These data suggest that, contrary to a widely accepted opinion, the hyperketonaemic effect of prolonged exercise in ketotic diabetic patients does not result from an exaggerated stimulation of ketogenesis, but from some defect in their removal capacities for ketones, possibly related to insulinopenia.     

The effects of parabiosis on serum and kidney glycosidase activities in spontaneously diabetic mice

Summary Spontaneously diabetic non-obese mice of the ICR strain were newly inbred in Shionogi laboratory, Japan. Animals became diabetic suddenly, more frequently and severely in females. Blood glucose levels were 452±73 mg/100 ml with serum insulin levels of < 1.0 U/ml in the fed state. Parabiosis with normal control ICR mice for 2 weeks decreased the blood glucose level to 260±51 mg/ 100ml (P<0.01) and resulted in serum insulin levels of 46.0±18.0 U/ml (P<0.01). Kidney homogenate -N-acetylglucosaminidase and -galactosidase activities were reduced in diabetic mice (42% and 44% decrease respectively) (P<0.025 and P<0.001), and restored almost to normal after 2 weeks of parabiosis. Renal -mannosidase activity was decreased 43% (P<0.001) in the diabetic mice but unaffected by parabiosis. Serum -N-acetylglucosaminidase, -galactosidase and -glucosidase activities were significantly increased in diabetic mice (179%; 233% and 58% increase respectively) (P<0.005, P<0.001 and P<0.001), and returned to normal with parabiosis.     

Immunohistochemical and functional studies of glycoprotein 60 (gp60) in platelets

Summary We showed by immunofluorescence, immunoelectron microscopy and Western blot analysis that the plasma glycoprotein (gp60), an Fc binding protein which inhibits complement-mediated prevention of immune precipitation, is present in platelets. The pg60 content of platelets in normal individuals and patients with rheumatoid arthritis was similar (mean 0.028 and 0.024 fg/platelet respectively). Immunoelectron microscopic studies showed that pg60 was present in the cytoplasm and the surface connecting structures but not in the granules, dense granules or lysosomes. Using this technique gp60 was also found on platelet membranes, an observation which was confirmed by immunofluorescence. Activation of platelets with thrombin, calcium ionophore, and immune complexes (IC) resulted in the release of the contents of the granules (-thromboglobulin), dense granules (5-hydroxytryptamine) and lysosomes (-glucuronidase) but did not induce gp60 secretion. The inability of Fab anti-gp60 to inhibit IC-mediated platelet aggregation and of F(ab)₂ anti-gp60 to produce platelet aggregation suggested that IC-mediated platelet aggregation did not occur as a result of the interaction of IC with platelet gp60. However, as the preincubation of IC with purified gp60 produced dose-dependent inhibition of the ability of IC to aggregate platelets it is possible that fluid-phase plasma gp60 modulates the interaction of IC with platelets.     

Kidney function and size in type 1 (insulin-dependent) diabetic patients before and during growth hormone administration for one week

Summary Kidney function and size were studied in seven well-controlled male Type 1 (insulin-dependent) diabetic patients before and after administration of highly purified human growth hormone for one week. Glomerular filtration rate, renal plasma flow (steady state infusion technique with urinary collections using ¹²⁵I-iothalamate and ¹³¹I-hippuran), kidney size (ultrasonic scanning) and urinary excretion rates of albumin and -2-microglobulin were measured. Highly purified growth hormone was injected subcutaneously, 2 IU in the morning and 4 IU in the evening. The growth hormone dosage applied induced an elevation in plasma growth hormone concentration from the normal level seen in these very well controlled diabetics to levels within the range previously demonstrated in normally controlled Type 1 diabetic patients. During the week of growth hormone administration, glycaemic control was maintained unchanged by increasing the insulin dose by 79 ±9% (mean ± SEM). Glomerular filtration rate increased from 122±3 to 131±3 ml/min × 1.73 m² (p <0.05) and renal plasma flow increased from 535±10 to 569±22 ml/min × 1.73 m² (p<0.05). Kidney size changed from 128±5 to 133±5 ml/1.73 m² (NS). Urinary excretion rates of albumin and -2-microglobulin were unchanged. The present findings suggest that the growth hormone elevation typically found in Type 1 diabetic patients with reasonable clinical control, contributes to the enhanced glomerular filtration rate and renal plasma flow present in that disease.     

Actions of salbutamol in late pregnancy: Plasma cyclic AMP,insulin and C-peptide,carbohydrate and lipid metabolites in diabetic and non-diabetic women

Summary Salbutamol was administered intravenously in doses increasing from 3.75 to 22.5 g/min to 5 non-diabetic and 7 diabetic women in the last trimester of pregnancy. In diabetic as well as nondiabetic women the diastolic blood pressure fell progressively with increasing doses, and the systolic BP and heart rate increased at doses above 7.5 g/min. The effect on fetal heart rate was less pronounced than the effect on maternal heart rate. Cyclic AMP levels in plasma were similar in non-diabetic and diabetic women before salbutamol. Twenty min following 3.75 g/min a significant increase was seen in both groups. The peak increase (3–5 fold) was higher in the diabetic than in the non-diabetic women. Plasma insulin and C-peptide levels rose in a dose-dependent manner in the non-diabetic and four of the diabetic women. However, in three of the diabetic women the insulin level was unaffected by salbutamol and C-peptide was almost undetectable. Plasma concentrations of glucose, glycerol, NEFA and 3-HB were higher in the diabetics than in the non-diabetics before salbutamol and the elevations induced by salbutamol were also significantly larger in the diabetic women. The present data show that salbutamol in doses employed clinically may cause pronounced metabolic effects, especially in diabetic women, and it is suggested that when intravenous infusion of salbutamol is given to pregnant diabetic women not only cardiovascular but also some metabolic variable such as glucose should be carefully monitored.     

Weakened cellular scavenging activity against oxidative stress in diabetes mellitus: regulation of glutathione synthesis and efflux

Summary Glutathione functions to scavenge oxidants or xenobiotics by covalently binding them and transporting the resulting metabolites through an adenosine 5-triphosphate-dependent transport system. It has been reported that the intracellular concentration of glutathione decreases in diabetes mellitus. In order to elucidate the physiological significance and the regulation of anti-oxidants in diabetic patients, changes in the activity of the glutathione-synthesizing enzyme, -glutamylcysteine synthetase, and transport of thiol [S-(2,4-dinitrophenyl)glutathione] were studied in erythrocytes from patients with non-insulin-dependent diabetes and K562 cells cultured with 27 mmol/l glucose for 7 days. The activity of -glutamylcysteine synthetase, the concentration of glutathione, and the thiol transport were 77%, 77% and 69%, respectively in erythrocytes from diabetic patients compared to normal control subjects. Treatment of patients with an antidiabetic agent for 6 months resulted in the restoration of -glutamylcysteine synthetase activity, the concentration of glutathione, and the thiol transport. A similar impairment of glutathione metabolism was observed in K562 cells with high glucose levels. The cytotoxicity by a xenobiotic (1-chloro-2,4-dinitrobenzene) was higher in K562 cells with high glucose than in control subjects (50% of inhibitory concentration. 300±24 mol/l vs 840±29 mol/l, p<0.01). Expression of -glutamylcysteine synthetase protein was augmented in K562 cells with high glucose, while enzymatic activity and expression of mRNA were lower than those in the control subjects. These results suggest that inactivation of glutathione synthesis and thiol transport in diabetic patients increases the sensitivity of the cells to oxidative stresses, and these changes may lead to the development of some complications in diabetes mellitus.Abbreviations ATP Adenosine 5-triphosphate - NIDDM non-insulin-dependent diabetes mellitus - GSH -glutamylcysteinyl glycine - GSSG glutathione disulphide - -GCS -glutamylcysteine synthetase - mRNA messenger ribonucleic acid - DNA deoxyribonucleic acid - C₅₀ 50% inhibitory concentration - CDNB 1-chloro-2,4-dinitrobenzene - GS-DNP S-(2,4-dinitrophenyl)glutathione - PSL photostimulated luminescence     

The regulation of adenylate cyclase in adipocyte plasma membrane from genetically obese (ob/ob) mice

Summary Adenylate cyclase activity was determined using a purified plasma membrane fraction prepared from isolated adipocytes by a Percoll gradient centrifugation procedure. The activation of adenylate cyclase by isoprenaline was reduced by approximately 50% in membranes from obese mice, although no reduction in the sensitivity of the response was apparent. Basal and fluoride- and 5-guanylyl-imidodiphosphate-stimulated activities were similar in both groups. However, two defects in the obese system were identified which suggested that an alteration in the properties of the regulatory protein may account for the impaired hormonal activation. The specific binding of ³H-dihydroalprenalol to membranes from obese animals also was decreased, suggesting a reduction in the number of -adrenergic receptors.     

The prognostic significance of cytological,histological and cytogenetic findings in refractory anaemia (RA) and RA with sideroblasts

Summary Two independent observers performed a double review of cytological and histological bone marrow material obtained at diagnosis and during follow up in 34 patients with the myelodysplastic syndrome (MDS), subtypes refractory anaemia (RA) and RA with ringed sideroblasts (RA-S) (26 and 8 patients, respectively). Average values were used for the analyses. Data obtained at diagnosis confirmed earlier observations that a worse prognosis was indicated by high blast cell counts (P<0.01), presence of blast foci and clonal cytogenetic abnormalities (P=0.08). Data obtained during follow up, in addition, showed that an increased probability of progression to FAB-subtype RA with an excess of blasts was related to both the occurrence of blast foci (P<0.05) and the occurrence of new or additional clonal abnormalities (karyotype shift) (P<0.01). The relationship between parameters investigated at diagnosis, during follow up, and in the pooled material, points to RA-S being a separate entity having a better prognosis than RA, and further substantiates an earlier observed relationship between blast cell accumulation and the frequency of cytogenetically abnormal metaphases.This work was supported by Grant no. 003/83 from The Danish Cancer Society     

Relationship between fat and ketone body metabolism in obese and nonobese diabetics and nondiabetics during norepinephrine infusion

Summary The effects of an intravenous infusion of norepinephrine, 0.08 g/kg.min on lipolysis (as measured by an increase of free glycerol and nonesterified fatty acids (NEFA)), on the blood concentration of ketone bodies and on the serum concentrations of immunoreactive insulin (IRI) and insulin-like activity (ILA) were studied in normal weight and obese nondiabetics and diabetics. Normal weight diabetics and nondiabetics showed the same increase in lipolysis. A significantly higher rate of lipolysis occurred in obese persons, irrespective of whether they were diabetic or not. Even the maximum absolute concentrations of free glycerol and NEFA during the infusion were higher in obese persons than in insulindependent diabetics, who showed the highest values before the beginning of the infusion. — In obese subjects, the infusion of norepinephrine according to the theoretical normal weight was still sufficient to produce a higher rate of lipolysis than in normal weight subjects. This probably reflects the greater mass of adipose tissue in obese subjects. — In diabetic and nondiabetic obese persons, the concentration of ketone bodies rose higher than in control subjects, which is in agreement with the higher rate of lipolysis in the obese groups. On the other hand, the normal weight insulin-dependent diabetics showed a significantly higher increase in the concentration of ketone bodies than the obese persons. This demonstrates that the degree of ketonaemia in man is not exclusively determined by the plasma level of NEFA. — The higher increase in the-hydroxybutyrate/acetoacetate ratio in insulindependent diabetics points to a higher rate of oxidation of fatty acids in the liver. —ILA and IRI responded in a different way to norepinephrine infusion, demonstrating again, that changes in ILA can, but may not always reflect changes in immunoreactive insulin. According to these results, changes in the rate of lipolysis and in ketonaemia in obese diabetics are determined by the factor obesity, whereas changes in these parameters in insulindependent diabetics are determined by the factor insulin deficiency.A part of this work has been presented at the 12. Symposion der Deutschen Gesellschaft für Endokrinologie, Wiesbaden, Deutschland, 21.–23. 4. 1966.     

Metabolic state,pancreatic insulin content and B-cell morphology of normoglycemic spiny mice (acomys cahirinus): Indications for an impairment of insulin secretion

Summary Plasma glucose, plasma IRI and pancreatic IRI content were measured and B-cell morphology was studied in fasted, fed and glucose-injected normoglycemic spiny mice of varying ages. Both high and low plasma IRI concentrations were observed at all ages, irrespective of the degree of pancreatic stimulation. In old but not in young animals, plasma IRI concentrations correlated with body weight, suggesting that accelerated weight gain was secondary to hyperinsulinemia. Pancreatic IRI content was higher than in other strains of non-diabetic mice and increased with age but was unrelated to either plasma IRI concentrations, or to body weight individual age groups. Relative to pancreatic IRI content, plasma IRI concentrations of spiny mice were lower than those of normal or obese-hyperglycemic mice of other strains. The B-cells showed an unusual degree of granulation. Pale granules predominated and had a characteristic tendency to fusion and confluence. With the exception of 1 out of 200 animals (in the islets of which emiocytosis was seen), no signs of enhanced insulin release could be observed. Neo-formation of-granules by the Golgi complex of already well granulated cells was the only feature consistently associated with pancreatic stimulation by glucose injection. The data are in agreement with the hypothesis of a B-cell defect resulting in an impairment of insulin secretion and also suggest that the B-cells of normoglycemic spiny mice may contain two compartments of insulin: one which is accessible to secretory stimulation and has a rapid turnover and one which is relatively inaccessible to stimulation and accumulates with age. Available data do not allow for the identification of the postulated defect or for the anatomical or physiological definition of the two compartments of insulin.Supported by the Fonds National Suisse de la Recherche Scientifique (Grants No. 4848.3 and 3.154.69).     

Effects of vasoactive intestinal polypeptide (VIP), secretin and gastrin on insulin secretion in the mouse

Summary The in vivo effects of vasoactive intestinal polypeptide (VIP), secretin and two different molecular forms of gastrin, gastrin 17 and pentagastrin, on basal and stimulated insulin secretion have been investigated in the mouse. All these peptides induced a moderate dose-dependent increase in basal insulin secretion. The different polypeptides showed complex effects on insulin release stimulated by glucose, the cholinergic agonist carbachol or the adrenergic agonist L-isopropylnoradrenaline (LIPNA), these effects being dependent on the nature of the secretagogue. VIP and secretin both potentiated glucose-induced insulin release. Secretin inhibited insulin secretion induced by carbachol and LIPNA, whereas VIP potentiated L-IPNA-induced insulin secretion and had no influence on the effect of carbachol. Gastrin 17 and pentagastrin did not affect glucose- or carbachol-induced insulin release, whereas they inhibited L-IPNA-induced insulin secretion. The results suggest that VIP, secretin and gastrin display their effects on insulin secretion through different mechanisms. The results indirectly suggest the existence of separate insulin secretory pathways which operate differently, or at least partly differently, after glucose stimulation, cholinergic stimulation, and -adrenergic stimulation.