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Östenson, C.; Khan, A.; Abdel-Halim, S.; Guenifi, A.; Suzuki, K.; Goto, Y.; Efendic, S.
doi: 10.1007/BF00399086pmid: 8436249
125 36 36 1 1 C. -G. Östenson A. Khan S. M. Abdel-Halim A. Guenifi K. Suzuki Y. Goto S. Efendic Department of Endocrinology Karolinska Institute and Hospital Stockholm Sweden Department of Medicine Tohoku Kosei-nenkin Hospital Sendai Japan Summary Insulin secretion and islet glucose metabolism were compared in pancreatic islets isolated from GK/Wistar (GK) rats with spontaneous Type 2 (non-insulin-dependent) diabetes mellitus and control Wistar rats. Islet insulin content was 24.5±3.1 μU/ng islet DNA in GK rats and 28.8±2.5 μU/ng islet DNA in control rats, with a mean (±SEM) islet DNA content of 17.3±1.7 and 26.5±3.4 ng ( p < 0.05), respectively. Basal insulin secretion at 3.3 mmol/l glucose was 0.19±0.03 μ · ng islet DNA −1 · h −1 in GK rat islets and 0.40±0.07 in control islets. Glucose (16.7 mmol/l) stimulated insulin release in GK rat islets only two-fold while in control islets five-fold. Glucose utilization at 16.7 mmol/l glucose, as measured by the formation of 3 H 2 O from (5- 3 H)glucose, was 2.4 times higher in GK rat islets (3.1±0.7 pmol · ng islet DNA −1 · h −1 ) than in control islets (1.3±0.1 pmol · ng islet DNA −1 · h −1 ; p <0.05). In contrast, glucose oxidation, estimated as the production of 14 CO 2 from (U- 14 C)glucose, was similar in both types of islets and corresponded to 15±2 and 30±3 % ( p <0.001) of total glucose phosphorylated in GK and control islets, respectively. Glucose cycling, i. e. the rate of dephosphorylation of the total amount of glucose phosphorylated, (determined as production of labelled glucose from islets incubated with 3 H 2 O) was 16.4±3.4% in GK rat and 6.4±1.0% in control islets, respectively ( p <0.01). We conclude that insulin secretion stimulated by glucose is markedly impaired in GK rat islets. Glucose metabolism is also altered in GK rat islets, with diminished ratio between oxidation and utilization of glucose, and increased glucose cycling, suggesting links between impaired glucose-induced insulin release and abnormal glucose metabolism.
Green, I.; Delaney, C.; Cunningham, J.; Karmiris, V.; Southern, C.
doi: 10.1007/BF00399087pmid: 7679657
125 36 36 1 1 I. C. Green C. A. Delaney J. M. Cunningham V. Karmiris C. Southern Biochemistry Laboratory School of Biological Sciences University of Sussex Brighton Yamanouchi Research Institute Littlemore Hospital Oxford UK Summary When islets were cultured with interleukin-1 β (1 or 100 pmol/l) for 12 h in arginine-containing medium, cyclic GMP levels were increased 1.6- and 4.5-fold respectively. The arginine analogue, N- ω -nitro- l -arginine methyl ester, which blocks nitric oxide formation and partially reverses inhibition of insulin secretion by 100 pmol/l interleukin-1 β , largely, but not completely, blocked generation of cyclic GMP. Treatment of islets with 100 pmol/l interleukin-1 β for 12 h significantly decreased islet cyclic AMP generation in the absence of isobutylmethylxanthine (from 13.1±0.7 to 9.3±0.8 fmol/μg islet protein), this fall was arginine-dependent and may have resulted from an effect on a cyclic AMP phosphodiesterase, since it was masked if isobutylmethylxanthine was present. Isobutylmethylxanthine (0.4 mmol/l) reduced the inhibitory potency of interleukin-1 β in 15 h slightly but significantly from 80.5 to 59.0%. The morpholinosydnonimine SIN-1, which is a nitric oxide donor, inhibited insulin secretion, raised islet cyclic GMP and lowered cyclic AMP; its effects were similar to those of interleukin-1 β . However, 6-anilinoquinoline-5,8-quinone, (LY83583 (1–10 μmol/l)), inhibited insulin secretion, and significantly decreased cyclic GMP while 8-bromocyclic GMP stimulated insulin secretion. Both low- and high-dose interleukin-1 β treatment give a large arginine-dependent and a small, yet significant, arginine-independent increase in cyclic GMP. The inhibitory effect of SIN-1 or interleukin-1 β on insulin secretion seems to depend to a small extent on decreased islet cyclic AMP, though sustained increases in nitric oxide or depleted islet GTP may directly affect the secretory process.
Kröncke, K.; Rodriguez, M.; Kolb, H.; Kolb-Bachofen, V.
doi: 10.1007/BF00399088pmid: 7679656
125 36 36 1 1 K. -D. Kröncke M. -L. Rodriguez H. Kolb V. Kolb-Bachofen Institute of Immunobiology, Department of Medicine Heinrich-Heine-University of Düsseldorf Deutschland Diabetes Research Institute Heinrich-Heine-University of Düsseldorf Deutschland Central Research, Department of Biotechnology Bayer AG Leverkusen FRG Summary Lysis of rat islet cells by syngeneic activated macrophages in vitro can be completely inhibited by the nitric oxide-synthase-inhibitor N G -methyl- l -arginine. This inhibition can be reversed by an excess of l -arginine. Time-dependent lysis of islet cells by activated macrophages is accompanied by increasing concentrations of nitrite and citrulline in the culture medium both of which are measures of nitric oxide formation derived from l -arginine. Lysis of isolated islet cells and disintegration of isolated whole islets is also obtained within 15 h by culture in the presence of the nitric oxide generating vasodilator sodium nitroprusside. We thus conclude that nitric oxide is extremely toxic for islet cells and that nitric oxide alone and in the absence of other macrophage-generated potentially toxic products can rapidly and completely kill islet cells.
Sten-Linder, M.; Wedell, A.; Iselius, L.; Efendic, S.; Luft, R.; Luthman, H.
doi: 10.1007/BF00399089pmid: 8094694
125 36 36 1 1 M. Sten-Linder A. Wedell L. Iselius S. Efendic R. Luft H. Luthman Department of Clinical Genetics, Karolinska Institute Karolinska Hospital Stockholm Sweden Department of Surgery, Karolinska Institute Karolinska Hospital Stockholm Sweden Department of Endocrinology, Karolinska Institute Karolinska Hospital Stockholm Sweden Summary The feasibility of disease association studies using polymorphic DNA markers in the tyrosine hydroxylase/insulin/insulin-like growth factor II chromosomal region was indicated by a high degree of linkage disequilibrium found in haplotypes. Haplotypes were resolved in the parents from Scandinavian nuclear families by studying the segregation of eight DNA polymorphisms. Comparison of observed vs expected frequencies of haplotypes, as well as pairwise measures of linkage disequilibrium, indicated a high degree of linkage disequilibrium. Five restriction fragment length polymorphisms linked to the tyrosine hydroxylase/insulin/ insulin growth factor II region of chromosome 11 were investigated in relation to Type 2 (non-insulin-dependent) diabetes mellitus, and to glucose and insulin responses to glucose infusion in healthy subjects. No significant differences in genotype frequencies between Type 2 diabetic ( n =53) and healthy subjects ( n =106) were found. A significant association ( p <0.001) was initially found between genotypes defined by a PstI polymorphism located 5′ of the tyrosine hydroxylase gene and the early glucose response to a standardized glucose infusion test in healthy subjects. However, a follow-up study of 112 healthy individuals failed to confirm this finding.
McVeigh, G.; Brennan, G.; Johnston, G.; McDermott, B.; McGrath, L.; Henry, W.; Andrews, J.; Hayes, J.
doi: 10.1007/BF00399090pmid: 8436250
125 36 36 1 1 G. E. McVeigh G. M. Brennan G. D. Johnston B. J. McDermott L. T. McGrath W. R. Henry J. W. Andrews J. R. Hayes Department of Therapeutics and Pharmacology The Queen's University of Belfast Belfast Northern Ireland Department of Medicine Belfast City Hospital Belfast Northern Ireland Department of Medicine Whiteabbey Hospital Belfast Northern Ireland Summary Decreased release of nitric oxide from damaged endothelium is responsible for the impaired endothelium-dependent vasodilator responses found in animal models of vascular disease. Dietary supplementation with fish oils has been shown to augment endothelium-dependent relaxations, principally by improving the release of nitric oxide from injured endothelium. Using forearm venous occlusion plethysmography we studied vascular responses to 60, 120, 180 and 240 nmol/min of acetylcholine (an endothelium-dependent vasodilator) and 3, 6 and 9 nmol/min of glyceryl trinitrate (an endothelium-independent vasodilator) infused into the brachial artery in 23 patients with Type 2 (non-insulin-dependent) diabetes mellitus. N G monomethyl- l -arginine was employed to inhibit stimulated and basal release of nitric oxide from the endothelium. On completion of the baseline studies patients randomly received either fish oil or matching olive oil capsules in a double-blind crossover fashion for 6 weeks followed by a 6-week washout period and a final 6-week treatment phase. Studies, identical to the initial baseline studies, were performed at the end of the active treatment periods at 6 and 18 weeks. Fish oil supplementation significantly improved forearm blood flow responses to each dose of acetylcholine when compared to the vasodilator responses recorded at baseline and after olive oil administration ( p <0.01). Neither fish oil nor olive oil supplementation produced any significant changes in forearm blood flow to the incremental infusions of glyceryl trinitrate when compared with responses recorded during the baseline studies. N G monomethyl- l -arginine significantly reduced forearm blood flow from maximal stimulated values to acetylcholine when compared to the uninhibited decline in flow to acetylcholine infusions at comparable time points ( p <0.01). Treatment with fish oils improved endothelium-dependent responses to acetylcholine without altering endothelium-independent responses to glyceryl trinitrate. By increasing stimulated nitric oxide release from the endothelium fish oils may afford protection against vasospasm and thrombosis in patients with diabetes mellitus.
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