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. 1996 Jan 1;97(1):180–186. doi: 10.1172/JCI118387

Mechanism of impaired glucose-potentiated insulin secretion in diabetic 90% pancreatectomy rats. Study using glucagonlike peptide-1 (7-37).

Y A Hosokawa 1, H Hosokawa 1, C Chen 1, J L Leahy 1
PMCID: PMC507077  PMID: 8550831

Abstract

Chronic hyperglycemia causes a near-total disappearance of glucose-induced insulin secretion. To determine if glucose potentiation of nonglucose secretagogues is impaired, insulin responses to 10(-9) M glucagonlike peptide-1 (GLP-1) (7-37) were measured at 2.8, 8.3, and 16.7 mM glucose with the in vitro perfused pancreas in rats 4-6 wk after 90% pancreatectomy (Px) and sham-operated controls. In the controls, insulin output to GLP-1 was > 100-fold greater at 16.7 mM glucose versus 2.8 mM glucose. In contrast, the increase was less than threefold in Px, reaching an insulin response at 16.7 mM glucose that was 10 +/- 2% of the controls, well below the predicted 35-40% fractional beta-cell mass in these rats. Px and control rats then underwent a 40-h fast followed by pancreas perfusion using a protocol of 20 min at 16.7 mM glucose followed by 15 min at 16.7 mM glucose/10(-9) M GLP-1. In control rats, fasting suppressed insulin release to high glucose (by 90%) and to GLP-1 (by 60%) without changing the pancreatic insulin content. In contrast, in Px the insulin response to GLP-1 tripled in association with a threefold increase of the insulin content, both now being twice normal when stratified for the fractional beta-cell mass. The mechanism of the increased pancreas insulin content was investigated by assessing islet glucose metabolism and proinsulin biosynthesis. In controls with fasting, both fell 30-50%. In Px, the degree of suppression with fasting was similar, but the attained levels both exceeded those of the controls because of higher baseline (nonfasted) values. In summary, chronic hyperglycemia is associated with a fasting-induced paradoxical increase in glucose-potentiated insulin secretion. In Px rats, the mechanism is an increase in the beta-cell insulin stores, which suggests a causative role for a lowered beta-cell insulin content in the impaired glucose-potentiation of insulin secretion.

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Selected References

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  1. Alarcón C., Leahy J. L., Schuppin G. T., Rhodes C. J. Increased secretory demand rather than a defect in the proinsulin conversion mechanism causes hyperproinsulinemia in a glucose-infusion rat model of non-insulin-dependent diabetes mellitus. J Clin Invest. 1995 Mar;95(3):1032–1039. doi: 10.1172/JCI117748. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Alarcón C., Lincoln B., Rhodes C. J. The biosynthesis of the subtilisin-related proprotein convertase PC3, but no that of the PC2 convertase, is regulated by glucose in parallel to proinsulin biosynthesis in rat pancreatic islets. J Biol Chem. 1993 Feb 25;268(6):4276–4280. [PubMed] [Google Scholar]
  3. Albano J. D., Ekins R. P., Maritz G., Turner R. C. A sensitive, precise radioimmunoassay of serum insulin relying on charcoal separation of bound and free hormone moieties. Acta Endocrinol (Copenh) 1972 Jul;70(3):487–509. doi: 10.1530/acta.0.0700487. [DOI] [PubMed] [Google Scholar]
  4. Ashcroft S. J., Bunce J., Lowry M., Hansen S. E., Hedeskov C. J. The effect of sugars on (pro)insulin biosynthesis. Biochem J. 1978 Aug 15;174(2):517–526. doi: 10.1042/bj1740517. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Ashcroft S. J., Weerasinghe L. C., Bassett J. M., Randle P. J. The pentose cycle and insulin release in mouse pancreatic islets. Biochem J. 1972 Feb;126(3):525–532. doi: 10.1042/bj1260525. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Becker T. C., BeltrandelRio H., Noel R. J., Johnson J. H., Newgard C. B. Overexpression of hexokinase I in isolated islets of Langerhans via recombinant adenovirus. Enhancement of glucose metabolism and insulin secretion at basal but not stimulatory glucose levels. J Biol Chem. 1994 Aug 19;269(33):21234–21238. [PubMed] [Google Scholar]
  7. Björklund A., Grill V. B-cell insensitivity in vitro: reversal by diazoxide entails more than one event in stimulus-secretion coupling. Endocrinology. 1993 Mar;132(3):1319–1328. doi: 10.1210/endo.132.3.7679978. [DOI] [PubMed] [Google Scholar]
  8. Björkman O., Eriksson L. S. Influence of a 60-hour fast on insulin-mediated splanchnic and peripheral glucose metabolism in humans. J Clin Invest. 1985 Jul;76(1):87–92. doi: 10.1172/JCI111982. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Bonner-Weir S., Baxter L. A., Schuppin G. T., Smith F. E. A second pathway for regeneration of adult exocrine and endocrine pancreas. A possible recapitulation of embryonic development. Diabetes. 1993 Dec;42(12):1715–1720. doi: 10.2337/diab.42.12.1715. [DOI] [PubMed] [Google Scholar]
  10. Bonner-Weir S., Trent D. F., Weir G. C. Partial pancreatectomy in the rat and subsequent defect in glucose-induced insulin release. J Clin Invest. 1983 Jun;71(6):1544–1553. doi: 10.1172/JCI110910. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Brockenbrough J. S., Weir G. C., Bonner-Weir S. Discordance of exocrine and endocrine growth after 90% pancreatectomy in rats. Diabetes. 1988 Feb;37(2):232–236. doi: 10.2337/diab.37.2.232. [DOI] [PubMed] [Google Scholar]
  12. Burch P. T., Trus M. D., Berner D. K., Leontire A., Zawalich K. C., Matschinsky F. M. Adaptation of glycolytic enzymes: glucose use and insulin release in rat pancreatic islets during fasting and refeeding. Diabetes. 1981 Nov;30(11):923–928. doi: 10.2337/diab.30.11.923. [DOI] [PubMed] [Google Scholar]
  13. Chen C., Bumbalo L., Leahy J. L. Increased catalytic activity of glucokinase in isolated islets from hyperinsulinemic rats. Diabetes. 1994 May;43(5):684–689. doi: 10.2337/diab.43.5.684. [DOI] [PubMed] [Google Scholar]
  14. Féry F., Balasse E. O. Glucose metabolism during the starved-to-fed transition in obese patients with NIDDM. Diabetes. 1994 Dec;43(12):1418–1425. doi: 10.2337/diab.43.12.1418. [DOI] [PubMed] [Google Scholar]
  15. Giroix M. H., Sener A., Bailbe D., Portha B., Malaisse W. J. Impairment of the mitochondrial oxidative response to D-glucose in pancreatic islets from adult rats injected with streptozotocin during the neonatal period. Diabetologia. 1990 Nov;33(11):654–660. doi: 10.1007/BF00400566. [DOI] [PubMed] [Google Scholar]
  16. Giroix M. H., Sener A., Pipeleers D. G., Malaisse W. J. Hexose metabolism in pancreatic islets. Inhibition of hexokinase. Biochem J. 1984 Oct 15;223(2):447–453. doi: 10.1042/bj2230447. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Gotoh M., Maki T., Satomi S., Porter J., Bonner-Weir S., O'Hara C. J., Monaco A. P. Reproducible high yield of rat islets by stationary in vitro digestion following pancreatic ductal or portal venous collagenase injection. Transplantation. 1987 May;43(5):725–730. doi: 10.1097/00007890-198705000-00024. [DOI] [PubMed] [Google Scholar]
  18. Greenwood R. H., Mahler R. F., Hales C. N. Improvement in insulin secretion in diabetes after diazoxide. Lancet. 1976 Feb 28;1(7957):444–447. doi: 10.1016/s0140-6736(76)91473-2. [DOI] [PubMed] [Google Scholar]
  19. Grey N. J., Goldring S., Kipnis D. M. The effect of fasting, diet, and actinomycin D on insulin secretion in the rat. J Clin Invest. 1970 May;49(5):881–889. doi: 10.1172/JCI106307. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Halter J. B., Graf R. J., Porte D., Jr Potentiation of insulin secretory responses by plasma glucose levels in man: evidence that hyperglycemia in diabetes compensates for imparied glucose potentiation. J Clin Endocrinol Metab. 1979 Jun;48(6):946–954. doi: 10.1210/jcem-48-6-946. [DOI] [PubMed] [Google Scholar]
  21. Hosker J. P., Kumar S., Gordon C., Bhatnagar D., France M., Boulton A. J. Diet treatment of newly presenting type 2 diabetes improves insulin secretory capacity, but has no effect on insulin sensitivity. Diabet Med. 1993 Jul;10(6):509–513. doi: 10.1111/j.1464-5491.1993.tb00111.x. [DOI] [PubMed] [Google Scholar]
  22. Hosokawa H., Hosokawa Y. A., Leahy J. L. Upregulated hexokinase activity in isolated islets from diabetic 90% pancreatectomized rats. Diabetes. 1995 Nov;44(11):1328–1333. doi: 10.2337/diab.44.11.1328. [DOI] [PubMed] [Google Scholar]
  23. Ishihara H., Asano T., Tsukuda K., Katagiri H., Inukai K., Anai M., Kikuchi M., Yazaki Y., Miyazaki J., Oka Y. Overexpression of hexokinase I but not GLUT1 glucose transporter alters concentration dependence of glucose-stimulated insulin secretion in pancreatic beta-cell line MIN6. J Biol Chem. 1994 Jan 28;269(4):3081–3087. [PubMed] [Google Scholar]
  24. Koranyi L., Bourey R., Turk J., Mueckler M., Permutt M. A. Differential expression of rat pancreatic islet beta-cell glucose transporter (GLUT 2), proinsulin and islet amyloid polypeptide genes after prolonged fasting, insulin-induced hypoglycaemia and dexamethasone treatment. Diabetologia. 1992 Dec;35(12):1125–1132. doi: 10.1007/BF00401365. [DOI] [PubMed] [Google Scholar]
  25. Leahy J. L., Bonner-Weir S., Weir G. C. Beta-cell dysfunction induced by chronic hyperglycemia. Current ideas on mechanism of impaired glucose-induced insulin secretion. Diabetes Care. 1992 Mar;15(3):442–455. doi: 10.2337/diacare.15.3.442. [DOI] [PubMed] [Google Scholar]
  26. Leahy J. L., Bumbalo L. M., Chen C. Beta-cell hypersensitivity for glucose precedes loss of glucose-induced insulin secretion in 90% pancreatectomized rats. Diabetologia. 1993 Dec;36(12):1238–1244. doi: 10.1007/BF00400800. [DOI] [PubMed] [Google Scholar]
  27. Leahy J. L., Bumbalo L. M., Chen C. Diazoxide causes recovery of beta-cell glucose responsiveness in 90% pancreatectomized diabetic rats. Diabetes. 1994 Feb;43(2):173–179. doi: 10.2337/diab.43.2.173. [DOI] [PubMed] [Google Scholar]
  28. Leahy J. L. Natural history of beta-cell dysfunction in NIDDM. Diabetes Care. 1990 Sep;13(9):992–1010. doi: 10.2337/diacare.13.9.992. [DOI] [PubMed] [Google Scholar]
  29. Leahy J. L., Weir G. C. Beta-cell dysfunction in hyperglycaemic rat models: recovery of glucose-induced insulin secretion with lowering of the ambient glucose level. Diabetologia. 1991 Sep;34(9):640–647. doi: 10.1007/BF00400993. [DOI] [PubMed] [Google Scholar]
  30. Levy J., Herchuelz A., Sener A., Malaisse W. J. The stimulus-secretion coupling of glucose-induced insulin release. XX. fasting: a model for altered glucose recognition by the B-cell. Metabolism. 1976 May;25(5):583–591. doi: 10.1016/0026-0495(76)90012-3. [DOI] [PubMed] [Google Scholar]
  31. Malaisse W. J., Malaisse-Lagae F., Wright P. H. Effect of fasting upon insulin secretion in the rat. Am J Physiol. 1967 Oct;213(4):843–848. doi: 10.1152/ajplegacy.1967.213.4.843. [DOI] [PubMed] [Google Scholar]
  32. Malaisse W. J., Sener A., Levy J. The stimulus-secretion coupling of glucose-induced insulin release. Fasting-induced adaptation of key glycolytic enzymes in isolated islets. J Biol Chem. 1976 Mar 25;251(6):1731–1737. [PubMed] [Google Scholar]
  33. Meglasson M. D., Matschinsky F. M. Pancreatic islet glucose metabolism and regulation of insulin secretion. Diabetes Metab Rev. 1986;2(3-4):163–214. doi: 10.1002/dmr.5610020301. [DOI] [PubMed] [Google Scholar]
  34. Milburn J. L., Jr, Hirose H., Lee Y. H., Nagasawa Y., Ogawa A., Ohneda M., BeltrandelRio H., Newgard C. B., Johnson J. H., Unger R. H. Pancreatic beta-cells in obesity. Evidence for induction of functional, morphologic, and metabolic abnormalities by increased long chain fatty acids. J Biol Chem. 1995 Jan 20;270(3):1295–1299. doi: 10.1074/jbc.270.3.1295. [DOI] [PubMed] [Google Scholar]
  35. Mojsov S., Weir G. C., Habener J. F. Insulinotropin: glucagon-like peptide I (7-37) co-encoded in the glucagon gene is a potent stimulator of insulin release in the perfused rat pancreas. J Clin Invest. 1987 Feb;79(2):616–619. doi: 10.1172/JCI112855. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Porte D., Jr Banting lecture 1990. Beta-cells in type II diabetes mellitus. Diabetes. 1991 Feb;40(2):166–180. doi: 10.2337/diab.40.2.166. [DOI] [PubMed] [Google Scholar]
  37. Sako Y., Grill V. E. Coupling of beta-cell desensitization by hyperglycemia to excessive stimulation and circulating insulin in glucose-infused rats. Diabetes. 1990 Dec;39(12):1580–1583. doi: 10.2337/diab.39.12.1580. [DOI] [PubMed] [Google Scholar]
  38. Thorens B., Waeber G. Glucagon-like peptide-I and the control of insulin secretion in the normal state and in NIDDM. Diabetes. 1993 Sep;42(9):1219–1225. doi: 10.2337/diab.42.9.1219. [DOI] [PubMed] [Google Scholar]
  39. Tjioe T. O., Bouman P. R. Effect of fasting on the incorporation of [3H]-L-phenylalanine into proinsulin-insulin and total protein in isolated rat pancreatic islets. Horm Metab Res. 1976 Jul;8(4):261–266. doi: 10.1055/s-0028-1093651. [DOI] [PubMed] [Google Scholar]
  40. Ward W. K., Bolgiano D. C., McKnight B., Halter J. B., Porte D., Jr Diminished B cell secretory capacity in patients with noninsulin-dependent diabetes mellitus. J Clin Invest. 1984 Oct;74(4):1318–1328. doi: 10.1172/JCI111542. [DOI] [PMC free article] [PubMed] [Google Scholar]
  41. Weir G. C., Knowlton S. D., Martin D. B. Glucagon secretion from the perfused rat pancreas. Studies with glucose and catecholamines. J Clin Invest. 1974 Dec;54(6):1403–1412. doi: 10.1172/JCI107887. [DOI] [PMC free article] [PubMed] [Google Scholar]
  42. Weir G. C., Mojsov S., Hendrick G. K., Habener J. F. Glucagonlike peptide I (7-37) actions on endocrine pancreas. Diabetes. 1989 Mar;38(3):338–342. doi: 10.2337/diab.38.3.338. [DOI] [PubMed] [Google Scholar]
  43. Williams G. Management of non-insulin-dependent diabetes mellitus. Lancet. 1994 Jan 8;343(8889):95–100. doi: 10.1016/s0140-6736(94)90822-2. [DOI] [PubMed] [Google Scholar]

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