Summary
In the early stages of Type 1 (insulin-dependent) diabetes mellitus patients present a deficient insulin response to glucose. The reasons for this defective response are unknown, but it has been suggested that it reflects a deleterious effect of excessive glucose stimulation on a reduced Beta-cell mass. Female non-obese diabetic (NOD) mice from our colony, at the age of 12–13 weeks, have a normal basal glycaemia but an impaired intravenous glucose tolerance test, insulitis and a defective insulin response to glucose. In order to characterize the potential effect of glucose on the Beta cells at that “pre-diabetic” stage, pancreatic islets were isolated from 12–13 week old female NOD mice. Immediately after isolation (day 0) the NOD islets displayed a defective insulin response to an acute stimulation with 16.7 mmol/l glucose. After seven days in culture at both 11 and 28 mmol/l glucose these islets showed an increased insulin release in response to an acute glucose stimulation. This increase was more pronounced in the islets cultured at 28 mmol/l glucose. Experiments performed in parallel, using islets obtained from a non-diabetes prone strain of mice (Naval Medical Research Institute, NMRI) showed that these islets had a similar insulin release in response to glucose both on day 0 and after seven days in culture at 11 mmol/l glucose. The insulin mRNA levels of NOD islets did not change over one week in culture at 11 or 28 mmol/l glucose, but culture at the high glucose concentration induced a decrease in the islet insulin content. The present data show that culture at high glucose concentrations does not impair the function of islets isolated from NOD mice. These observations make excessive glucose stimulation, as a single factor, an unlikely explanation for the defective insulin release observed in NOD islets in the “prediabetic” period.
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References
Eisenbarth GS (1986) Type 1 diabetes mellitus. A chronic autoimmune disease. N Engl J Med 314: 1360–1368
Ganda OP, Srikanta S, Brink SJ, Morris MA, Gleason RE, Soeldner JS, Eisenbarth GS (1984) Differential sensitivity to β-cell secretagogues in “early”, type 1 diabetes mellitus. Diabetes 33: 516–521
Weir GC, Leahy JL, Bonner-Weir S (1986) Experimental reduction of B-cell mass: implications for the pathogenesis of diabetes. Diabetes Metab Rev 2: 125–161
Portha B, Blondel O, Serradas P, McEvoy RC, Giroix M-H, Kergoat M, Bailbe D (1989) The rat models of non-insulin dependent diabetes induced by neonatal streptozotocin. Diabete Metab 15: 61–75
Leiter EH, Prochazka M, Coleman D (1987) The non-obese diabetic (NOD) mouse. Am J Pathol 128: 380–383
Lampeter EF, Signore A, Gale EAM, Pozzilli P (1989) Lessons from the NOD mouse for the pathogenesis and immunotherapy of human Type 1 (insulin-dependent) diabetes mellitus. Diabetologia 32: 703–708
Kano Y, Kanatsuma T, Nakamura N, Kitagawa Y, Mori H, Kajiyama S, Nakano K, Kondo M (1986) Defect of the firstphase insulin secretion to glucose stimulation in the perfused pancreas of the nonobese diabetic (NOD) mouse. Diabetes 35: 486–490
Strandell E, Eizirik DL, Sandler S (1990) Reversal of β-cell suppression in vitro in pancreatic islets isolated from nonobese diabetic mice during the phase preceding insulin-dependent diabetes mellitus. J Clin Invest 85: 1994
Sandler S, Andersson A (1985) Modulation of streptozotocin-induced insulitis and hyperglycaemia in the mouse. Acta Pathol Microbiol Immunol Scand Sect [A] 93: 93–98
Howell SL, Taylor KW (1968) Potassium ions and the secretion of insulin by islets of Langerhans incubated in vitro. Biochem J 108: 17–24
Andersson A (1978) Isolated mouse pancreatic islets in culture: effects of serum and different culture media on the insulin production of the islets. Diabetologia 14: 397–404
Heding LG (1972) Determination of total serum insulin (IRI) in insulin-treated diabetic patients. Diabetologia 8: 260–266
Krebs HA, Henseleit K (1932) Untersuchungen über die Harnstoffbildung im Tierkörper. Hoppe-Seylers Z Physiol Chem 210: 33–66
Kissane JM, Robins E (1958) The fluorometric measurement of deoxyribonucleic acid in animal tissues with special reference to the central nervous system. J Biol Chem 233: 184–188
Hinegardner RT (1971) An improved fluorometric assay for DNA. Anal Biochem 39: 197–201
Thomas PS (1980) Hybridization of denaturated RNA and small DNA fragments transferred to nitrocellulose. Proc Natl Acad Sci USA 77: 5201–5205
White BA, Bancroft FC (1982) Cytoplasmic dot hybridization. Simple analysis of relative mRNA levels in multiple small cell of tissue samples. J Biol Chem 257: 8569–8572
Eizirik DL, Sandler S, Welsh N, Hellerström C (1988) Preferential reduction of insulin production in mouse pancreatic islets maintained in culture after streptozotocin exposure. Endocrinology 122: 1242–1249
Chan SJ, Noyes BE, Agarwal KL, Steiner DF (1979) Construction and selection of recombinant plasmids containing full-length complementary DNAs corresponding to rat insulins I and II. Proc Natl Acad Sci USA 76: 5036–5040
Wallenstein S, Zucker CL, Fleiss JL (1980) Some statistical methods useful in circulation research. Circ Res 47: 1–9
Eizirik DL, Sandler S (1989) Function and metabolism of pancreatic β-cells maintained in culture following experimentally induced damage. Pharmacol Toxicol 65: 163–168
Eizirik DL, Sandler S, Hallberg A, Bendtzen K, Sener A, Malaisse WJ (1989) Differential sensitivity to β-cell secretagogues in cultured rat pancreatic islets exposed to human interleukin-1β. Endocrinology 125: 752–759
Eizirik DL, Strandell E, Sandler S (1988) Culture of mouse pancreatic islets in different glucose concentrations modifies B-cell sensitivity to streptozotocin. Diabetologia 31: 168–174
Giroix M-H, Serradas P, Portha B (1989) The desensitization of normal B-cells to glucose in vitro is transient and not related to high glucose levels. Endocrinology 125: 1999–2007
Sandler S, Andersson A (1987) Cryopreservation of mouse pancreatic islets: effects of different glucose concentrations in the post-thaw culture medium on islet recovery. Cryobiology 24: 285–391
Schnell Landström AH, Westman J, Borg H (1988) Lysosomes and pancreatic islet function. Time course of insulin biosynthesis, insulin secretion and lysosomal transformation after rapid changes in glucose concentration. Diabetes 37: 309–316
Eizirik DL, Sandler S (1989) Sustained exposure of toxically damaged mouse pancreatic islets to high glucose does not increase β-cell dysfunction. J Endocrinol 123: 47–51
Andersson A, Borglund E, Brolin SE (1974) Effects of glucose on the content of ATP and glycogen and the role of glucose phosphorylation of isolated pancreatic islets maintained in tissue culture. Biochem Biophys Res Commun 56: 1045–1051
Welsh M, Brunstedt J, Hellerström C (1986) Effect of D-glucose, L-leucine and 2-ketoisocaproate on insulin mRNA levels in mouse pancreatic islets. Diabetes 35: 228–231
Andersson A, Westman J, Hellerström C (1974) Effects of glucose on the ultra-structure and insulin biosynthesis of isolated mouse pancreatic islets maintained in tissue culture. Diabetologia 10: 743–753
Tochino Y (1986) Discovery and breeding of the NOD mouse. In: Tarui S, Tochino Y, Nonaka K (eds) Insulitis and Type 1 diabetes. Lessons from the NOD mouse. Academic, Tokyo Orlando San Diego New York, pp 3–10
Welsh N, Hellerström C (1990) In vitro restoration of insulin production in islets from adult rats treated neonatally with streptozotocin. Endocrinology 126: 1842–1848
Eizirik DL, Strandell E, Bendtzen K, Sandler S (1988) Functional characteristics of rat pancreatic islets maintained in culture following exposure to human interleukin 1. Diabetes 37: 916–919
Mirouze J, Selam JL, Pham TC, Mendoza E, Orsetti A (1978) Sustained insulin-induced remission of juvenile diabetes by means of an external artificial pancreas. Diabetologia 14: 223–227
Madsbad S, Krarup T, Faber OK, Binder C, Regeur L (1982) The transient effect of strict glycaemic control on B-cell function in newly diagnosed Type 1 (insulin-dependent) diabetic patients. Diabetologia 22: 16–20
Shah S, Malone JI, Simpson NE (1989) A randomized trial of intensive insulin therapy in newly diagnosed insulin-dependent diabetes mellitus. N Engl J Med 320: 550–554
Kämpe O, Andersson A, Björk E, Hallberg A, Karlsson FA (1989) High-glucose stimulation of 64,000-Mr islet cell autoantigen expression. Diabetes 38: 1326–1328
Dotta F, Ziegler R, O'Neil JJ, Hayak RC, Eisenbarth GS, Appel MC (1989) Islet autoimmunity: identification and initial characterization of a metabolically regulable pancreatic ganglioside. Diabetologia 32: 438A
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Eizirik, D.L., Strandell, E. & Sandler, S. Prolonged exposure of pancreatic islets isolated from “pre-diabetic” non-obese diabetic mice to a high glucose concentration does not impair Beta-cell function. Diabetologia 34, 6–11 (1991). https://doi.org/10.1007/BF00404017
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DOI: https://doi.org/10.1007/BF00404017