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October 1977, Vol 131, No. 10 >
Article | October 1977

Viral and Immunological Bases of Beta Cell Failure in Insulin-Dependent Diabetes FREE

Noel K. Maclaren, MD
[+] Author Affiliations

Reprint requests to Pediatric Endocrinology and Metabolism, University of Maryland School of Medicine, 685 W Baltimore St, Baltimore, MD 21201 (Dr Maclaren).


Am J Dis Child. 1977;131(10):1149-1154. doi:10.1001/archpedi.1977.02120230095018.
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Comments

• Pathologists have confirmed the specific nature of the insulitis lesion in diabetes requiring insulin. Data from genetic studies implicate both genetic and environmental influences as important in the appearance of overt disease. Certain HLA histocompatibility antigens are associated with insulin-dependent diabetes and have been interpreted as markers for closely linked immune response genes, a situation that may lead to beta cell susceptibility to viral injury or to uncontrolled beta cell autoaggression following beta cell damage. There is much circumstantial evidence that viruses may precipitate the disease (coxsackie) or may precede the disease onset by a long interval (mumps, rubella). However, susceptibility to virus, if it exists in human insulin-requiring diabetes, would appear on clinical grounds to be localized to the pancreas. Autoimmune phenomena are common in insulin-requiring diabetes, and there is both human and animal evidence that suggest that cell-mediated immunity may have a central pathogenic role. The recent explosion of new findings should lead to a clearer understanding of the nature of the disease, and this knowledge will hopefully lend itself to the prevention or arrest of the disease through immunological intervention, vaccination programs, or other means yet to be discovered.

(Am J Dis Child 131:1149-1154, 1977)

REFERENCES

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2 +
Heiberg KA:  Über Diabetes bei Kindern . Arch Kinderheilk 56:403-405, 1911;.
3 +
Weichselbaum A:  Über die Ver änderungen des Pankreas bei Diabetes Mellitus . S B Akad Wiss Wien math-nat Kl 119:73-75, 1910;.
4 +
Von Meyenburg H:  Über Insulitis bei Diabetes . Schweiz Med Wochenschr 21:554-561, 1940;.
5 +
Le Compte PM:  "Insulitis" in early juvenile diabetes . Arch Pathol 66:540-547, 1958;.
6 +
Warren S, Le Compte PM, Legg MA: The Pathology of Diabetes Mellitus , ed 4. London, Kimpton, 1966;
7 +
Ogilvie RF:  The endocrine pancreas in human and experimental diabetes , in Cameron MD, O'Connor M (eds): Etiology of Diabetes Mellitus and Its Complications: Ciba Foundation Colloquia on Endocrinology . London, Churchill, 1964;, vol 15, pp 619-633.
8 +
Gepts W:  Pathological anatomy of the pancreas in juvenile diabetes mellitus . Diabetes 14:619-633, 1965;.
9 +
Gepts W:  Insulitis: Autoimmune aspects , in Bastenie PA, Gepts W (eds): Immunity and Autoimmunity in Diabetes Mellitus . Amsterdam, Excerpta Medica, 1974;, pp 173-174.
10 +
Doniach I, Morgan AG:  Islets of Langerhans in juvenile diabetes mellitus . Clin Endocrinol 2:233-248, 1973;.
Link to Article
11 +
Le Compte PM, Legg MA:  Insulitis (lymphocytic infiltration of islets) in late-onset diabetes . Diabetes 21:762-769, 1972;.
12 +
Doniach I:  Pathology of the islets of Langerhans in diabetes mellitus , in Bastenie PA, Gepts W (eds): Immunity and Autoimmunity in Diabetes Mellitus . Amsterdam, Excerpta Medica, 1974;, pp 175-182.
13 +
Vracko R, Benditt EP:  Manifestations of diabetes mellitus—their possible relationships to an underlying cell defect . Am J Pathol 75:204-221, 1974;.
14 +
Frias JL, Rosenbloom AL:  The genetics of diabetes . Metabolism 22:355-357, 1973;.
Link to Article
15 +
Tattersall RB, Pyke DA:  Genetic susceptibility in diabetic identical twins . Lancet 1:1120-1122, 1972;.
Link to Article
16 +
Nelson PG, Pyke DA, Cudworth AG, et al:  Histocompatibility antigens in diabetic identical twins . Lancet 2:193-194, 1975;.
Link to Article
17 +
Pyke DA: Genetics of Diabetes . New York, Springer-Verlag, 1976;, p 197.
18 +
Rosenthal MB, Goldfine ID, Siperstein MD:  Genetic origin of diabetes: Re-evaluation of twin data . Lancet 2:250, 1976;.
Link to Article
19 +
Gottlieb MS, Root HF:  Diabetes mellitus in twins . Diabetes 17:693-704, 1968;.
20 +
Burch PRJ:  Diabetes mellitus: Concordance in monozygotic twins , letter to the editor. Lancet 2:632, 1976;.
Link to Article
21 +
Pyke DA, Theophanides CG, Tattersall RB:  Genetic origin of diabetes: Re-evaluation of twin data , letter to the editor. Lancet 2:464, 1976;.
Link to Article
22 +
Tattersall RB, Fajans SS:  A difference between the inheritance of classical juvenile onset and maturity onset type diabetes of young people . Diabetes 24:44-53, 1975;.
Link to Article
23 +
Tattersall LB, Fajans SS:  Prevalence of diabetes and glucose intolerance in 199 offspring of 37 conjugal diabetic parents . Diabetes 24:452-462, 1975;.
Link to Article
24 +
Singal DP, Blajchman MA:  Histocompatibility (HL-A) antigens, lymphotoxic antibodies and tissue antibodies in patients with diabetes mellitus . Diabetes 22:429-432, 1973;.
25 +
Nerup J, Platz P, Anderson OQ, et al:  HL-A antigens and diabetes mellitus . Lancet 2:864-865, 1974;.
Link to Article
26 +
Cudworth AG, Woodrow JC:  HL-A system and diabetes mellitus . Diabetes 24:345-349, 1975;.
Link to Article
27 +
Cudworth AG, Woodrow JC:  Evidence for HL-A linked genes in "juvenile" diabetes mellitus . Br Med J 3:133-136, 1975;.
Link to Article
28 +
Cudworth AG, Woodrow JC:  Genetic susceptibility in diabetic identical twins , letter to the editor. Lancet 2:518, 1976;.
Link to Article
29 +
Landgrat R, Landgrat-Leurs M, Lander T, et al:  HL-A haplotypes and glucose tolerance in families of patients with juvenile onset diabetes mellitus , letter to the editor. Lancet 2:1084, 1976;.
Link to Article
30 +
Kawa A, Nakazawa M, Sakaguchi S, et al:  HLA system in Japanese patients with diabetes mellitus . Diabetes 26:591-595, 1977;.
Link to Article
31 +
Christy M, Nerup J, Botazzo GF, et al:  Association between HLA-B8 and autoimmunity in juvenile diabetes mellitus , letter to the editor. Lancet 2:142-143, 1976;.
Link to Article
32 +
Friedman JM:  Inheritance of susceptibility to histocompatibility-associated disease , letter to the editor. Lancet 1:49, 1976;.
Link to Article
33 +
Hansen HE, Ryder LP, Nielson LS:  Recombination between the second and third series of the HL-A system . Tissue Antigens 6:275-277, 1975;.
Link to Article
34 +
Maugh T II:  Diabetes: Epidemiology suggests a viral connection, research news . Science 347-351, 1975;.
35 +
Harris HF:  A case of diabetes mellitus quickly following mumps . Boston Med Surg J 140:465-467, 1899;.
Link to Article
36 +
Gunderson E:  Is diabetes of infectious origin? J Infect Dis 41:197-202, 1927;.
Link to Article
37 +
Melin K, Ursing B:  Diabetes mellitus som Komplikation till parotitis epidemica . Nord Med 60:1715-1717, 1958;.
38 +
Sultz HA, Hart BA, Zielozny M:  Editors column: Is mumps virus an etiologic factor in juvenile diabetes? J Pediatr 86:654-656.
39 +
Sultz HA, Sokal D, Sdao M: Epidemiologic evidence for mumps virus etiology of childhood diabetes. Read before the American Diabetes Association Research Symposium, Indianapolis, Oct 1975.
40 +
Rawls WE:  Congenital rubella. The significance of virus persistence . Prog Med Virol 10:238-285, 1968;.
41 +
Forrest JM, Menser MA, Harley JD:  Diabetes mellitus and congenital rubella . Pediatrics 44:445-447, 1969;.
42 +
Forrest JM, Menser MA, Burgess JA:  High frequency of diabetes mellitus in young adults with congenital rubella . Lancet 2:332-334, 1971;.
Link to Article
43 +
Gamble DR, Taylor KW:  Seasonal incidence of diabetes mellitus . Br Med J 3:631-633, 1969;.
Link to Article
44 +
Gamble DR, Kinsley ML, Fitzgerald MG, et al:  Viral antibodies in diabetes mellitus . Br Med J 3:627-639, 1969;.
Link to Article
45 +
Gamble DR, Taylor KW:  Coxsackie B virus and diabetes . Br Med J 1:289-290, 1973;.
Link to Article
46 +
Barboni E, Manocchio I:  Alterazionia pancreatic in bovini con diabete mellito postaftoso . Arch Vet Ital 13:477-483, 1962;.
47 +
Barboni E, Manocchio I, Asdrubali G:  Observations on diabetes mellitus associated with experimental foot and mouth disease in cattle . Arch Vet Ital 17:362-369, 1966;.
48 +
Craighead JE, McLane MF:  Diabetes mellitus: Induction in mice by encephalomyocarditis virus . Science 162:913-914, 1968;.
Link to Article
49 +
Boucher DW, Notkins AL:  Virus induced diabetes mellitus: I. Hyperglycemia and hypoinsulinoma in mice infected with encephalomyocarditis virus . J Exp Med 137:1226-1239, 1973;.
Link to Article
50 +
Hayashi K, Boucher DW, Notkins AL:  Virus-induced diabetes mellitus: II. Relationship between beta cell damage and hyperglycemia in mice infected with encephalomyocarditis virus . Am J Pathol 75:91-97, 1974;.
51 +
Wolf RO, Ross ME, Notkins AL:  Amylase isoenzymes during viral infections of the pancreas and salivary glands . J Lab Clin Med 83:750-756, 1974;.
52 +
Craighead JE, Higgins DA:  Genetic influences affecting the occurrence of a diabeteslike syndrome disease in mice infected with the encephalomyocarditis virus . J Exp Med 139:414-426, 1974;.
Link to Article
53 +
Yoon J-W, Notkins AL:  Virus-induced diabetes mellitus: VI. Genetically determined host differences in the replication of encephalomyocarditis virus in pancreatic beta cells . J Exp Med 143:1170-1185, 1976;.
Link to Article
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Webb SR, Loria RM, Madge GE, et al:  Susceptibility of mice to group Coxsackie B virus is influenced by the diabetic gene . J Exp Med 143:1239-1248, 1976;.
Link to Article
55 +
Taylor KW:  The diabetogenic effect of Coxsackie B viruses , in Bastenie PA, Gepts W (eds): Immunity and Autoimmunity in Diabetes Mellitus . Amsterdam, Excerpta Medica, 1974;, pp 242-244.
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Ogle JW:  On disease of the brain as a result of diabetes mellitus . St Georges Hosp Rep 1:157-160, 1866;.
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Irvine WJ, Barnes EW:  Addison's disease and associated conditions with particular reference to premature ovarian failure, diabetes mellitus and hypoparathyroidism , in Coombs RRA, Gell PH, Lachman P (eds): Clinical Aspects of Immunology , ed 3. Oxford, England, Blackwell Scientific Publications, 1974;, pp 46-58.
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Nerup J, Binder C:  Thyroid gastric and adrenal autoimmunity in diabetes mellitus . Acta Endocrinol 72:279-286, 1973;.
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Link to Article

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Country-Specific Mortality and Growth Failure in Infancy and Yound Children and Association With Material Stature

Use interactive graphics and maps to view and sort country-specific infant and early dhildhood mortality and growth failure data and their association with maternal

References

1 +
Schmidt MB:  Über die beziehung der Langerhans' schen Inseln des Pankreas zum Diabetes Mellitus . Munch Med Wochenschr 49:51-52, 1902;.
2 +
Heiberg KA:  Über Diabetes bei Kindern . Arch Kinderheilk 56:403-405, 1911;.
3 +
Weichselbaum A:  Über die Ver änderungen des Pankreas bei Diabetes Mellitus . S B Akad Wiss Wien math-nat Kl 119:73-75, 1910;.
4 +
Von Meyenburg H:  Über Insulitis bei Diabetes . Schweiz Med Wochenschr 21:554-561, 1940;.
5 +
Le Compte PM:  "Insulitis" in early juvenile diabetes . Arch Pathol 66:540-547, 1958;.
6 +
Warren S, Le Compte PM, Legg MA: The Pathology of Diabetes Mellitus , ed 4. London, Kimpton, 1966;
7 +
Ogilvie RF:  The endocrine pancreas in human and experimental diabetes , in Cameron MD, O'Connor M (eds): Etiology of Diabetes Mellitus and Its Complications: Ciba Foundation Colloquia on Endocrinology . London, Churchill, 1964;, vol 15, pp 619-633.
8 +
Gepts W:  Pathological anatomy of the pancreas in juvenile diabetes mellitus . Diabetes 14:619-633, 1965;.
9 +
Gepts W:  Insulitis: Autoimmune aspects , in Bastenie PA, Gepts W (eds): Immunity and Autoimmunity in Diabetes Mellitus . Amsterdam, Excerpta Medica, 1974;, pp 173-174.
10 +
Doniach I, Morgan AG:  Islets of Langerhans in juvenile diabetes mellitus . Clin Endocrinol 2:233-248, 1973;.
Link to Article
11 +
Le Compte PM, Legg MA:  Insulitis (lymphocytic infiltration of islets) in late-onset diabetes . Diabetes 21:762-769, 1972;.
12 +
Doniach I:  Pathology of the islets of Langerhans in diabetes mellitus , in Bastenie PA, Gepts W (eds): Immunity and Autoimmunity in Diabetes Mellitus . Amsterdam, Excerpta Medica, 1974;, pp 175-182.
13 +
Vracko R, Benditt EP:  Manifestations of diabetes mellitus—their possible relationships to an underlying cell defect . Am J Pathol 75:204-221, 1974;.
14 +
Frias JL, Rosenbloom AL:  The genetics of diabetes . Metabolism 22:355-357, 1973;.
Link to Article
15 +
Tattersall RB, Pyke DA:  Genetic susceptibility in diabetic identical twins . Lancet 1:1120-1122, 1972;.
Link to Article
16 +
Nelson PG, Pyke DA, Cudworth AG, et al:  Histocompatibility antigens in diabetic identical twins . Lancet 2:193-194, 1975;.
Link to Article
17 +
Pyke DA: Genetics of Diabetes . New York, Springer-Verlag, 1976;, p 197.
18 +
Rosenthal MB, Goldfine ID, Siperstein MD:  Genetic origin of diabetes: Re-evaluation of twin data . Lancet 2:250, 1976;.
Link to Article
19 +
Gottlieb MS, Root HF:  Diabetes mellitus in twins . Diabetes 17:693-704, 1968;.
20 +
Burch PRJ:  Diabetes mellitus: Concordance in monozygotic twins , letter to the editor. Lancet 2:632, 1976;.
Link to Article
21 +
Pyke DA, Theophanides CG, Tattersall RB:  Genetic origin of diabetes: Re-evaluation of twin data , letter to the editor. Lancet 2:464, 1976;.
Link to Article
22 +
Tattersall RB, Fajans SS:  A difference between the inheritance of classical juvenile onset and maturity onset type diabetes of young people . Diabetes 24:44-53, 1975;.
Link to Article
23 +
Tattersall LB, Fajans SS:  Prevalence of diabetes and glucose intolerance in 199 offspring of 37 conjugal diabetic parents . Diabetes 24:452-462, 1975;.
Link to Article
24 +
Singal DP, Blajchman MA:  Histocompatibility (HL-A) antigens, lymphotoxic antibodies and tissue antibodies in patients with diabetes mellitus . Diabetes 22:429-432, 1973;.
25 +
Nerup J, Platz P, Anderson OQ, et al:  HL-A antigens and diabetes mellitus . Lancet 2:864-865, 1974;.
Link to Article
26 +
Cudworth AG, Woodrow JC:  HL-A system and diabetes mellitus . Diabetes 24:345-349, 1975;.
Link to Article
27 +
Cudworth AG, Woodrow JC:  Evidence for HL-A linked genes in "juvenile" diabetes mellitus . Br Med J 3:133-136, 1975;.
Link to Article
28 +
Cudworth AG, Woodrow JC:  Genetic susceptibility in diabetic identical twins , letter to the editor. Lancet 2:518, 1976;.
Link to Article
29 +
Landgrat R, Landgrat-Leurs M, Lander T, et al:  HL-A haplotypes and glucose tolerance in families of patients with juvenile onset diabetes mellitus , letter to the editor. Lancet 2:1084, 1976;.
Link to Article
30 +
Kawa A, Nakazawa M, Sakaguchi S, et al:  HLA system in Japanese patients with diabetes mellitus . Diabetes 26:591-595, 1977;.
Link to Article
31 +
Christy M, Nerup J, Botazzo GF, et al:  Association between HLA-B8 and autoimmunity in juvenile diabetes mellitus , letter to the editor. Lancet 2:142-143, 1976;.
Link to Article
32 +
Friedman JM:  Inheritance of susceptibility to histocompatibility-associated disease , letter to the editor. Lancet 1:49, 1976;.
Link to Article
33 +
Hansen HE, Ryder LP, Nielson LS:  Recombination between the second and third series of the HL-A system . Tissue Antigens 6:275-277, 1975;.
Link to Article
34 +
Maugh T II:  Diabetes: Epidemiology suggests a viral connection, research news . Science 347-351, 1975;.
35 +
Harris HF:  A case of diabetes mellitus quickly following mumps . Boston Med Surg J 140:465-467, 1899;.
Link to Article
36 +
Gunderson E:  Is diabetes of infectious origin? J Infect Dis 41:197-202, 1927;.
Link to Article
37 +
Melin K, Ursing B:  Diabetes mellitus som Komplikation till parotitis epidemica . Nord Med 60:1715-1717, 1958;.
38 +
Sultz HA, Hart BA, Zielozny M:  Editors column: Is mumps virus an etiologic factor in juvenile diabetes? J Pediatr 86:654-656.
39 +
Sultz HA, Sokal D, Sdao M: Epidemiologic evidence for mumps virus etiology of childhood diabetes. Read before the American Diabetes Association Research Symposium, Indianapolis, Oct 1975.
40 +
Rawls WE:  Congenital rubella. The significance of virus persistence . Prog Med Virol 10:238-285, 1968;.
41 +
Forrest JM, Menser MA, Harley JD:  Diabetes mellitus and congenital rubella . Pediatrics 44:445-447, 1969;.
42 +
Forrest JM, Menser MA, Burgess JA:  High frequency of diabetes mellitus in young adults with congenital rubella . Lancet 2:332-334, 1971;.
Link to Article
43 +
Gamble DR, Taylor KW:  Seasonal incidence of diabetes mellitus . Br Med J 3:631-633, 1969;.
Link to Article
44 +
Gamble DR, Kinsley ML, Fitzgerald MG, et al:  Viral antibodies in diabetes mellitus . Br Med J 3:627-639, 1969;.
Link to Article
45 +
Gamble DR, Taylor KW:  Coxsackie B virus and diabetes . Br Med J 1:289-290, 1973;.
Link to Article
46 +
Barboni E, Manocchio I:  Alterazionia pancreatic in bovini con diabete mellito postaftoso . Arch Vet Ital 13:477-483, 1962;.
47 +
Barboni E, Manocchio I, Asdrubali G:  Observations on diabetes mellitus associated with experimental foot and mouth disease in cattle . Arch Vet Ital 17:362-369, 1966;.
48 +
Craighead JE, McLane MF:  Diabetes mellitus: Induction in mice by encephalomyocarditis virus . Science 162:913-914, 1968;.
Link to Article
49 +
Boucher DW, Notkins AL:  Virus induced diabetes mellitus: I. Hyperglycemia and hypoinsulinoma in mice infected with encephalomyocarditis virus . J Exp Med 137:1226-1239, 1973;.
Link to Article
50 +
Hayashi K, Boucher DW, Notkins AL:  Virus-induced diabetes mellitus: II. Relationship between beta cell damage and hyperglycemia in mice infected with encephalomyocarditis virus . Am J Pathol 75:91-97, 1974;.
51 +
Wolf RO, Ross ME, Notkins AL:  Amylase isoenzymes during viral infections of the pancreas and salivary glands . J Lab Clin Med 83:750-756, 1974;.
52 +
Craighead JE, Higgins DA:  Genetic influences affecting the occurrence of a diabeteslike syndrome disease in mice infected with the encephalomyocarditis virus . J Exp Med 139:414-426, 1974;.
Link to Article
53 +
Yoon J-W, Notkins AL:  Virus-induced diabetes mellitus: VI. Genetically determined host differences in the replication of encephalomyocarditis virus in pancreatic beta cells . J Exp Med 143:1170-1185, 1976;.
Link to Article
54 +
Webb SR, Loria RM, Madge GE, et al:  Susceptibility of mice to group Coxsackie B virus is influenced by the diabetic gene . J Exp Med 143:1239-1248, 1976;.
Link to Article
55 +
Taylor KW:  The diabetogenic effect of Coxsackie B viruses , in Bastenie PA, Gepts W (eds): Immunity and Autoimmunity in Diabetes Mellitus . Amsterdam, Excerpta Medica, 1974;, pp 242-244.
56 +
Ogle JW:  On disease of the brain as a result of diabetes mellitus . St Georges Hosp Rep 1:157-160, 1866;.
57 +
Irvine WJ, Barnes EW:  Addison's disease and associated conditions with particular reference to premature ovarian failure, diabetes mellitus and hypoparathyroidism , in Coombs RRA, Gell PH, Lachman P (eds): Clinical Aspects of Immunology , ed 3. Oxford, England, Blackwell Scientific Publications, 1974;, pp 46-58.
58 +
Zozak GP:  Diabetes and other endocrinologic disorders , in Marble A, White P, Bradley RF, et al: Joslin's Diabetes Mellitus , ed 11. Philadelphia, Lea & Febiger Publishers, 1971;, p 666.
59 +
Nerup J, Binder C:  Thyroid gastric and adrenal autoimmunity in diabetes mellitus . Acta Endocrinol 72:279-286, 1973;.
60 +
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