The accelerator hypothesis: weight gain as the missing link between type I and type II diabetes
Open accessAbstract
Blood glucose concentrations are controlled by a loop incorporating two components, the beta cells which secrete insulin and the insulin-sensitive tissues (liver, muscle, adipose) which respond to it. Loss of blood glucose control might result from failure of the beta cells to secrete insulin, resistance of the tissues to its action, or a combination of both. The distinctions between Type I (insulin-dependent) and Type II (non-insulin-dependent) diabetes mellitus are becoming increasingly blurred both clinically and aetiologically, where beta-cell insufficiency is the shared characteristic. The 'Accelerator Hypothesis' identifies three processes which variably accelerate the loss of beta cells through apoptosis: constitution, insulin resistance and autoimmunity. None of the accelerators leads to diabetes without excess weight gain, a trend which the 'Accelerator Hypothesis' deems central to the rising incidence of both types of diabetes in the industrially developed world. Weight gain causes an increase in insulin resistance, which results in the weakening of glucose control. The rising blood glucose (glucotoxicity) accelerates beta-cell apoptosis directly in all and, by inducing beta-cell immunogens, further accelerates it in a subset genetically predisposed to autoimmunity. Rather than overlap between two types of diabetes, the 'Accelerator Hypothesis' envisages overlay. Body mass is central to the development and rising incidence of all diabetes. Only tempo distinguishes the 'types'. The control of weight gain, and with it insulin resistance, could be the means of minimising both.
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Cites
The Instructive Role of Innate Immunity in the Acquired Immune Response
Fearon, D. T., & Locksley, R. M. (1996) · Science · doi:10.1126/science.272.5258.50 · Cited by 1,718 · see citing works
Pickup, J. C., Mattock, M. B., Chusney, G. D., & Burt, D. J. (1997) · Diabetologia · doi:10.1007/s001250050822 · Cited by 1,241 · see citing works
Obesity in Britain: gluttony or sloth?
Prentice, A. M., & Jebb, S. A. (1995) · BMJ · doi:10.1136/bmj.311.7002.437 · Cited by 1,163 · see citing works
The Pathogenesis of Insulin-Dependent Diabetes Mellitus
Epstein, F. H., Atkinson, M. A., & Maclaren, N. K. (1994) · New England Journal of Medicine · doi:10.1056/nejm199411243312107 · Cited by 1,074 · see citing works
Hattersley, A. T., & Tooke, J. E. (1999) · The Lancet · doi:10.1016/s0140-6736(98)07546-1 · Cited by 909 · see citing works
Insulin resistance during puberty: results from clamp studies in 357 children.
Moran, A., Jacobs, D. R., Steinberger, J., Hong, C. P., Prineas, R. J., Luepker, R. V., & Sinaiko, A. R. (1999) · Diabetes · doi:10.2337/diabetes.48.10.2039 · Cited by 869 · see citing works
Assessing obesity: classification and epidemiology
Seidell, J. C., & Flegal, K. M. (1997) · British Medical Bulletin · doi:10.1093/oxfordjournals.bmb.a011611 · Cited by 499 · see citing works
Body fat distribution, insulin resistance, and metabolic diseases
Björntorp, P. (1997) · Nutrition · doi:10.1016/s0899-9007(97)00191-3 · Cited by 470 · see citing works
Surgical removal of visceral fat reverses hepatic insulin resistance.
Barzilai, N., She, L., Liu, B. Q., Vuguin, P. M., Cohen, P., Wang, J., & Rossetti, L. (1999) · Diabetes · doi:10.2337/diabetes.48.1.94 · Cited by 373 · see citing works
Risk factors for worsening to diabetes in subjects with impaired glucose tolerance
Kadowaki, T., Miyake, Y., Hagura, R., Akanuma, Y., Kajinuma, H., Kuzuya, N., Takaku, F., & Kosáka, K. (1984) · Diabetologia · doi:10.1007/bf00252262 · Cited by 315 · see citing works
Kitagawa, T., Ōwada, M., Urakami, T., & Yamauchi, K. (1998) · Clinical Pediatrics · doi:10.1177/000992289803700208 · Cited by 310 · see citing works
Cutting Edge: Bystander Apoptosis Triggers Dendritic Cell Maturation and Antigen-Presenting Function
Rovere, P. Q., Vallinoto, C., Bondanza, A., Crosti, M., Rescigno, M., Ricciardi‐Castagnoli, P., Rugarli, C., & Manfredi, A. A. (1998) · The Journal of Immunology · doi:10.4049/jimmunol.161.9.4467 · Cited by 309 · see citing works
The global epidemiology of non-insulin-dependent diabetes mellitus and the metabolic syndrome
Zimmet, P., McCarty, D. J., & de Courten, M. (1997) · Journal of Diabetes and its Complications · doi:10.1016/s1056-8727(96)00090-6 · Cited by 294 · see citing works
Breast-fed infants are leaner than formula-fed infants at 1 y of age: the DARLING study
Dewey, K., Heinig, M. J., Nommsen, L., Peerson, J., & Lönnerdal, B. (1993) · American Journal of Clinical Nutrition · doi:10.1093/ajcn/57.2.140 · Cited by 279 · see citing works
Concordance rate for Type II diabetes mellitus in monozygotic twins: actuarial analysis
Medici, F., Hawa, M. I., Ianari, A., Pyke, D. A., & Leslie, R. D. (1999) · Diabetologia · doi:10.1007/s001250051132 · Cited by 214 · see citing works
Autoantibodies and the physiological role of immunoglobulins
GRABAR, P. (1983) · Immunology Today · doi:10.1016/0167-5699(83)90169-x · Cited by 199 · see citing works
Apoptosis and the pathogenesis of IDDM: a question of life and death.
Mauricio, D., & Mandrup-Poulsen, T. R. (1998) · Diabetes · doi:10.2337/diabetes.47.10.1537 · Cited by 156 · see citing works
Glucose regulation of the autoantigen GAD65 in human pancreatic islets
Björk, E., Kämpe, O., Karlsson, F. A., PIPELEERS, D. G., Andersson, A., Hellerström, C., & Eizirik, D. L. (1992) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jcem.75.6.1464667 · Cited by 112 · see citing works
Increase in Incidence of Insulin-Dependent Diabetes Mellitus among Children in Finland
Tuomilehto, J. O., Virtala, E. T., Karvonen, M., Lounamaa, R., PITKĀNIEMI, J., Reunanen, A., Tuomilehto‐Wolf, E., & Toivanen, L. (1995) · International Journal of Epidemiology · doi:10.1093/ije/24.5.984 · Cited by 105 · see citing works
Hypothesis: muscle insulin resistance is the ("not-so") thrifty genotype
Reaven, G. M. (1998) · Diabetologia · doi:10.1007/s001250050933 · Cited by 98 · see citing works
Damm, P., Kühl, C., Buschard, K., Jakobsen, B. K., Svejgaard, A., Sodoyez‐Goffaux, F., Shattock, M., Bottazzo, G. F., & Mølsted‐Pedersen, L. (1994) · Diabetic Medicine · doi:10.1111/j.1464-5491.1994.tb02035.x · Cited by 81 · see citing works
Tuomilehto‐Wolf, E., Tuomilehto, J., Hitman, G. A., Nissinen, A. E. T., Stengård, J., Pekkanen, J., Kivinen, P., Kaarsalo, E., & Karvonen, M. J. (1993) · BMJ · doi:10.1136/bmj.307.6897.155 · Cited by 73 · see citing works
The Epidemiology of Insulin-dependent Diabetes Mellitus (IDDM) in Finland and in Northern Europe
Åkerblom, H. K., & Reunanen, A. (1985) · Diabetes Care · doi:10.2337/diacare.8.1.s10 · Cited by 73 · see citing works
Seasonality of birth of patients with childhood diabetes in Britain: Fig 1
Rothwell, P. M., Staines, A. S., Smail, P. J., Wadsworth, E. J. K., & McKinney, P. A. (1996) · BMJ · doi:10.1136/bmj.312.7044.1456 · Cited by 69 · see citing works
Staines, A. S., Bodansky, H. J., Lilley, H. E. B., Stephenson, C. R., McNally, R., & Cartwright, R. A. (1993) · Diabetologia · doi:10.1007/bf00400806 · Cited by 67 · see citing works
Zimmet, P. (2001) · Journal of Internal Medicine · doi:10.1046/j.1365-2796.2001.00625.x · Cited by 67 · see citing works
Dietary triggers of insulin-dependent diabetes in the BB rat.
Daneman, D., Fishman, L., Clarson, C. L., et al. (1987) · PubMed · Cited by 62 · see citing works
Seasonality of birth in patients with childhood diabetes in The Netherlands
Jongbloet, P. H., Groenewoud, H. M. M., Hirasing, R. A., & Van Buuren, S. (1998) · Diabetes Care · doi:10.2337/diacare.21.1.190 · Cited by 45 · see citing works
RELATIVE CONTRIBUTIONS OF INSULIN DEFICIENCY AND INSULIN RESISTANCE IN MATURITY-ONSET DIABETES
Turner, R. C., Holman, R. R., Matthews, D. R., & Peto, J. (1982) · The Lancet · doi:10.1016/s0140-6736(82)91753-6 · Cited by 42 · see citing works
Dual-parameter model for prediction of type I diabetes mellitus.
Eisenbarth, G. S., Gianani, R., Yu, L., et al. (1998) · PubMed · Cited by 41 · see citing works
The role of DQ alpha–beta heterodimers in genetic susceptibility to insulin‐dependent diabetes
Deschamps, I., & Khalil, I. (1993) · Diabetes/Metabolism Reviews · doi:10.1002/dmr.5610090202 · Cited by 23 · see citing works
Minute oxidative stress is sufficient to induce apoptotic death of NIT‐1 insulinoma cells
Olejnicka, B. T., Dalen, H., & Brunk, U. T. (1999) · Apmis · doi:10.1111/j.1699-0463.1999.tb01469.x · Cited by 23 · see citing works
Early nutrition and diabetes mellitus.
Wilkin, T. (1993) · BMJ · doi:10.1136/bmj.306.6873.283 · Cited by 19 · see citing works
Self-citationDietary cow's milk protein does not alter the frequency of diabetes in the BB rat
Malkani, S., Nompleggi, D., Hansen, J. W., et al. (1997) · Diabetes · doi:10.2337/diabetes.46.7.1133 · Cited by 17 · see citing works
High proinsulin levels in late PRE-IDDM stage
Rodrı́guez-Villar, C., Conget, I., Casamitjana, R., et al. (1997) · Diabetes Research and Clinical Practice · doi:10.1016/s0168-8227(97)00055-7 · Cited by 12 · see citing works
Endocrine Feedback Control in Health and Disease
Wilkin, T. J. (1997) · Principles of medical biology · doi:10.1016/s1569-2582(97)80028-1 · Cited by 10 · see citing works
Self-citationA new marker in the HLA class I region is associated with the age at onset of IDDM
Demaine, A. G., Hibberd, M. L., Mangles, D., et al. (1995) · Diabetologia · doi:10.1007/s001250050329 · Cited by 4 · see citing works
Egger, M., Davey Smith, G., Stettler, C., & Diem, P. (1997) · Diabetic Medicine · doi:10.1002/(sici)1096-9136(199711)14:11
Flagged first, then by citations
Research works printed but not linked: 1
- UK Prospective Diabetes Study Group (1995) UK pro- spective study 16. Overview of six years' therapy of Type II diabetes. Diabetes 44: 1249±1258 41. Yu l, Eisenbarth GS (1998) Immunology of Type I diabetes and related endocrine disorders.In: Klibanski A, Biller BMK (eds) Clinical endocrinology update. The Endocrine Society Press, Bethesda pp258±266
Cited by
Sorted by citations
Type 2 diabetes as an inflammatory disease
Donath, M. Y., & Shoelson, S. E. (2011) · Nature Reviews Immunology · doi:10.1038/nri2925 · Cited by 3,737 · see citing works
Patterson, C. C., Dahlquist, G. G., Gyürüs, E., Green, A., & Soltész, G. (2009) · The Lancet · doi:10.1016/s0140-6736(09)60568-7 · Cited by 1,854 · see citing works
Epidemiology of type 1 diabetes
Maahs, D. M., West, N. A., Lawrence, J. M., & Mayer-Davis, E. J. (2010) · Endocrinology and Metabolism Clinics of North America · doi:10.1016/j.ecl.2010.05.011 · Cited by 1,092 · see citing works
Obesity in autoimmune diseases: Not a passive bystander
Versini, M., Jeandel, P.-Y., Rosenthal, E., & Shoenfeld, Y. (2014) · Autoimmunity Reviews · doi:10.1016/j.autrev.2014.07.001 · Cited by 694 · see citing works
Environmental risk factors for type 1 diabetes
Rewers, M., & Ludvigsson, J. (2016) · The Lancet · doi:10.1016/s0140-6736(16)30507-4 · Cited by 676 · see citing works
Inflammatory mediators and islet ?-cell failure: a link between type 1 and type 2 diabetes
Donath, M. Y., St�rling, J., Maedler, K., & Mandrup-Poulsen, T. (2003) · Journal of Molecular Medicine · doi:10.1007/s00109-003-0450-y · Cited by 422 · see citing works
Worldwide childhood type 1 diabetes incidence–what can we learn from epidemiology?
Soltesz, G., Patterson, C., Dahlquist, G., & EURODIAB Study Group (2007) · Pediatric Diabetes · doi:10.1111/j.1399-5448.2007.00280.x · Cited by 371 · see citing works
Thirty Years of Prospective Nationwide Incidence of Childhood Type 1 Diabetes
Berhan, Y., Waernbaum, I., Lind, T., Möllsten, A., Dahlquist, G., & for the Swedish Childhood Diabetes Study Group* (2011) · Diabetes · doi:10.2337/db10-0813 · Cited by 237 · see citing works
Obesity, insulin resistance, and type 1 diabetes mellitus
Polsky, S., & Ellis, S. L. (2015) · Current Opinion in Endocrinology, Diabetes & Obesity · doi:10.1097/med.0000000000000170 · Cited by 235 · see citing works
Increasing incidence of type 1 diabetes in 0- to 17-year-old Colorado youth
Vehik, K., Hamman, R. F., Lezotte, D., Norris, J. M., Klingensmith, G., Bloch, C., Rewers, M., & Dabelea, D. (2007) · Diabetes Care · doi:10.2337/dc06-1837 · Cited by 226 · see citing works
Nutritional risk predictors of β cell autoimmunity and type 1 diabetes at a young age
Virtanen, S. M., & Knip, M. (2003) · The American Journal of Clinical Nutrition · doi:10.1093/ajcn/78.6.1053 · Cited by 220 · see citing works
Diabetes and beta cell function: from mechanisms to evaluation and clinical implications
Cernea, S., & Dobreanu, M. (2013) · Biochemia Medica · doi:10.11613/bm.2013.033 · Cited by 203 · see citing works
Diabetes in African American Youth
Mayer-Davis, E. J., Beyer, J., Bell, R. A., Dabelea, D., D'Agostino, R., Imperatore, G., Lawrence, J. M., Liese, A. D., Liu, L., Marcovina, S., et al. (2009) · Diabetes Care · doi:10.2337/dc09-s203 · Cited by 180 · see citing works
Current understandings of the pathogenesis of type 1 diabetes: genetics to environment
Giwa, A. M., Ahmed, R., Omidian, Z., Majety, N., Karakus, K. E., Omer, S. M., Donner, T., & Hamad, A. R. A. (2020) · World Journal of Diabetes · doi:10.4239/wjd.v11.i1.13 · Cited by 137 · see citing works
Weets, I., De Leeuw, I. H., Du Caju, M. V. L., Rooman, R., Keymeulen, B., Mathieu, C., Rottiers, R., Daubresse, J.-C., Rocour-Brumioul, D., Pipeleers, D. G., et al. (2002) · Diabetes Care · doi:10.2337/diacare.25.5.840 · Cited by 137 · see citing works
Increasing Incidence of Type 1 Diabetes in Youth
Lipman, T. H., Levitt Katz, L. E., Ratcliffe, S. J., Murphy, K. M., Aguilar, A., Rezvani, I., Howe, C. J., Fadia, S., & Suarez, E. (2013) · Diabetes Care · doi:10.2337/dc12-0767 · Cited by 116 · see citing works
Autoimmune Aspects of Type 2 Diabetes Mellitus - A Mini-Review
Itariu, B. K., & Stulnig, T. M. (2014) · Gerontology · doi:10.1159/000356747 · Cited by 107 · see citing works
Trends in high-risk HLA susceptibility genes among Colorado youth with type 1 diabetes
Vehik, K., Hamman, R. F., Lezotte, D., Norris, J. M., Klingensmith, G. J., Rewers, M., & Dabelea, D. (2008) · Diabetes Care · doi:10.2337/dc07-2210 · Cited by 82 · see citing works
The Peripheral Peril: Injected Insulin Induces Insulin Insensitivity in Type 1 Diabetes
Gregory, J. M., Cherrington, A. D., & Moore, D. J. (2020) · Diabetes · doi:10.2337/dbi19-0026 · Cited by 76 · see citing works
Rising incidence of type 1 diabetes is associated with altered immunophenotype at diagnosis
Long, A. E., Gillespie, K. M., Rokni, S., Bingley, P. J., & Williams, A. J. K. (2012) · Diabetes · doi:10.2337/db11-0962 · Cited by 60 · see citing works
Haskell, B. D., Flurkey, K., Duffy, T. M., Sargent, E. E., & Leiter, E. H. (2002) · Laboratory Investigation · doi:10.1097/01.lab.0000018915.53257.00 · Cited by 47 · see citing works
The Role of Age and Excess Body Mass Index in Progression to Type 1 Diabetes in At-Risk Adults
Ferrara, C. T., Geyer, S. M., Evans-Molina, C., Libman, I. M., Becker, D. J., Wentworth, J. M., Moran, A., Gitelman, S. E., Redondo, M. J., & Type 1 Diabetes TrialNet Study Group (2017) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2017-01490 · Cited by 33 · see citing works
Fetal growth is increased by maternal type 1 diabetes and HLA DR4-related gene interactions
Hummel, M., Marienfeld, S., Huppmann, M., Knopff, A., Voigt, M., Bonifacio, E., & Ziegler, A.-G. (2007) · Diabetologia · doi:10.1007/s00125-007-0607-2 · Cited by 29 · see citing works
MUSIL, F., ŠMAHELOVÁ, A., BLÁHA, V., HYŠPLER, R., TICHÁ, A., LESNÁ, J., ZADÁK, Z., & SOBOTKA, L. (2013) · Physiological Research · doi:10.33549/physiolres.932381 · Cited by 12 · see citing works
- Authors
- Wilkin, T. J.
- Affiliations
- Derriford Hospital (GB)
- Corresponding author
- Wilkin, T. J.
- Venue
- Diabetologia
- Published
- 2001-07-01
- Volume
- 44
- Issue
- 7
- Pages
- 914-922
- ISSN
- 0012-186X (ISSN-L)
- 1432-0428
- OpenAlex
- W1966671518
- Cited by
- 623
- References
- 38
- Citations by year
- 2026: 14 · 2025: 13 · 2024: 20 · 2023: 20 · 2022: 27 · 2021: 24 · 2020: 18 · 2019: 21 · 2018: 19 · 2017: 20 · 2016: 22 · 2015: 20 · 2014: 31 · 2013: 30 · 2012: 26
- FWCI
- 3.65
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Diabetologia (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Surgery › Pancreatic function and diabetes
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Diabetes and associated disorders
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes, Cardiovascular Risks, and Lipoproteins
- Keywords
- type 1 diabetes, type 2 diabetes, beta-cell apoptosis, weight gain, insulin resistance, glucotoxicity, autoimmunity, body mass, diabetes incidence
- MeSH terms
- Blood Glucose, Diabetes Mellitus, Type 1, Diabetes Mellitus, Type 2, Humans, Insulin Resistance, Models, Biological, Phagocytosis, Risk Factors, Weight Gain, Prevalence, Apoptosis, Developed Countries
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