Gender and neurogenin3 influence the pathogenesis of ketosis‐prone diabetes
Abstract
Ketosis‐prone diabetes (KPD) is a phenotypically defined form of diabetes characterized by male predominance and severe insulin deficiency. Neurogenin3 (NGN3) is a proendocrine gene, which is essential for the fate of pancreatic β cells. Mice lacking ngn3 develop early insulin‐deficient diabetes. Thus, we hypothesized that gender and variants in NGN3 could predispose to KPD. We have studied clinical and metabolic parameters according to gender in patients with KPD (n = 152) and common type 2 diabetes (T2DM) (n = 167). We have sequenced NGN3 in KPD patients and screened gene variants in T2DM and controls (n = 232). In KPD, male gender was associated with a more pronounced decrease in β‐cell insulin secretory reserve, assessed by fasting C–peptide [mean (ng/ml) ± s.d., M: 1.1 ± 0.6, F: 1.5 ± 0.9; p = 0.02] and glucagon‐stimulated C–peptide [mean (ng/ml) ± s.d., M: 2.2 ± 1.1, F: 3.1 ± 1.7; p = 0.03]. The rare affected females were in an anovulatory state. We found two new variants in the promoter [−3812T/C (af: 2%) and −3642T/C (af: 1%)], two new coding variants [S171T (af: 1%) and A185S (af: 1%)] and the variant already described [S199F (af: 69%)]. These variants were not associated with diabetes. Clinical investigation revealed an association between 199F and hyperglycaemia assessed by glycated haemoglobin [HbA1c (%, ±s.d.) S199: 12.6 ± 1.6, S199F: 12.4 ± 1.4 and 199F: 14.1 ± 2.2; p = 0.01]. In vitro , the P171T, A185S and S199F variants did not reveal major functional alteration in the activation of NGN3 target genes. In conclusion, male gender, anovulatory state in females and NGN3 variations may influence the pathogenesis of KPD in West Africans. This has therapeutic implications for potential tailored pharmacological intervention in this population.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
In ketosis-prone diabetes, women are protected unless they are in a hypoestrogenic state.
“In ketosis-prone diabetes, women are protected unless they are in a hypoestrogenic state [43, 45].”
From Sex differences in metabolic homeostasis, diabetes, and obesity (2015) · cites this paper as [45]
Cites
A genome-wide association study identifies novel risk loci for type 2 diabetes
Sladek, R., Rocheleau, G., Rung, J., Dina, C., Shen, L., Serre, D., Boutin, P., Vincent, D., Belisle, A., Hadjadj, S., et al. (2007) · Nature · doi:10.1038/nature05616 · Cited by 2,993 · see citing works
Self-citationMutations in the hepatocyte nuclear factor-1α gene in maturity-onset diabetes of the young (MODY3)
Yamagata, K., Oda, N., Kaisaki, P. J., Menzel, S., Furuta, H., Vaxillaire, M., Southam, L., Cox, R., Lathrop, M. G., Boriraj, V. V., et al. (1996) · Nature · doi:10.1038/384455a0 · Cited by 1,610 · see citing works
neurogenin3 is required for the development of the four endocrine cell lineages of the pancreas
Gradwohl, G., Dierich, A., LeMeur, M., & Guillemot, F. (2000) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.97.4.1607 · Cited by 1,435 · see citing works
Mutations in the hepatocyte nuclear factor-4α gene in maturity-onset diabetes of the young (MODY1)
Yamagata, K., Furuta, H., Oda, N., Kaisaki, P. J., Menzel, S., Cox, N. J., Fajans, S. S., Signorini, S. G., Stoffel, M., & Bell, G. I. (1996) · Nature · doi:10.1038/384458a0 · Cited by 975 · see citing works
Early-onset type-ll diabetes mellitus (MODY4) linked to IPF1
Staffers, D. A., Ferrer, J. P., Clarke, W. L., & Habener, J. F. (1997) · Nature Genetics · doi:10.1038/ng1097-138 · Cited by 880 · see citing works
Mutation in hepatocyte nuclear factor–1β gene (TCF2) associated with MODY
Horikawa, Y., Iwasaki, N., Hara, M., Furuta, H., Hinokio, Y., Cockburn, B. N., Lindner, T. H., Yamagata, K., Ogata, M., Tomonaga, O., et al. (1997) · Nature Genetics · doi:10.1038/ng1297-384 · Cited by 878 · see citing works
Froguel, P., Zouali, H., Vionnet, N., Velho, G., Vaxillaire, M., Sun, F., Lesage, S., Stoffel, M., Takeda, J., Passa, P., et al. (1993) · New England Journal of Medicine · doi:10.1056/nejm199303113281005 · Cited by 726 · see citing works
Mutations in NEUROD1 are associated with the development of type 2 diabetes mellitus
Malecki, M. T., Jhala, U. S., Antonellis, A., Fields, L., Doria, A., Orban, T., Saad, M. F., Warram, J. H., Montminy, M., & Królewski, A. S. (1999) · Nature Genetics · doi:10.1038/15500 · Cited by 619 · see citing works
Gale, E. A. M., & Gillespie, K. M. (2001) · Diabetologia · doi:10.1007/s001250051573 · Cited by 558 · see citing works
A subtype of diabetes mellitus associated with a mutation of mitochondrial DNA.
Kadowaki, T., Kadowaki, H., Mori, Y., Tobe, K., Sakuta, R., Suzuki, Y., Tanabe, Y., Sakura, H., Awata, T., Goto, Y.-I., et al. (1994) · New England Journal of Medicine · doi:10.1056/nejm199404073301403 · Cited by 551 · see citing works
May, C. L., Chu, K., Hu, M., Ortega, C. S., Simpson, E. R., Korach, K. S., Tsai, M., & Mauvais‐Jarvis, F. (2006) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0602956103 · Cited by 500 · see citing works
Self-citationStentz, F. B., Umpierrez, G. E., Cuervo, R., & Kitabchi, A. E. (2004) · Diabetes · doi:10.2337/diabetes.53.8.2079 · Cited by 497 · see citing works
Dunaif, A. E., & Finegood, D. T. (1996) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jcem.81.3.8772555 · Cited by 454 · see citing works
German, M. S., Wang, J., Chadwick, R. B., & Rutter, W. J. (1992) · Genes & Development · doi:10.1101/gad.6.11.2165 · Cited by 390 · see citing works
Self-citationAge and sex associations of 40 autoimmune diseases
Beeson, P. B. (1994) · The American Journal of Medicine · doi:10.1016/0002-9343(94)90173-2 · Cited by 354 · see citing works
Narrative Review: Ketosis-Prone Type 2 Diabetes Mellitus
Umpierrez, G. E., Smiley, D., & Kitabchi, A. E. (2006) · Annals of Internal Medicine · doi:10.7326/0003-4819-144-5-200603070-00011 · Cited by 299 · see citing works
Ketosis-Prone Type 2 Diabetes in Patients of Sub-Saharan African Origin
Mauvais-Jarvis, F., Sobngwi, E., Porcher, R., Riveline, J.-P., Kevorkian, J.-P., Vaisse, C., Charpentier, G., Guillausseau, P.-J., Vexiau, P., & Gautier, J.-F. (2004) · Diabetes · doi:10.2337/diabetes.53.3.645 · Cited by 294 · see citing works
Self-citationBanerji, M. A., Chaiken, R. L., Huey, H., Tuomi, T., Norin, A. J., Mackay, I. R., Rowley, M. J., Zimmet, P. Z., & Lebovitz, H. E. (1994) · Diabetes · doi:10.2337/diab.43.6.741 · Cited by 266 · see citing works
Regulation of the Pancreatic Pro-Endocrine Gene Neurogenin3
Lee, J. C., Smith, S. B., Watada, H., Lin, J., Scheel, D., Wang, J., Mirmira, R. G., & German, M. S. (2001) · Diabetes · doi:10.2337/diabetes.50.5.928 · Cited by 258 · see citing works
Self-citationMaturity-Onset Diabetes of Youth in Black Americans
Winter, W. E., Maclaren, N. K., Riley, W. J., Clarke, D. W., Kappy, M. S., & Spillar, R. P. (1987) · New England Journal of Medicine · doi:10.1056/nejm198702053160601 · Cited by 258 · see citing works
Diabetic Ketoacidosis in Obese African-Americans
Umpierrez, G., Casals, M. M., Gebhart, S., Mixon, P. S., Clark, W., & Phillips, L. (1995) · Diabetes · doi:10.2337/diab.44.7.790 · Cited by 252 · see citing works
Defects in beta-cell function in functional ovarian hyperandrogenism
O’Meara, N., Blackman, J. D., Ehrmann, D. A., Barnes, R. B., Jaspan, J. B., Rosenfield, R. L., & Polonsky, K. S. (1993) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jcem.76.5.8496316 · Cited by 243 · see citing works
Maldonado, M., Hampe, C. S., Gaur, L. K., D’Amico, S., Iyer, D., Hammerle, L. P., Bolgiano, D. C., Rodriguez, L., Rajan, A. S., Lernmark, Å., et al. (2003) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2003-030180 · Cited by 236 · see citing works
PAX4 gene variations predispose to ketosis-prone diabetes
Mauvais‐Jarvis, F., Smith, S. B., May, C. L., Leal, S. M., Gautier, J., Molokhia, M., Riveline, J., Rajan, A. S., Kévorkian, J.-P., Zhang, S., et al. (2004) · Human Molecular Genetics · doi:10.1093/hmg/ddh341 · Cited by 127 · see citing works
Self-citationNeurogenin3 and Hepatic Nuclear Factor 1 Cooperate in Activating Pancreatic Expression of Pax4
Smith, S. B., Gasa, R., Watada, H., Wang, J., Griffen, S. C., & German, M. S. (2003) · Journal of Biological Chemistry · doi:10.1074/jbc.m302229200 · Cited by 116 · see citing works
Self-citationLee, C. S., León, D. D. D., Kaestner, K. H., & Stoffers, D. A. (2006) · Diabetes · doi:10.2337/diabetes.55.02.06.db05-1300 · Cited by 113 · see citing works
Blohm�, G., Nystr�m, L., Arnqvist, H. J., Lithner, F., Littorin, B., Olsson, P.-O., Scherst�n, B., Wibell, L. B., & �stman, J. (1992) · Diabetologia · doi:10.1007/bf00400852 · Cited by 112 · see citing works
Idiopathic Type 1 Diabetes in Dallas, Texas
Pinero-Pilona, A., Litonjua, P., Avilés-Santa, L. M., & Raskin, P. (2001) · Diabetes Care · doi:10.2337/diacare.24.6.1014 · Cited by 83 · see citing works
Sobngwi, E., Gautier, J., Kévorkian, J.-P., Villette, J., Riveline, J., Zhang, S., Vexiau, P., Leal, S. M., Vaisse, C., & Mauvais‐Jarvis, F. (2005) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2004-2545 · Cited by 83 · see citing works
Self-citationSmith, S. B., Watada, H., Scheel, D. W., Mrejen, C., & German, M. S. (2000) · Journal of Biological Chemistry · doi:10.1074/jbc.m005202200 · Cited by 80 · see citing works
Self-citationDistinct Gene Expression Programs Function in Progenitor and Mature Islet Cells
Watada, H., Scheel, D. W., Leung, J., & German, M. S. (2003) · Journal of Biological Chemistry · doi:10.1074/jbc.m213196200 · Cited by 80 · see citing works
Self-citationJackson, A. E., Cassell, P. G., North, B. V., Vijayaraghavan, S., Gelding, S. V., Ramachandran, A., Snehalatha, C., & Hitman, G. A. (2004) · Diabetes · doi:10.2337/diabetes.53.8.2122 · Cited by 22 · see citing works
del Bosque‐Plata, L., Lin, J., Horikawa, Y., Schwarz, P. E. H., Cox, N. J., Iwasaki, N., Ogata, M., Iwamoto, Y., German, M. S., & Bell, G. I. (2001) · Diabetes · doi:10.2337/diabetes.50.3.694 · Cited by 15 · see citing works
Self-citationJensen, J. N., Hansen, L., Ekstrøm, C. T., Pociot, F., Nerup, J., Hansen, T. F., & Pedersen, O. B. (2001) · Diabetologia · doi:10.1007/s001250051589 · Cited by 14 · see citing works
Mutation Screening of the Neurogenin-3 Gene in Autosomal Dominant Diabetes1
Kim, S., Warram, J. H., Królewski, A. S., & Doria, A. (2001) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jcem.86.5.7482 · Cited by 9 · see citing works
Mutation Screening of the Neurogenin-3 Gene in Autosomal Dominant Diabetes
Kim, S. (2001) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.86.5.2320 · Cited by 7 · see citing works
Variants of neurogenin 3 gene are not associated with Type II diabetes in Japanese subjects
Okada, T., Tobe, K., Hara, K., Yasuda, K., Kawaguchi, Y., Ikegami, H., Ito, C., & Kadowaki, T. (2001) · Diabetologia · doi:10.1007/s001250051606 · Cited by 5 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Sex differences in metabolic homeostasis, diabetes, and obesity
Mauvais-Jarvis, F. (2015) · Biology of Sex Differences · doi:10.1186/s13293-015-0033-y · Cited by 626 · see citing works
“In ketosis-prone diabetes, women are protected unless they are in a hypoestrogenic state [43, 45].”
BackgroundSelf-citationGender differences in glucose homeostasis and diabetes
Mauvais-Jarvis, F. (2018) · Physiology & Behavior · doi:10.1016/j.physbeh.2017.08.016 · Cited by 377 · see citing works
Self-citationTiano, J. P., Delghingaro‐Augusto, V., May, C. L., Liu, S., Kaw, M., Khuder, S. S., Latour, M. G., Bhatt, S. A., Korach, K. S., Najjar, S. M., et al. (2011) · Journal of Clinical Investigation · doi:10.1172/jci44564 · Cited by 181 · see citing works
Self-citationSex differences in energy metabolism: natural selection, mechanisms and consequences
Mauvais‐Jarvis, F. (2023) · Nature Reviews Nephrology · doi:10.1038/s41581-023-00781-2 · Cited by 162 · see citing works
Self-citationSex differences in metabolism and cardiometabolic disorders
Krishnan, K. C., Mehrabian, M., & Lusis, A. J. (2018) · Current Opinion in Lipidology · doi:10.1097/mol.0000000000000536 · Cited by 142 · see citing works
Minireview: Estrogenic Protection of β-Cell Failure in Metabolic Diseases
Liu, S., & Mauvais‐Jarvis, F. (2009) · Endocrinology · doi:10.1210/en.2009-1107 · Cited by 135 · see citing works
Self-citationSex differences underlying pancreatic islet biology and its dysfunction
Gannon, M., Kulkarni, R. N., Tse, H. M., & Mauvais-Jarvis, F. (2018) · Molecular Metabolism · doi:10.1016/j.molmet.2018.05.017 · Cited by 133 · see citing works
Self-citationEpidemiology of Gender Differences in Diabetes and Obesity
Mauvais‐Jarvis, F. (2017) · Advances in experimental medicine and biology · doi:10.1007/978-3-319-70178-3_1 · Cited by 91 · see citing works
Self-citationTan, H., Zhou, Y., & Yu, Y. (2012) · Diabetes Research and Clinical Practice · doi:10.1016/j.diabres.2012.05.004 · Cited by 85 · see citing works
Diabetic ketoacidosis: A common debut of diabetes among African Americans with type 2 diabetes
Vellanki, P., & Umpierrez, G. E. (2017) · Endocrine Practice · doi:10.4158/ep161679.ra · Cited by 73 · see citing works
Nalini, R., Özer, K., Maldonado, M., Patel, S. G., Hampe, C. S., Guthikonda, A., Villanueva, J., Smith, E. O., Gaur, L. K., & Balasubramanyam, A. (2010) · Metabolism · doi:10.1016/j.metabol.2010.01.009 · Cited by 60 · see citing works
Lean versus obese diabetes mellitus patients in the United States minority population
Coleman, N. J., Miernik, J., Philipson, L., & Fogelfeld, L. (2014) · Journal of Diabetes and its Complications · doi:10.1016/j.jdiacomp.2013.11.010 · Cited by 59 · see citing works
Estrogen Receptor α Regulates β-Cell Formation During Pancreas Development and Following Injury
Yuchi, Y., Cai, Y., Legein, B., Groef, S. D., Leuckx, G., Coppens, V., Overmeire, E. V., Staels, W., Leu, N. D., Martens, G. A., et al. (2015) · Diabetes · doi:10.2337/db14-1798 · Cited by 58 · see citing works
Male predominance in ketosis-prone diabetes mellitus
WANG, X., & Tan, H. (2015) · Biomedical Reports · doi:10.3892/br.2015.461 · Cited by 27 · see citing works
The Clinical And Metabolic Characteristics Of Young-Onset Ketosis-Prone Type 2 Diabetes In China
Zhang, M., Li, Y., Cui, W., Yang, P., Li, H., Sheng, C., Cheng, X., & Qu, S. (2015) · Endocrine Practice · doi:10.4158/ep15778.or · Cited by 27 · see citing works
Qadir, M. M. F., Elgamal, R. M., Song, K., Kudtarkar, P., Sakamuri, S. S. V. P., Katakam, P. V. G., El-Dahr, S. S., Kolls, J. K., Gaulton, K. J., & Mauvais‐Jarvis, F. (2024) · The EMBO Journal · doi:10.1038/s44318-024-00313-z · Cited by 25 · see citing works
Self-citationH1N1 Influenza: The Trigger of Diabetic Ketoacidosis in a Young Woman With Ketosis-Prone Diabetes
Tan, H., Wang, C., & Yu, Y. (2011) · The American Journal of the Medical Sciences · doi:10.1097/maj.0b013e3182376cc4 · Cited by 22 · see citing works
Sexual hormones and diabetes: The impact of estradiol in pancreatic β cell
Merino, B., & García‐Arévalo, M. (2021) · International review of cytology · doi:10.1016/bs.ircmb.2021.02.004 · Cited by 18 · see citing works
Ketosis-Onset Diabetes and Ketosis-Prone Diabetes: Same or Not?
Liu, B., Yu, C., Li, Q., & Li, L. (2013) · International Journal of Endocrinology · doi:10.1155/2013/821403 · Cited by 15 · see citing works
Balti, E. V., Nemb, M. N., Lontchi‐Yimagou, E., Atogho‐Tiedeu, B., Effoe, V. S., Akwo, E. A., Dehayem, M. Y., Mbanya, J. C., Gautier, J., & Sobngwi, E. (2014) · Diabetes Research and Clinical Practice · doi:10.1016/j.diabres.2014.10.002 · Cited by 10 · see citing works
Self-citationAtypical diabetes subtypes in Black African populations
Katte, J.-C. N., Bavuma, C. M., Wild, S. H., Hawkins, M. A., Thomas, N., Sobngwi, E., Nyirenda, M. J., & Kibirige, D. (2026) · Diabetologia · doi:10.1007/s00125-026-06697-3 · Cited by 7 · see citing works
Du, S., Yang, X., Shi, D., & Su, Q. (2016) · International Journal of Endocrinology · doi:10.1155/2016/3010243 · Cited by 3 · see citing works
THESE POUR LE DOCTORAT EN MEDECINE
Grégoire, B. (2015)
Current literature in diabetes
(2009) · Diabetes/Metabolism Research and Reviews · doi:10.1002/dmrr.918
Development and validation of a novel nomogram for prediction of ketosis-prone type 2 diabetes
Min, R., Liao, Y., & Peng, B. (2023) · Frontiers in Endocrinology · doi:10.3389/fendo.2023.1235048
Unraveling A‐β+ ketosis‐prone diabetes: An evolving diagnosis with an elusive pathogenesis
Suda, N., Page‐Wilson, G., Lonier, J. Y., & Pajvani, U. B. (2026) · Journal of Diabetes Investigation · doi:10.1111/jdi.70239
- Authors
- Louet, J. ‐., Smith, S. B., Gautier, J. ‐., Molokhia, M., Virally, M. ‐., Kevorkian, J. ‐., Guillausseau, P. ‐., Vexiau, P., Charpentier, G., German, M. S., Vaisse, C., Urbanek, M., & Mauvais‐Jarvis, F.
- Affiliations
- Baylor College of Medicine (US)
- University of California, San Francisco (US)
- Université Paris Cité (FR)
- London School of Hygiene & Tropical Medicine (GB)
- Centre Hospitalier Sud Francilien (FR)
- Northwestern University (US)
- Corresponding author
- Mauvais‐Jarvis, F.
- Venue
- Diabetes, Obesity and Metabolism
- Publisher
- Wiley
- Published
- 2008-09-15
- Volume
- 10
- Issue
- 10
- Pages
- 912-920
- ISSN
- 1462-8902 (ISSN-L)
- 1463-1326
- OpenAlex
- W2019676137
- Cited by
- 26
- References
- 37
- Citations by year
- 2026: 2 · 2024: 1 · 2023: 2 · 2021: 1 · 2018: 2 · 2017: 3 · 2016: 1 · 2015: 5 · 2014: 1 · 2013: 2 · 2012: 1
- FWCI
- 1.76
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Diabetes Obesity and Metabolism (publishedVersion)
- PubMed (publishedVersion)
- Research Portal (King's College London) (submittedVersion)
- Funders
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK021344, R21DK069362, R01DK074970)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (P50HD044405)
- 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 Management and Research
- Keywords
- KPD, neurogenin 3, sex differences, anovulation, insulin secretion, beta-cell function, C-peptide, type 2 diabetes, promoter polymorphism, HbA1c, hyperglycemia, pancreatic beta cells, genetic susceptibility, insulin deficiency
- MeSH terms
- Insulin Secretion, Adult, Anovulation, C-Peptide, Diabetes Mellitus, Type 2, Female, Genotype, Glucagon, Humans, Insulin, Male, Middle Aged, Nerve Tissue Proteins, Promoter Regions, Genetic, Sex Factors, Biomarkers, Gene Expression, Chi-Square Distribution, Case-Control Studies, Diabetic Ketoacidosis, Black People, Basic Helix-Loop-Helix Proteins, Basic Helix-Loop-Helix Transcription Factors
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
