J Diabetes Res. 2015;2015:485132.

The Genetic Profile from HLA and Non-HLA Loci Allows Identification of Atypical Type 2 Diabetes Patients.


Fabregat M1, Fernandez M1, Javiel G2, Vitarella G3, Mimbacas A1.
  • 1Biodiversity and Genetic Department, Instituto de Investigaciones Biológicas Clemente Estable, 11600 Montevideo, Uruguay.
  • 2Teaching Care Unit, Unit of Diabetes “Hospital Pasteur”, ASSE, Ministry of Public Health, 11600 Montevideo, Uruguay ; Diabetology Service of “Centro de Asistencia del Sindicato Médico del Uruguay”, 11800 Montevideo, Uruguay.
  • 3Diabetology Service of “Centro de Asistencia del Sindicato Médico del Uruguay”, 11800 Montevideo, Uruguay.



The complex diagnosis and treatment of diabetes highlight the need for markers to define how to monitor patients correctly during the course of their disease. Different studies demonstrate the existence of patients who cannot be clearly classified. We have previously shown that it is possible to differentiate “atypical diabetic patients” based on genotyping the HLA. In this work we show that the analysis of non-HLA related to type 1 diabetes in the INS-VNTR, SNP rs689, and rs3842753 improves the identification of these patients. We genotyped 913 individuals comprising controls from the general population and “classic” and “atypical” diabetic patients. We compared the distribution of these loci and analyzed linkage disequilibrium. The haplotype was in LD for all the SNPs that were evaluated. Regarding their association with the disease, the haplotype IAC was associated with type 1 (odds 2.60, 1.82-3.72, CI 95%) and “atypical diabetes” (odds 1.50, 1.01-2.23, CI 95%), whereas we did not observe an association with type 2 diabetes. Therefore, our results confirm that atypical diabetes is a different entity of the disease where the patient presents with a genetic background of T1D and a T2D phenotype, findings that are likely to be relevant for patient diagnosis and management in the clinic.

PMID: 26273670



Today, diabetes is a major challenge for physicians. It is a disease with varied and complex clinical characteristics, such as age of onset and symptoms, as well as differences in biochemical profiles and response to treatments. Moreover, it has been demonstrated the existence of patients who would not well adjust to international classification. On the other hand, there are differences in diverse populations according to the degree of miscegenation. Uruguay is one of the smallest countries in South America, with approximately 3,600,000 inhabitants (1), with 8% diabetes prevalence (2). Its population has tri-hybrid origin (Caucasian, Amerindian and African) with an intense process of miscegenation between three ethnicities which, unlike other Latin American countries, no isolated communities (3-9) remained. This feature has important consequences in relation to frequencies of different genetic variants in the general population and their association with diabetes. In the course of the last years working together diabetologists, clinical physicians and geneticists we observed the presence of atypical patients who attended in tertiary care health level who not always were possible to classify in one or other groups of diabetes and sometimes, presenting treatment difficulties. In this sense, questions that arose from the exchange between researchers and clinicians led us to think that beyond ethnic factors there may be genetic variants influencing the results that complicate the presentation of the disease and classification of some patients in particular.

For this reasons we decided to analyze our diabetes DNA and serum bank for the presence of genes and antibodies associated with type 1 diabetes independently of the initial diagnosis of the disease. The results showed that the phenotypic classification did not reflect the autoimmune disease.

Diverse researchs have shown that in our population there is a high percentage of particular patients diagnosed as type 2 who share genes of type 1 diabetes. These patients showed a difficult management, generally showed inadequate response to treatment plans, and sometimes failed to reach metabolic goals. We named this type of presentation as “atypical diabetes”. It could be present at any age in presence of overweight or obesity.

Our different investigations allow applying the research findings in optimizing the clinical diagnosis with the consequent adjustment of atypical disease treatment. In addition to the clinical background, they provide the health team with a scientific basis to modify therapy and thus shortenning the period of “trial and error”. Is important to remark that a proper diagnosis is not based solely on clinical and humoral studies, and that wrong decisions might lead to a poor outcome that could culminate in the early development of chronic complications of diabetes.

The phenotype is not sufficient to properly classify each patient. We suggest that genetics is a powerful tool that helps distinguish the difficulties in categorizing complex patients. Much is said about the high costs of molecular techniques. However, it is noteworthy that these studies are conducted once in an individual’s life. Moreover, when we evaluate the cost benefit of a correct diagnosis in atypical patients, becomes especially important that it would be helping to solve problems in the near future patient´s health of individual and social costs.

This population represents a challenge for clinicians regarding their response to therapy, the achievement of metabolic goals and their development of pathology. In conclusion, the availability of a large population genotyped and attended for our multidisciplinary group has represented a start for taking genetics into account as an accessible tool in clinical practice.






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