RESUMEN
The prevalence of youth-onset type 2 diabetes (T2D) is rapidly increasing worldwide, disproportionately affecting Indigenous youth with Oji-Cree heritage from central Canada. Candidate gene screening has uncovered a novel and private polymorphism in the Oji-Cree population in the hepatocyte nuclear factor-1 alpha (HNF-1α) gene, where a highly conserved glycine residue at position 319 is changed to a serine (termed HNF-1αG319S or simply G319S). Oji-Cree youth who carry one or two copies of the "S-allele" present at diagnosis with less obesity, reduced indicators of insulin resistance, and lower plasma insulin levels at diagnosis, suggestive of a primary defect in the insulin-secreting ß cells. Few studies on the impact of the HNF-1αG319S variant on ß cell function have been performed to date; however, much can be learned from other clinical phenotypes of HNF-1α-deficiency, including HNF-1α mutations that cause maturity-onset diabetes of the young 3 (MODY3). In addition, evaluation of Hnf-1α-deficient murine models reveals that HNF-1α plays a central role in the regulation of insulin secretion by regulating the expression of key genes involved in ß cell glucose-sensing, mitochondrial function, and the maintenance of the ß cell phenotype in differentiated ß cells. The overall goal of this minireview is to explore the impact of HNF-1α-deficiency on the ß cell to better inform future research into the mechanisms of ß cell dysfunction in Oji-Cree youth with T2D.
Asunto(s)
Diabetes Mellitus Tipo 2/genética , Modelos Animales de Enfermedad , Factor Nuclear 1-alfa del Hepatocito/genética , Células Secretoras de Insulina/metabolismo , Polimorfismo Genético/genética , Animales , Canadá , Diabetes Mellitus Tipo 2/metabolismo , Factor Nuclear 1-alfa del Hepatocito/deficiencia , Factor Nuclear 1-alfa del Hepatocito/metabolismo , Humanos , MutaciónRESUMEN
OBJECTIVE: To compare the long-term risks of end stage renal disease and death among First Nations and non-First Nations people with youth-onset diabetes. METHODS: Using Saskatchewan Ministry of Health administrative databases covering the period between 1980 and 2005, we conducted a retrospective cohort study of end stage renal disease and death among youth with diabetes diagnosed before age 20. We developed Fine and Gray sub-distribution hazards models and cumulative incidence functions for the 2 outcomes by First Nations status and duration of diabetes. RESULTS: Incident cases of youth-onset diabetes were diagnosed in 352 First Nations and 2288 non-First Nations people. Mean ages at diabetes diagnoses were 11.7 and 11.2 years, respectively (p=0.13). Adjusted for sex and age at diabetes diagnosis, the risk for end stage renal disease was 2.59 (95% CI, 1.11-6.04) times higher, and the risk for death 2.64 (95% CI, 1.44-4.87) times higher for First Nations compared to non-First Nations people. After 25 years, the cumulative incidence of end stage renal disease was 12.3% for First Nations people compared to 4.3% in their non-First Nations counterparts. Corresponding mortality rates were 14.6% and 7.2%, respectively. CONCLUSIONS: First Nations people with youth-onset diabetes experience higher long-term risks for end stage renal disease and death than their non-First Nations counterparts. Early identification of type 2 diabetes and secondary prevention of diabetic nephropathy are feasible short-term goals for this high-risk group. More effective primary prevention initiatives and programs to delay diabetes onset are imperative to reverse current trends.