Читать книгу Clinical Dilemmas in Diabetes - Группа авторов - Страница 57

Having somewhat downplayed the notion that there are two discrete forms of diabetes, one must acknowledge that the extremes of the disease spectrum are fairly easy to recognize and seem to differ in their genetic predisposition. Both type 1 and type 2 exhibit genetic predisposition to the disease but the environmental contribution to type 2 diabetes is much more prominent [23].

Common genetic variation in more than 200 loci has been associated with type 2 diabetes. The risk conferred by most of these variants is small – indeed knowledge of genetic variation at the 18 loci with greatest effect on disease risk did not appreciably alter the performance of a prediction model utilizing anthropometric information and family history [24]. Although later models incorporating genetic information from additional loci improved their predictive performance, especially in younger adults, it remains apparent that genetic information is unhelpful in predicting type 2 diabetes risk at an individual level [25].

In contrast, genetic variation in the human leukocyte antigen (HLA) confers more than half of the genetic risk of type 1 diabetes. HLA binds and processes antigen‐presentation to the immune system. A handful of other loci involved in immune response pathways confer significant additional risk. Other variants (~50) also contribute smaller effects. Most of the loci associated with type 1 diabetes alter immune regulation [26–28].

The environmental events, if any, that trigger the cascade of immune‐mediated destruction in type 1 diabetes are not well defined. Often hyperglycemia is detected for the first time in the context of a febrile illness, but it is well accepted that significant islet destruction has occurred by the time hyperglycemia develops. In contrast, excess caloric intake and physical inactivity are associated with type 2 diabetes. However, this is not uniform, so that of all patients coming to bariatric surgery in the United States (BMI > 35 kg/m²) only a third have diabetes. The reasons for this heterogeneity are unclear at present [29]. Another interesting observation is the association of shift work and circadian misalignment with type 2 diabetes – this may be mediated through effects on insulin synthesis and secretion. Genetic variation in the melatonin receptor (MTNR1B) – a key part of circadian signaling – is associated with type 2 diabetes [30, 31].