The Genetics of Type 2 Diabetes and Related Traits PDF – Biology Physiology and Translation

The Genetics of Type 2 Diabetes and Related Traits PDF

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When Victor Neel termed type 2 diabetes (T2D) “the geneticist’s nightmare,” (Neel 1962) it was already evident that T2D harbored a familial component; yet its polygenic genetic architecture, the inherent limitations in the techniques available at the time, and the strong (and growing!) influence of environmental determinants made genetic discovery an arduous task. In the 50 years since then, the public health impact of T2D has only skyrocketed, fueled by the changes in modern lifestyle increasingly adopted by developing societies and the expansion of caloric superabundance.
As a result, T2D and its complications represent one of the most serious challenges to public health in the twenty-first century. We live in the midst of a worldwide pandemic that threatens to undermine the significant gains we have made against cardiovascular disease over the last few decades. Despite its status as one of the oldest known endocrinopathies, the availability of a molecular therapy since 1920, and the existence of over a dozen drug classes approved for the management of the disease, we are largely unable to cure it and are losing the population battle in both the developed and developing worlds.
The population and healthcare costs are enormous and only expected to rise. Stoked by the snowballing obesity epidemic, diabetes affects over 29 million Americans, with more than 80 million at high risk. People with Asian, African, and American indigenous ancestry experience a higher risk, with the worldwide prevalence of diabetes expected to hit 500 million by 2030. In the USA alone, diabetes and its complications account for $245 billion annually. With its concomitant life-threatening complications of cardiovascular disease, renal failure, visual loss, and peripheral vascular disease, T2D can undermine the global economy, with a disproportionate burden on underprivileged groups and low- and middle-income countries.
At the crux of our lack of clinical effectiveness lies our incomplete understanding of its pathogenesis, evolution, and metabolic consequences. Definite causal triggers, the interplay between various risk factors, and specific mechanisms that underlie long-term complications remain largely unknown. Thus, T2D has become the quintessential complex disease, with substantial genetic and environmental components, significant variation in prevalence across ethnic groups, pathophysiological heterogeneity, multiple treatment modalities, and poorly defined interactions with related metabolic phenotypes.

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