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Risk factors in the development of T2DM

Genetic predisposition

Genetics are of fundamental importance in the emergence and the
progression of T2DM, but deciphering which genes code for which
proteins in the bewildering complexities of the metabolic regulatory
mechanisms and how they interact will take many more years of in-
tense study to fully elucidate. This area has been further complicated
by our growing understanding of epigenetics. Epigenetics relates to
heritable differences that are not caused directly by underlying ge-
netic mechanisms. Typically, these can be caused by methylation of
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the genome causing some genes to be activated and others to be
deactivated, although other mechanisms are also possible. 36

Epigenetics aside, around 50 candidate genes involved mainly in pan-
creatic β-cell function, but also in insulin action/glucose metabolism
and other metabolic mechanisms that increase T2DM risk have been
identified, but their individual role enhances the risk for T2DM by less
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than 20-30 %. Thus multiple polymorphisms must be present to substan-
tially influence individual diabetes risk.

The more well-known candidate genes include transcription factor
7-like 2 (TCF7L2) gene, peroxisome proliferator-activated receptor-γ
(PPARγ), ATP binding cassette, subfamily C, member 8 (ABCC8) and
CAPN10. It has been postulated that TCF7L2 gene variants may af-
fect the susceptibility to T2DM by indirectly altering GLP-1 levels. The
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PPARγ gene is important in adipocytes and lipid metabolism, with one
form (Pro) decreasing insulin sensitivity and increasing T2DM risk several
fold. ABCC8 codes for the receptors and potassium channels that
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regulate the release of hormones from the pancreas. A mutation in the
receptor or channel can affect the secretion of hormones, such as in-
sulin. CAPN10 codes an enzyme (calpain 10), variations in the activity
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of which can affect insulin secretion.
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Obesity

Obesity is the most potent risk factor for developing T2DM. The cor-
relation between diabetes and obesity is well-known (Figure 5). In an
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evolutionary context, the obesity epidemic is a consequence of mal-
adaptation, i.e. the human genotype has not adapted to the modern
lifestyle with food abundance relative to shortage (as was typical for
our ancestors). Evolution equipped humans with the ability to survive
on meagre, albeit intermittently abundant, food resources – a situation
that prevailed for the vast majority of human evolution. Compared with
our ancient ancestors, our anatomy and physiology are unchanged,
but in recent centuries, lifestyles have changed immeasurably in the

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