Hyperglycaemia, Pre-Diabetes and Diabesity: Can we Choose who to 'Fast-Track' into Diabetes Prevention?
Abstract
Global numbers of overweight and obesity have been
increasing steadily for the past few decades, driving a rapid parallel
increase in type 2 diabetes (T2D) morbidity and associated mortality.
Hindered by our inability to clearly define the characteristics and
therefore the assessment biomarkers for 'pre-diabetes', there remains
significant difficulty in identifying those most at risk, essential in
order to prioritize public health initiatives for those who would most
benefit from 'fast-track' prevention. Implementation of a
population-wide approach to T2D prevention is likely to be prohibitively
expensive and unsuccessful, so more focused strategies are required.
'Pre-diabetes' is defined by any/all of 4 biomarker methods, comprising
impaired fasting glucose (IFG), impaired glucose tolerance (IGT), IFG
plus IGT, and mildly raised HbAlc. Each definition defines quite
different sub-cohorts of the population, hence quite different risk
profile, and may lead to both 'missed' and 'false positive'
prediabetics. This problem must be resolved before we are able to make
substantial strides and reliably choose who is most at risk and would
most benefit from 'fast-track' into diabetes lifestyle and or
pharmaceutical prevention.
Abbrevations: ADA: American Diabetes Association; T2D: Type 2 Diabetes; IFG: Impaired Fasting Glucose; IGT: Impaired Glucose Tolerance; WHO: World Health Organisation
Opinion
Despite considerable global efforts the number of
people diagnosed each year with type 2 diabetes (T2D) continues to
increase, hindered by our inability to both clearly define and to
identify those most at risk, and therefore in turn to prioritise public
health initiatives for those who could most benefit from 'fast-track'
prevention. T2Dis a disease with its origins in poor diet and lifestyle
with excess weight gain and adiposity as the primary cause, and hence
prevention of weight gain and/ or weight loss is a central tenant to any
prevention program. Global numbers of overweight and obesity have been
increasing steadily for the past few decades [1-3],
with little sign of slowing, despite significant global efforts to halt
the increase, with the World Health Organisation (WHO) estimating that
almost 2 billion adults have a body mass index of 25kg/m2 or above [4]. In parallel T2D is becoming increasingly common [5].
In 1994 approximately 1 million people globally were reported with T2D,
which increased to 382 million in 2013, and now with a projected
increase to 592 million over the next 20 years [6].
Those who have high levels of central adiposity are at particular risk
of T2D, with abdominal obesity strongly associated with important
changes in body composition including lipid infiltration into critical
organs such as pancreas and liver [7].
WHO also estimates that up to 80% of heart disease, stroke and T2D
could be prevented by eliminating risk factors resulting from an
unhealthy lifestyle [8],
resulting in significant improvement both to the individual and
national health care systems. In the US alone the medical consequences
of obesity have been estimated to in excess of $US150billion each year [9].
Key to prevention is the identification of those who
are most at risk and who are most likely to benefit from intervention.
Certainly some success has been achieved by several large international
programs investigating lifestyle and pharmaceutical (metformin)
approaches for T2D prevention [10-13],
yet the inexorable climb in patient numbers highlights the urgent
continued problem. There is a strong fiscal argument against
implementation of a population-wide approach, likely tobe prohibitively
expensive in many countries. Asia is an example of recent 'nutrition
transition' to Westernized lifestyle, where T2D is a rapidly growing
problem for many countries. China alone comprises a population of
lbillion, where up to 10% of adults are living withT2D and a further 30%
estimated to be overweight and at risk of later disease [14].
An alternate and likely more successful strategy is to identify these
individuals who are at greatest risk of later development of T2D,
commonly termed as those with 'pre-diabetes', and focus resources into
prevention for these sub-cohorts of the wider population. A major
problem with this strategy however is how to identify those who truly
are high-risk, and who left untreated will develop T2D in the following
years.
The term 'pre-diabetes' has been used since the 1950s [15], and today is defined using a (wide) variety of criteria set by several different international bodies [16-18].
In short, prediabetes may be identified in 4 main ways. Firstly,
through raised fasting plasma glucose (isolated impaired fasting
glucose, IFG), indicative of individuals who primarily have hepatic
insulin resistance hence raised glucose concentrations resulting from
increased gluconeogenesis and hepatic glucose output even in the fasting
state; secondly through impaired glucose tolerance (isolated IGT)
identified during a standardised 2 hour oral glucose tolerance test
(OGTT), indicative of individuals who have insulin resistance at the
site of skeletal muscle and hence poor insulin-mediated glucose disposal
following consumption of a meal; thirdly those withboth IFG and IGT;
and fourthly those individuals who are identified with raised levels of
glycated haemoglobin (HbA1c), more recently proposed by the American
Diabetes Association (ADA) [17]
as an indicator of prolonged raised glucose levels resulting from
long-term exposure to both basal and post-meal hyperglycaemia,and
potentially representative of the combination of adverse pathologiesthat
underly IFG and IGT. However, HbAlc clearly identifies a different pool
of individuals as pre-diabetic compared to those identified using
glucose cut offs, in addition to effects of gender and ethnicity,
possibly a result of differences in glycation and/or red cell survival.
Depending on the definition chosen, these tests
identify very different populations with quite different aetiology of
prediabetes [19]
and it may be expected that they will have very different risks of
converting to full blown T2D. Indeed Barry and colleagues (2017) have
recently shown by meta-analysis that as these different tests for
pre-diabetes define vastly different populations, significant
misclassification does occur [20].
This results in two opposing outcomes where large numbers of
individuals are either(i) 'missed' pre-diabetics who fail to be
correctly identified as high risk and so not fast tracked for
intervention, or (ii) 'false' pre-diabetics likely to take up lifestyle
or pharmaceutical treatment unnecessarily. Clearly this problem must be
resolved before we are able to make substantial strides and reliably
choose who to 'fast-track' into diabetes prevention.
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