Clinical Science (2015) 128, 405–410 (Printed in Great Britain) doi: 10.

1042/CS20140553

Normal weight individuals who develop Type 2

diabetes: the personal fat threshold
Roy Taylor* and Rury R. Holman†

*Magnetic Resonance Centre, Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, U.K.
†Diabetes Trials Unit, University of Oxford, U.K.
www.clinsci.org

Abstract
Type 2 diabetes (T2DM) is frequently regarded as a disease of obesity and its occurrence in individuals of normal
body mass index (BMI) is often regarded as indicating a non-obesity-related subtype. However, the evidence for such
a distinct, common subtype is lacking. The United Kingdom Prospective Diabetes Study (UKPDS) cohort of people
diagnosed with T2DM in the 1970s and 1980s had a median BMI of only 28 kg/m2 . UKPDS data form the basis of
current understanding of the condition even though one in three of those studied had a BMI of less than 25 kg/m2 .
BMI, though, is a population measure and not a rigid personal guide. Weight loss is considered de rigueur for
treating obese diabetic individuals, but it is not usually considered for those deemed to have a normal BMI. Given
the new evidence that early T2DM can be reversed to normal glucose tolerance by substantial weight loss, it is
important to explain why non-overweight people respond to this intervention as well as obese individuals. We
hypothesize that each individual has a personal fat threshold (PFT) which, if exceeded, makes likely the
development of T2DM. Subsequent weight loss to take the individual below their level of susceptibility should allow
return to normal glucose control. Crucially, the hypothesized PFT is independent of BMI. It allows both
understanding of development of T2DM in the non-obese and remission of diabetes after substantial weight loss in
people who remain obese by definition. To illustrate this concept, we present the distribution curve of BMI at
diagnosis for the UKPDS cohort, together with a diagram explaining individual behaviour within the population. The
concept of PFT is of practical benefit in explaining the onset of diabetes and its logical management to the
non-obese majority of people with T2DM.
Clinical Science

Key words: aetiology, obesity, pathogenesis, Type 2 diabetes, weight loss

INTRODUCTION however, has not always been obvious. In the 1970s, when the
average weight of the UK population was considerably less than
Type 2 diabetes (T2DM) is a condition of relative insulin defi- at present, the Whitehall study showed only a small association
ciency, in which hyperglycaemia develops when a person’s β-cell between obesity and T2DM [6]. At that time it was considered
function is no longer sufficient to meet their insulin requirement that there was no major effect of obesity on the development of
[1,2]. Insulin resistance is common in people with T2DM and ex- T2DM [6–8].
acerbated by obesity, but individuals with normal weight can de- This article examines the scientific basis for the belief that the
velop T2DM if their β-cell function is sufficiently compromised pathophysiology of T2DM may be driven by individual weight
[3]. The interplay between the degree of insulin resistance and gain, rather than achieving a population-derived body mass in-
the level of β-function is likely to contribute to the heterogeneity dex (BMI) threshold and that this may be reversible. It considers
of T2DM presentation, especially in non-obese individuals [4,5]. data on populations and individuals and examines possible ex-
The identification of monogenic causes of maturity onset dia- planations of the phenomena observed. We hypothesize that each
betes of youth (MODY), which are unrelated to obesity, has rein- individual could have a personal fat threshold (PFT) which de-
forced the notion that ‘classical’ T2DM is linked to obesity and termines their susceptibility to developing T2DM, in relation to
that all non-obese people may probably have a different diabetes their degree of β-cell function and insulin sensitivity. Gaining
subtype. The perceived relationship between T2DM and obesity, sufficient weight to cross their PFT will trigger the condition,

Abbreviations: BMI, body mass index; MODY, maturity onset diabetes of youth; PFT, personal fat threshold; T2DM, Type 2 diabetes; UKPDS, United Kingdom Prospective Diabetes
Study

Correspondence: Professor Roy Taylor (email [email protected]).


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 R. Taylor and R. R. Holman

whereas losing their ‘excess weight’ could return them to normal

glucose tolerance.

IS THE ASSUMED PATHOPHYSIOLOGICAL

DIFFERENCE IN NON-OBESE AND OBESE
T2DM INDIVIDUALS REAL?

It is widely believed that non-obese people with T2DM have less

insulin resistance but a greater β-cell defect than those who are
overweight or obese [3,5,9,10]. However, insulin resistance also
increases as a function of increasing BMI whether or not an indi-
vidual is dysglycaemic [11]. Accordingly, to determine the effect
of insulin resistance on the development of T2DM, comparisons
need to be made between people matched for BMI. When this
is done, it can be seen that people with T2DM have modestly
greater insulin resistance at any level of BMI, but that there is
no greater insulin resistance in obese than in non-obese people
with T2DM, relative to their BMI matched normoglycaemic peers Figure 1 Population BMI distribution frequency plot for the entire
[12]. This is also seen when people with T2DM are compared 1977–1991 UKPDS cohort with newly diagnosed diabetes
with BMI matched late-onset auto-immune diabetes [13]. The
apparent enigma of the sometimes higher-fasting plasma insulin
levels seen in obese individuals with T2DM, compared with their
shown in Figure 1. These data have not previously been published
non-diabetic counterparts, is explained when the compensatory
as a distribution curve. The curve is unimodal with a slight skew
fasting hyperglycaemia of obesity is taken into account [14,15].
to the right showing that only a minority have a BMI greater than
Equally, test meals elicit similar increases in plasma C-peptide
35 kg/m2 . There is no interruption of the smooth left-hand side
in non-obese and obese people with T2DM (2.5- and 1.8-fold re-
of the distribution curve, suggesting that there is no dichotomy
spectively) [16]. Concepts of β-cell impairment have been swayed
and that a separate entity of non-obese T2DM is either too small
by the lower fasting plasma insulin in non-obese compared with
to visualize or absent. It is also notable that 36 % had a BMI less
obese people with T2DM. Just as for the normoglycaemic popula-
than 25 kg/m2 . The distribution observed is right-shifted from
tion, this merely reflects their lower degree of insulin resistance.
that of a contemporaneous adult UK population in which 64 %
However, direct measurement of β-cell response to a glucose
had a BMI less than 25 kg/m2 [21]. From today’s perspective, it
challenge shows the more relevant abnormality of T2DM. The
is remarkable that so many people with newly diagnosed T2DM
first phase insulin response to an intravenous glucose challenge
had normal BMIs. Nevertheless, given that the risk of T2DM
is absent in T2DM, whatever the BMI, and in impaired glucose
rises steeply at higher BMI’s and that higher BMI’s are now more
tolerance no effect of BMI has been demonstrated on either first-
prevalent, it is not surprising that the association between obesity
or second-phase insulin secretion [16].
and T2DM is much more evident today.
The concept that non-obese people with T2DM have lesser
Confirmatory information on the effect of population changes
degrees of insulin resistance and greater β-cell impairment has
in BMI distribution over time is available. As subsistence farm-
been extrapolated to therapeutic decisions. The American Dia-
ers, the Pima Indians had neither excess obesity nor excess dia-
betes Association/European Association for the Study of Dia-
betes [22,23]. In 1940, after displacement from their traditional
betes (ADA/EASD) guidelines note that ‘Common practice has
agricultural lifestyle, the prevalence was similar to that of the
favoured metformin in heavier patients’ [17] and it is assumed that
general US population [24]. Following inactivity, food oversup-
non-obese patients will respond less-well to the glucose-lowering
ply and dramatic increase in rates of obesity, the prevalence of
effect of metformin. This assumption has been examined and dis-
T2DM in adult Pima Indians rose to 38 % [25]. Although there
proven with the improvement in HbA1c (glycated haemoglobin)
must be an underlying genetic basis for the high susceptibility
between matched non-obese and obese groups with T2DM given
to T2DM in this population, its development is conditional upon
metformin shown to be almost identical [18,19].
lifestyle [26]. This is demonstrated by contemporaneous com-
parison with ethnically identical Pima Indians living in Arizona
and in Mexico [25]. Non-obese Pima Indians living in Mexico
POPULATION DATA: NO DISTINCT under nutritional conditions which limit adult weight gain, have a
SUBCATEGORY OF NON-OBESE T2DM T2DM prevalence which is less than one-fifth that of their obese
counterparts living in Arizona. In populations, the incidence and
The BMI frequency distribution for the 5102 people with newly prevalence of T2DM rises or falls depending simply upon the state
diagnosed diabetes, enrolled between 1977 and 1991 into the of the food supply as documented in Cuba in 1990–1996 and in
United Kingdom Prospective Diabetes Study (UKPDS) [20] is Britain during the first and second world wars [27,28]. The

406 
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C 2015 Biochemical Society
Normal weight individuals who develop Type 2 diabetes: the personal fat threshold

Nurses’ Health Study has shown that there is a 4-fold in-

crease in T2DM prevalence for women of BMI 23–25 com-
pared with those of BMI less than 22 kg/m2 as well as
confirming that the prevalence increases steadily with higher
BMIs [29].
Recently, a new perspective has been added by the demon-
stration that people with recent onset T2DM could regain normal
glucose control and normal β-cell function when the fat content
of the liver and the pancreas was decreased by a weight loss diet-
ary regimen. This reversal of T2DM was found to be achievable
equally readily by people with lower initial BMI [30,31]. Weight
loss effectiveness studies in T2DM have typically excluded those
with BMIs less than 25 kg/m2 [32,33]. The UKPDS, however,
included all newly diagnosed patients with T2DM who were
treated with diet alone for their 3–4 month run-in period. During
this time, 16 % of the cohort achieved a fasting plasma glucose
of <6.0 mmol/l, with no relationship between achieving fasting
normoglycaemia and initial body weight. Indeed, with presenting
plasma glucose of 8–10 mmol/l, normoglycaemia was achieved
with a mean weight loss of 13 % if body weight was normal,
whereas a mean weight loss of 21 % of body weight was required
to achieve this in the whole cohort. Additionally, at 15 months
into the study, fasting blood glucose depended upon the degree
of achieved weight loss and not body weight at diagnosis. These
data illustrate the good glycaemic response to weight loss in non-
obese people with T2DM [34]. Following widespread popular
interest in applying information on weight loss to reverse T2DM
[35], the knowledge that people who are not overweight can suc- Figure 2 The presonal fat threshold versus popultation metric
cessfully achieve this has reached a wide audience in the lay press (A) Representative frequency distribution of BMI for a group of indi-
[36]. viduals with T2DM. (B) Frequency distribution of BMIs in blue for the
individuals depicted in (A) before they gained weight. The red frequency
distribution, when diabetes had developed, is right shifted (red arrow)
and usually interpreted as indicating a higher prevalence of obesity. (C)
Three illustrative individuals from (B) are shown demonstrating their rel-
ative positions within the population BMI distribution. One is obese, one
INDIVIDUAL DATA COMPARED WITH overweight and one normal weight. Weight loss of 15 kg in each case
POPULATION DATA resulted in return to normal glucose tolerance although their classifica-
tion by the population measure of BMI did not change. It is hypothesized
that each individual has a PFT (dotted line) above which excess fat is
Figure 2 illustrates individual and population BMI data. Instead stored within the liver and the pancreas. This individual susceptibility
of a line graph summarizing the population BMI frequency dis- has no relationship to BMI despite the higher probability of diabetes
tribution, as in Figure 1, the BMIs of a number of representative being precipitated in the obese range. For each individual, moving to
the right of their PFT triggers T2DM (red arrows) and moving to the left
individuals with T2DM are depicted as red dots (Figure 2A). If of the line restores normal glucose tolerance (blue arrows).
the same individuals had been living in an environment of rel-
ative food scarcity, the prevalence of T2DM would be expected
to be low and personal weight gain would not have occurred.
In Figure 2(B), the normoglycaemic individuals in this notional low which it is normal. It can be seen that the effect of crossing
slimmer state are shown in blue, together with their heavier T2DM the PFT is identical for any individual, wherever he or she is
alter egos shown in red. Viewed as a population, the rate of obesity within the BMI distribution of the population. The person with
has increased and the BMI distribution curve merely shifts to the the lowest BMI merely moves down to their appropriate posi-
right. But for every individual there is a finite increase in their tion, which is still within the normal distribution of the lighter
body weight, whatever their starting point. groups of individuals who do not have diabetes (Figure 2B, blue
Figure 2(C) shows three such individuals from the upper panel dots).
who have early T2DM and BMIs of 36, 29 and 24 kg/m2 respect- Viewed from a population perspective, individuals may have
ively. One is obese by definition, one is overweight and one is a BMI considerably greater than 30 kg/m2 or less than 25 kg/m2
normal weight. Each individual succeeded in losing 15 kg in but are still a part of the overall BMI frequency distribution. If the
weight and regained normoglycaemia [30]. All three, therefore, whole population distribution of BMI shifts to the right, as has
moved from their relative place in the red distribution to that in occurred in Western society in the last few decades, then people
the blue and reversed their diabetes. In doing so, each must have who are thought not to have excess fat, when categorized by con-
crossed their PFT, above which glucose control is lost and be- ventional BMI metrics, behave not according to their BMI status


C The Authors Journal compilation 
C 2015 Biochemical Society 407
 R. Taylor and R. R. Holman

but behave according to whether they are carrying more fat than a first-phase insulin response can be used as the most direct index
they can tolerate individually. Personal excess fat is overlooked of reversal or return of the diabetic pathophysiology. It has been
in less heavy individuals when population metrics are applied to postulated that this is a consequence of the excess fat acting at
individuals. the level of the β-cells [31,48,49].
Our hypothesis predicts that β-cell insulin responses in normal
BMI and obese individuals with T2DM who have just completed
an 8-week low-calorie liquid diet will be similar and identically
MECHANISMS UNDERLYING THE PFT
affected by exposure to excess lipid metabolites. Both first-phase
and total insulin secretory responses could be tested on two sep-
The physiological mechanisms underlying an individual’s sus-
arate days, once after overnight intralipid infusion and once after
ceptibility to develop T2DM at a particular weight must be con-
saline infusion. Matched controls with no personal or family
sidered. Four critical factors may be identified. First, accumula-
history of T2DM would also be studied. The lack of effect of
tion of liver fat can now be seen as pivotal [31], but the extent
triacylglycerol (triglyceride) over-provision on insulin secretion
of this varies considerably at any weight or BMI [37]. Secondly,
in those not susceptible to diabetes and the distinct effect upon
the susceptibility of individuals to develop hepatic insulin res-
people at risk of T2DM has been demonstrated previously [50].
istance at any given level of liver fat accumulation is variable
The stepped insulin secretion tests described by Lim et al. [30]
even though the biochemical mechanism is understood [38]. The
should be used in order that the first phase and total insulin re-
variable effect is illustrated by one known genetic influence in
sponses could be quantified directly. We hypothesize that in both
that individuals with the G-allelle of patatin-like phospholipase
normal BMI and obese groups, β-cell function will be simil-
3 gene have a higher liver fat level but normal hepatic insulin
arly returned to the diabetic state of absent first phase insulin
sensitivity [39]. It is likely that complex polygenetic traits also
response by over-provision of triacylglycerol and that there will
contribute to this. The third and fourth factors relate to the same
be no such effect upon the controls. The return of a normal
considerations in the pancreas: extent and susceptibility to ad-
first-phase response from the characteristically absent response
verse effects of fat accumulation. Pancreas fat levels are raised in
in T2DM remains the most striking aspect of Lim’s paper and
T2DM [30,40] and fall as normal insulin secretion is restored by
this is the essence of being above or below the PFT.
a very low calorie diet [30]. It is known that chronic exposure to
excess fatty acids decreases glucose-mediated insulin secretion
by the β-cells [41]. However, there is considerable overlap in
pancreas fat levels between normal and Type 2 diabetic individu-
als suggesting differing susceptibility [31]. Extent of visceral
DISCUSSION
fat accumulation is a surrogate marker for intra-organ fat ex-
cess, but is not pathophysiologically related to adverse metabolic
The PFT concept is of practical use in explaining the need for
consequences [42,43]. Overall, the PFT for any one person is
weight loss to individuals with T2DM, even if they are not obese.
hypothesized to be determined both by extent of intra-hepatic
For any one person, the degree of susceptibility to the adverse
and intra-pancreatic fat accumulation and by susceptibility to the
effects of excess fat varies and their T2DM susceptibility cannot
local biochemical effects of lipid excess.
be known unless their PFT is exceeded. Once T2DM is triggered,
Comparative data from populations of different ethnicity re-
substantial weight loss will be needed to reverse it. This hypothet-
veal substantial ethnic differences in the susceptibility to de-
ical PFT for a person could be determined by careful observation
velop diabetes depending upon the burden of fat. A large popu-
during a weight loss intervention and would be the BMI at which
lation study has observed that the equivalent degree of risk for a
their first-phase insulin response became normal. Following pub-
Caucasian of BMI greater than 30 kg/m2 is expressed in South
lication of Lim’s study, individuals now report normal glucose
Asians at 25.2 kg/m2 and at 27 kg/m2 in African/Caribbeans [44].
control for up to 3 years to date [35,36]. It is notable that in
Within the ethnic groups, genetic polymorphisms, which are as-
the LookAhead, weight loss was 8.6 % by 1 year declining to
sociated with non-alcoholic fatty liver disease, can be identified
4.7 % by 4 years. Even this modest weight loss brought about
[45]. Liver fat content is strongly correlated with insulin sensit-
return of normoglycaemia sustained for at least 2 years in 9.2 %
ivity also in people of Asian ethnicity [46] and predicts future
of the group and, in keeping with the PFT hypothesis, the weight
onset of T2DM [47].
gain was associated with a fall in rate of sustained remission of
diabetes to 3.5 % [32].
In normal weight individuals presenting with possible T2DM,
TESTING THE HYPOTHESIS it is essential to exclude MODY and slow onset Type 1 diabetes,
even though most will have an ultimate diagnosis of classical
The PFT hypothesis could best be tested in those at highest risk for T2DM. Recognition that T2DM has similar pathophysiology, ir-
developing diabetes. The most homogenous group of individuals respective of BMI classification, is an important step in determin-
who would be closest to their PFT are those who have just reversed ing the most appropriate management for the individual patient.
their diabetes and are normoglycaemic with a normal first-phase The concept of a PFT is of practical benefit in explaining both
insulin response [30]. The defining characteristic for T2DM is the onset of diabetes and its logical management to all people
inadequate β-cell insulin secretion and the restoration or loss of presenting with T2DM.

408 
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Normal weight individuals who develop Type 2 diabetes: the personal fat threshold

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Received 8 September 2014/7 October 2014; accepted 24 October 2014

Published on the Internet 9 December 2014, doi: 10.1042/CS20140553

410 
C The Authors Journal compilation 
C 2015 Biochemical Society