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DIABETICMedicine

Change in pancreatic B-cell function (HOMA-B) varies in

Original
Effect
Original
Oxford,ofUK
Diabetic
DME
Blackwell
0742-3071
23 Article onLtd
article
migration
Medicine
Publishing
Publishing, HOMA-B A. Heald et al.
2006

different populations with similar genetic backgrounds

but different environments

A. H. Heald, S. G. Anderson*†, J. Patel‡, A. Rudenski, A. Vyas*†, A. Yates§, E. Hughes‡,

D. Prabharakan¶, S. Reddy¶, P. Durrington†, J. M. Gibson, D. Bhatnagar†,
J. K. Cruickshank*†, and I. Laing§

Department of Endocrinology, University of
Manchester, Salford NHS Trust, Salford, *Clinical
Epidemiology Group, University of Manchester
Medical School, †University Department of
Medicine, Manchester Royal Infirmary, Manchester,
‡Department of Clinical Biochemistry, Sandwell
General Hospital, Birmingham, §Clinical
Biochemistry Department, Manchester Royal
Infirmary, Manchester, UK and ¶All India Institute
of Medical Sciences, New Delhi, India
Accepted 7 August 2006
Abstract
Objective To determine whether pancreatic B-cell function varies in different
populations with similar genetic backgrounds but different environments.
Research design/methods We compared a specific migrant Gujarati community
in the UK (n = 205) with people still resident in the same villages of origin in
Gujarat, India (n = 246). Pancreatic B-cell function (HOMA-B) was determined
and the influence of age, migration and other factors was explored.
Results As anticipated, there was an age-related decline in log(HOMA-B)
in both groups. However, the age-related fall in log(HOMA-B) was more
pronounced in the UK than in Gujarat (normalized β −0.29 vs. −0.14, P for
difference = 0.03). The decline of HOMA-B with age persisted after adjustment
for body mass index (UK β = −0.31; Gujarat β = −0.16, P = 0.015, P < 0.001).
There was no significant change in insulin sensitivity (HOMA-S) with age at
either site, although insulin sensitivity was lower in the UK. Fasting non-estrified
fatty acid (NEFA) levels rose with age in the UK but not in Gujarat (P = 0.003
for difference in gradients). In multiple linear regression analysis, lower
log(HOMA-B) was independently associated with higher fasting log(NEFA)
levels; normalized β = −0.24, P < 0.001, age; β = −0.16, P = 0.005, higher
log(insulin-like growth factor binding protein-1); β = −0.19, P = 0.007 and lower
body mass index; β = 0.26, P = 0.001. This model accounted for 25% of the
variability in HOMA-B.
Conclusions HOMA-B as a measure of B-cell function declines more rapidly with
age in the migrant UK group than in Gujarat. This may be a direct consequence
of chronically higher NEFA exposure in the UK group.
Diabet. Med. 24, 145–153 (2007)
Keywords age, HOMA-B, migration, non-esterified fatty acid

Abbreviations BMI, body mass index; CRP, C-reactive protein; CV, coefficients
of variation; HOMA, homeostasis model assessment; HOMA-B, pancreatic B-
cell function; HOMA-S, insulin sensitivity; IGF-I, insulin-like growth factor-I;
IGFBP-1, insulin-like growth factor binding protein-1; NEFA, non-esterified
fatty acid; WHO, World Health Organization; WHR, waist–hip ratio

Correspondence to: Dr A H Heald, Department of Diabetes and Endocrinology,
University of Manchester, Salford Royal Hospitals University Trust, Hope
Hospital, Stott Lane, Salford, Greater Manchester, M6 8HD, UK.
E-mail: aheald@fs1.ho.man.ac.uk
Introduction
Both the American Diabetes Association [1] and the World
Health Organization (WHO) [2] have introduced new diag-
nostic criteria for diabetes mellitus, reducing diagnostic fasting

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DIABETICMedicine Effect of migration on HOMA-B • A. H. Heald et al.

glucose cut-off points from 7.8 to 7.0 mmol/l. This increase in

diagnostic sensitivity and the strong linkage of Type 2 diabetes
with age have increased significantly the number of positive
diagnoses. This emphasizes the need for a better understand-
ing of the influence of age on glucose homeostasis and the
development of Type 2 diabetes.
For any ethnic group, lifestyle has a profound effect on
insulin metabolism and on the incidence of Type 2 diabetes
and cardiovascular disease [3]. In people of South Asian origin
in the UK, glucose intolerance and coronary heart disease are
commoner than in white Europeans [4–6], but direct measures
of exposure associated with migration and the mechanisms
resulting in increased disease rates have rarely been studied
in detail.
Previous studies have shown that lifestyle change accom-
panying migration is associated with a significant decline in
insulin sensitivity and an increased risk of Type 2 diabetes [7].
Deteriorating glucose homeostasis can arise by decreasing
insulin sensitivity or pancreatic B-cell dysfunction, either
individually or in combination.
B-cell function remained unaffected by age in some studies
[8], but decreased with age in others [9,10]. The evidence for
an age-related decline in insulin sensitivity is equally con-
tradictory, with a decline in some reports [11] but not others
[9,10]. Homeostasis model assessment (HOMA) is a simple
way of deriving indices of pancreatic B-cell function (HOMA-
B) and tissue insulin sensitivity (HOMA-S). It compares well
with ‘gold standard’ methods for assessing these functions
[12].
Our hypothesis was that the lifestyle changes that occur
with population migration result in a change in the relation
between parameters of glucose homeostasis, specifically
HOMA-B and age.
Subjects, materials and methods
Study cohort
The study design was a direct comparative population-based
community study, between Gujaratis from the same village of
origin, living in Sandwell, UK (first generation migrants)
(n = 205) and those still in Gujarat, India around the town of
Navsari (n = 246). Representative random sampling from
population-based registers supplemented by the electoral rolls
was conducted at each site [13]. Mean ages (95% CI) by site
and gender are given in Table 1. Response rates were 72% in
Sandwell and 67% in Navsari, Gujarat. Migration to the UK
had occurred from Gujarat, North-West India. Twenty-two per
cent of Sandwell participants had migrated to the UK before
puberty.
The participants in the study gave informed consent. Ethical
approval for the study was obtained both in Sandwell and
Gujarat from the respective responsible local ethics committees.
Baseline examination
Participants attended clinics having fasted from 22.00 h on the
previous evening at both sites. Participants were questioned
prior to venesection to confirm that they had indeed fasted
overnight and the timing of commencement of the fast. There
was no significant difference between the sites in the numbers
of participants travelling by motor vehicle to the clinic. Venous
blood was taken between 08.00 and 09.00 h, separated and
stored appropriately. Participants without previously diagnosed
diabetes on the basis of self-report/health records and a fasting
capillary glucose < 7 mmol/l were asked to complete a glucose
tolerance test (GTT) [2]. A 75-g equivalent glucose load was
administered as a fruit-flavoured drink (Maxijoul; SHS Supplies,
Liverpool, UK). Venous blood samples were collected at 30 and

Table 1 Age-adjusted lifestyle risk factors in Gujarati Indians in Sandwell (UK) compared with contemporaries living in Navsari (India)

Men Women

Lifestyle factors UK (n = 103) Gujarat (n = 128) UK (n = 102) Gujarat (n = 118)

Age (years) 49.0 (46.8–51.3) 49.1 (46.8–51.5) 49.2 (47.1–51.3) 48.5 (46.3–51.3)
Height (m)† 1.67 (1.63, 1.72)* 1.64 (1.60, 1.69) 1.53 (1.50, 1.57) 1.52 (1.49, 1.55)
BMI (kg/m2)† 25.2 (22.9, 28.0)** 20.2 (18.2, 23.2) 26.2 (23.5, 29.2)** 20.4 (17.8, 24.6)
Waist–hip ratio† 0.91 (0.87, 0.95)** 0.86 (0.86, 0.92) 0.81 (0.76, 0.85)* 0.78 (0.74, 0.83)
Systolic blood pressure (mmHg) 134 (131–138)*** 122 (119–126) 121 (117–125)** 111 (108–115)
Diastolic blood pressure (mmHg) 84 (82–85)*** 75 (73–77) 75 (73–77)*** 69 (67–70)
Total energy intake (kcal/day) 2221 (2054–2386)** 1478 (1347–1610) 1720 (1595–1847)** 1260 (1174–1348)
Fasting plasma glucose (mmol/l) 5.6 (5.3–6.0) 5.8 (5.5–6.1) 5.4 (5.0–5.7) 5.3 (5.1–5.7)
Two-hour glucose (mmol/l) 5.4 (5.0–5.8)*** 6.8 (6.4–7.2) 5.7 (5.3–6.1)* 6.5 (6.1–6.8)
Fasting insulin (pmol/l)† 69.5 (49.9, 99.4)** 52.4 (32.3, 81.6) 59.7 (50.7, 98.2) 59.5 (42.2, 76.8)
Fasting NEFA (mmol/l)† 0.45 (0.27, 0.56)*** 0.22 (0.15, 0.53) 0.42 (0.31, 0.57)*** 0.17 (0.14, 0.31)
HOMA-S%† 64.5 (41.3, 85.4)* 79.8 (50.0–131.3) 71.1 (44.0, 84.0) 72.2 (54.6, 100.9)
HOMA-B%† 118.3 (86.4, 158.3)* 94.5 (61.0, 126.0) 121.5 (99.2–155.5) 111.3 (84.7, 135.2)

Values are percentage or arithmetic mean (95% CI), except when denoted by † for anthropometric variables, and non-normally distributed
variables which are given as median with interquartile range (P25–P75).
*P < 0.05, **P < 0.001, ***P < 0.0001: Gujarat vs. Sandwell.

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120 min after glucose challenge. Blood samples were centrifuged
and aliquots of plasma or serum were frozen at − 70 ° C until
analysis [14].
Fieldwork was rigorously standardized, a process repeated
within teams monthly, with regular cross-site visits every 4 months.
Standardized measures of anthropometry as body mass index
(BMI), weight in kg divided by height in m2, and waist–hip ratio
(WHR) were taken by trained fieldworkers, after subjects had
responded to a detailed lifestyle questionnaire [15].
Plasma glucose was determined in the Department of Bio-
chemistry, Sandwell Hospital and the Mankodi Laboratory,
Navsari. Both sites used glucose oxidase autoanalyser methods,
the Vitros 950 (Vitros, Raritan, NJ, USA) in the UK and
Technicon RA-50 (Bayer Diagnostics, Gujarat) in Gujarat.
Tight quality control was maintained by the use of the same
control specimens at both laboratories.
Serum insulin was measured as reported elsewhere [16]. The
assay has 30% cross-reactivity for pro-insulin. The insulin
assay has a lower limit of detection of 2.5 pmol/l. Intra-assay
coefficients of variation (CV; at 25 pmol/l) is 6.3% and inte-
rassay CV (at 25 pmol/l) is 6.1%.
Plasma and serum aliquots were transported from India to the
UK by air, using dry ice (dry shippers; BDH-Merck, Nottingham,
UK) for measurement of serum insulin, insulin growth factor-1
(IGF-I) and insulin growth factor binding protein-1 (IGFBP-1).
HOMA-S and HOMA-B were calculated from fasting insulin
and glucose concentrations. A computer-solved model was
used to predict the homeostatic concentrations which arise
from varying degrees of B-cell deficiency and insulin resistance
[homeostasis model assessment (HOMA)]. Comparison of a
patient’s fasting values with the model’s predictions allows
a quantitative assessment of the contributions of insulin re-
sistance and deficient B-cell function to the fasting hyperg-
lycaemia. The accuracy and precision of the estimate have
been determined by comparison with independent measures
of insulin resistance and B-cell function using hyperglycaemic
and euglycaemic clamps and an intravenous glucose tolerance
test [12].
Serum non-esterified fatty acids (NEFA) were analysed by an
enzymatic colourimetric method (Wako Chemicals GmbH,
Neuss, Germany). IGF-I was measured using the DPC (Los
Angeles, California, USA) Immulite Autoanalyser. IGF-I was
measured using the DPC Immulite Autoanalyser (DPC, Los
Angeles, CA, USA). IGFBP-1 levels were determined by previously
reported antibody-based assay [17], with a detection limit
3 mg/l and within and between assay CV of < 8%.
C-reactive protein (CRP) was measured using an in-house
high-sensitivity ELISA method using antibodies from Dako
(Glostrop, Denmark) [18]. The detection limit was 0.1 mg / l,
within-batch CV, 6% at 3 mg / l and between-batch CV 10% at
3 mg / l.
Statistical analysis
The data were analysed using the statistical package Intercooled
Stata version 8.0 (Stata Corporation, College Station, TX, USA).
Anthropometric and metabolic data are expressed as arithmetic
means with 95% CI. Comparison of means was by t-test or ANOVA
and of medians by the sign rank test. The Kolmogorov–Smirnov
© 2007 The Authors.
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DIABETICMedicine
test was used to test normality of distribution. Variables which
were not normally distributed (NEFA, insulin, CRP, IGF-I,
IGFBP-1, HOMA-S, HOMA-B) were logarithmically trans-
formed before analysis. For univariate correlation between
continuous variables, Spearman coefficients were used, with
partial coefficients for multivariate correlation. A P-value
< 0.05 was considered significant.
The standardized beta coefficients presented allow direct
comparison (along a scale of 0 –1) of the strength of each associa-
tion between ethnic groups, as well as for the total sample. In
Stata, tests for the homogeneity of slopes uses the formula:
anova y a × a * x, cont(x). The null hypothesis was that the
slopes were the same. In order to avoid confusion with statistical
terms, we have simply stated ‘differences in the regression
coefficients’ using the standard methods best illustrated by the
example on the UCLA Academic Technology website (http://
www.ats.ucla.edu/stat/stata/faq/compreg2.htm).
As not all subjects had all measurements owing to missing
samples, numbers varied between analyses. Similarly, patients
with known diabetes were excluded from all analyses.
Results
General characteristics
As previously reported [14], men and women in both locations
were of similar age (Table 1). Mean ages were similar at 50.1
(48.5–51.7) years in Sandwell and 48.9 (47.4 –50.4) years in
Navsari. Duration of stay in the UK correlated positively with
age (Spearman’s ρ = 0.38, P < 0.0001).
Men in Sandwell were taller than contemporaries in
Gujarat, but female height was similar. BMI and WHR were
significantly higher in men and women in Sandwell compared
with Gujarat, as were systolic and diastolic blood pressure.
For Navsari subjects, WHR increased with age (ρ = 0.36;
P < 0.0001), as it did in Sandwell (ρ = 0.24; P = 0.0002). There
was a direct relation between BMI and age in Navsari
(ρ = 0.13; P = 0.03), but not in Sandwell. As described pre-
viously [14], rates of total Type 2 diabetes (known and new on
the basis of oral glucose tolerance testing, WHO 1999 criteria)
[2] were similar between the sites for men [Sandwell 19.2%
(12.9–25.4); Navsari 17.1% (10.8–23.4)], but higher for
women in Sandwell [17.1% (10.3–23.9)] than Navsari
[10.3% (4.8–15.9)]. There was no difference in fasting glucose
by site for either men or women. Two-hour glucose was higher
in both Navsari men and Navsari women (Table 1).
HOMA-B, HOMA-S and age
There were negative associations between logarithmically
transformed HOMA-B, log(HOMA-B), and age at both sites,
but the decrease of log(HOMA-B) with age was steeper in
Sandwell (Fig. 1a; Sandwell normalized β = −0.29, P < 0.0001;
Navsari normalized β = −0.14, P = 0.031). Specifically for
Sandwell log(HOMA-B) = 5.403 – 0.014 × age and for Navsari
log(HOMA-B) = 4.833 – 0.005 × age. The t-value for the
147
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difference in regression coefficients was 2.11; P = 0.03
indicating a stronger relation between age and HOMA-B in
Sandwell than Navsari. For Sandwell, the loss in B-cell
function was 1.4% per annum and for Navsari approximately
0.05% per annum.
This relative decline of HOMA-B with age persisted even
after adjustment for BMI at both sites (Sandwell normalized
β = −0.31, P < 0.001; Navsari normalized β = −0.16, P =
0.015). In a separate analysis, adjusting for WHR provided a
similar relation between HOMA-B and age (Sandwell nor-
malized β = −0.28, P < 0.0001; Navsari normalized β = −0.012,
P = 0.052).
When adjustment was made for duration of stay in the UK,
there was no change in the inverse relation between HOMA-B
and age for Sandwell (normalized β = −0.32, P < 0.0001).
There was no change in HOMA-S with age at either site
(Fig. 1b, and Table 1). HOMA-S was lower in Sandwell men
than Navsari men, with no difference by site for women.
148
Effect of migration on HOMA-B • A. H. Heald et al.
FIGURE 1 (a) The effect of age on Ln(HOMA-
B) in participants from Sandwell and Navsari.
The decrease in log HOMA-B with age was
steeper in the UK. (b) The effect of age on
Ln(HOMA-S) in participants from Sandwell
and Navsari. There was no significant change in
log HOMA-S with age at either site.
Relationship of other metabolic variables with age
In Sandwell, fasting glucose rose more steeply than in Navsari:
glucose = 3.343 + 0.045 × age; glucose = 4.609 + 0.020 × age,
respectively (t = −1.96, P = 0.02 for difference in regression
coefficients; Fig. 2a). There was a trend for 2-h glucose to rise
more steeply in Sandwell than in Navsari: glucose = 3.918
+ 0.035 × age; glucose = 6.123 + 0.010 × age, respectively
(t = −1.57, P = 0.06 for difference in regression coefficients;
Fig. 2b). Fasting glucose was higher in Navsari men, but there
was no difference in fasting glucose in women. Two-hour
glucose was higher in both Navsari men and women (Table 1).
Exclusion of participants with a fasting glucose > 7 mmol/l or
2 h glucose > 11.1 mmol/l did not materially alter the results.
Thirty-minute insulin increment [defined as (insulin concen-
tration at 30 min minus fasting insulin)/glucose concentration
at 30 min)] was higher in Sandwell but declined with age
(β = −0.12, P = 0.02): Sandwell 30-min insulin increment =
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Original article DIABETICMedicine

FIGURE 2 (a) The effect of age on fasting

glucose in participants from Sandwell and
Navsari. Fasting glucose rose more steeply in
participants from Sandwell than Navsari.
(b) The effect of age on 2-h post-challenge
glucose in participants from Sandwell and
Navsari. The difference in the slope of the lines
did not reach significance.

13.4 – 0.12 × age, P = 0.02; there was no change in the 30-min
insulin increment with age in Navsari (30-min insulin increment
= 6.49 – 0.027 × age, P = NS; Fig. 3).
IGF-I fell with age at a similar rate at both sites [Sandwell
log(IGFI) = 5.526 – 0.013 × age, Navsari log(IGFI) = 5.132 –
0.013 × age].
Fasting NEFA increased with age in Sandwell (P = 0.0009;
but did not significantly alter with age in Navsari, P = 0.58 for
change with age; Fig. 4), so that the regression coefficients
were significantly different (t-value for the difference = 2.17,
P = 0.003). The relation between 2-h NEFA with age (P = 0.31
and P = 0.084 for Sandwell and Navsari, respectively) was
not significantly different (t-value for the difference = −1.68,
P = 0.095).
When the relation between fasting NEFA and HOMA-B is
examined by age (Fig. 5), it is clear that, for older age groups
(highest tertile), higher circulating NEFA levels are associated
with lower HOMA-B. However, with decreasing age tertiles,
the strength of this relation diminishes.
Fasting NEFA was significantly higher in Sandwell than
Navsari for both men and women (Table 1).
Multivariate linear regression analysis
Decreasing log HOMA-B was independently and significantly
associated with higher fasting log NEFA levels; normalized
β = − 0.24, P < 0.001, age; β = − 0.16, P = 0.005, higher
log(IGFBP-1); β = −0.19, P = 0.007 and lower BMI; β = 0.26,
P = 0.001, in a model which also included log(IGF-I), log(CRP),
gender and migrant status. The model accounted for 25% of
the variability in HOMA-B. Including WHR in a separate
analysis gave similar relations.
Discussion
In this cross-sectional study of two Gujarati populations from
the same villages of origin, we have found that a measure of
pancreatic B-cell mass (HOMA-B) declines more rapidly with

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age in the migrant Sandwell group than in the group remaining
in Navsari. The greater rise in fasting and 2-h glucose with age
in Sandwell vs. Navsari reflects the steeper fall in HOMA-B in
Sandwell, in relation to insulin sensitivity. Insulin sensitivity
itself remained stable over time for both groups. While
increasing age was one of a number of factors shown in both
univariate and multivariate analysis to be related to a lower
HOMA-B, its contribution was statistically significant and
physiologically relevant as shown previously [10]. There is
no evidence that the cohort of individuals who migrated from
Gujarat to the UK were different at the time of migration in
terms of social, educational or professional make-up than the
sample of the population who remained in Gujarat.
150
Effect of migration on HOMA-B • A. H. Heald et al.
FIGURE 3 The effect of age on 30-min post-
challenge insulin increment in participants from
Sandwell and Navsari. The 30-min insulin
increment was higher in participants from
Sandwell but declined with age. There was no
change in the 30-min insulin increment with age
in Navsari participants.
FIGURE 4 The effect of age on fasting
Ln NEFA in participants from Sandwell and
Navsari. Fasting NEFA increased with age in
Sandwell participants but did not significantly
alter with age in Gujarat residents.
Inappropriately high concentrations of plasma NEFA have
been shown to alter glucose-stimulated insulin secretion in
a time-dependent manner. Short-term in vitro incubation of
islets with long-chain fatty acids increased insulin release
during glucose stimulation [19,20]. This was also seen in vivo
in healthy volunteers after a short-term increase of plasma
NEFA concentrations by Intralipid(tm) and heparin [21–24],
with the effect being greatest for mono-unsaturated fatty acids
[25]. Contrary findings have been observed after a long-term
increase of plasma NEFA concentrations. Studies showed that
a prolonged (24– 48 h) increase of NEFA concentrations either
impaired [24] or increased [23] glucose-stimulated insulin
secretion in healthy volunteers.
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Original article
Figure 5 Relationship of fasting logNEFA with logHOMA-B by
age tertile.
Our results suggest that chronic exposure to elevated NEFA
levels may be important in the development of impaired
pancreatic B-cell function, which is an important factor in the
progress towards Type 2 diabetes mellitus. The concentrations
of fasting NEFA seen in the Gujarati individuals studied here
are similar to those reported in non-diabetic South Asians by
Shelgikar et al. in 1997 [26]. However, other factors must be
taken into account, such as the association of lower BMI and
higher IGFBP-1 with low HOMA-B, which indicates that
declining insulin secretion and hepatic insulin action occur
in the context of failing body weight regulation with age.
Furthermore, other possible differences between the two sites
that are unidentified—micronutrients, vitamin D, etc.—and
that have been identified—calorie intake, saturated fat intake,
calorie expenditure [27]—and may be relevant to the relation
of HOMA-B with age.
Both obesity and Type 2 diabetes are characterized by
increased plasma non-esterified fatty acid concentrations [28].
Raised fasting plasma NEFA concentrations are a risk marker
for the development of Type 2 diabetes in Pima Indians [29]
and in Caucasian subjects [30]. Increased plasma NEFA con-
centrations can have adverse effects on various tissues. Excess
plasma NEFA concentrations can lead to a reduced skeletal
muscle glucose uptake and oxidation [31,32], increased
hepatic glucose output [33] and a decrease in hepatic insulin
clearance [34,35]. These mechanisms could lead to glucose
intolerance and insulin resistance leading to Type 2 diabetes.
While there is significant variation in HOMA-B for individuals
in both Navsari and Sandwell, similar variation has been seen
previously using this model [10] and relates to interpersonal
variation rather than assay imprecision or problems with
sample collection or storage. HOMA-B is a good measure of
basal homeostatic B-cell function. Furthermore, the 30-min
insulin/glucose increment results showing decline by age in
Sandwell but not in Navsari were consistent with the HOMA-
B results. Dynamic models such as continuous infusion of
glucose with model assessment (CIGMA) measure the response
of insulin to glucose stimulation, but are not practicable for
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DIABETICMedicine
studies with large numbers of participants, such as here. The
apparent lack of decline in insulin sensitivity (HOMA-S) in
both groups may be a feature of the configuration of the
HOMA model itself. The model ascribes worsening degrees of
glucose tolerance to either decline in B-cell function or insulin
sensitivity, depending on the insulin concentration. The fact
that the ascribed fall in B-cell function correlates well with
the decline in 30-min insulin increment tends to confirm the
validity of the HOMA estimates.
It is theoretically possible that the cross-site differences that
we describe could be related to different sample handling in
Navsari and Sandwell. However, identical protocols were
adhered to at both sites with regard to sample handling, this
being closely monitored by the principal investigators, as were
transit arrangements and the condition of the samples on arrival.
The data presented here are preliminary. It is difficult to
achieve perfect one-to-one matching of subjects at the different
sites, and the effects of environment are complex. However,
the fundamental point is that the difference between the
environments in the UK and Gujarat appears to result in a
difference in the rate of decline of pancreatic B-cell function
with age.
Both in vitro [36] and animal studies [37] indicate that
IGF-1 may have a protective effect on pancreatic B-cells by
reducing B-cell apoptosis, and stimulation of B-cell replication.
The decline in IGF-I with age found here could relate to the
progressive fall in HOMA-B seen at both sites. Conversely, the
lower HOMA-B, and by inference lower prehepatic portal
insulin levels in older subjects, may result in lower hepatic
IGF-I synthesis and so decreased circulating IGF-I levels. Lower
IGF-I may also influence insulin sensitivity; prospectively, we
found that lower IGF-I levels were closely associated with and
predicted incident impaired glucose handling at 4.5 years
follow-up in the UK Ely study [38].
It would be interesting to see if there were differences in
pro-insulin concentrations between the two populations, in
case this was a confounding factor in the HOMA estimates.
Pro-insulin was not measured in this study, but high concen-
trations can influence insulin measurements as a result of
cross-reactivity. If this had occurred in our study, then
HOMA-B would tend to be overestimated, particularly in
older subjects, given the relative increase in pro-insulin with
age which has been reported [39]. We still see a predominant
effect of age in the migratory group, so, if anything, we may
have underestimated the detrimental effect of migration on
beta-cell function.
This study has confirmed previous observations of declining
HOMA-B with age in both populations studied [40,41]. The
rate of decrease of HOMA-B with age was greater in the
migrant Sandwell group than in Navsari, probably related to
lifestyle differences, with a consequently greater decline in
hepatic glucose regulation with age. How this age-related
decline in HOMA-B relates to the development of Type 2
diabetes remains to be determined. We propose that the
greater rate of loss of B-cell function in the UK Gujarati group
151
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DIABETICMedicine
contributes to the faster increase in fasting and 2-h glucose
levels observed in the UK Gujarati group than is the case for
their contemporaries still living in Gujarat.
Acknowledgements
The authors gratefully acknowledge the support of the British
Heart Foundation and the NHS Research and Development
Levy for funding this study. Insulin was assayed in Dr Ian
Laing’s laboratory at the Manchester Royal Infirmary and IGF-I
and IGFBP1 by Dr Gibson of Hope Hospital, Salford, UK.
Competing interests
None declared.
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