ArticlePDF Available

Type 2 Diabetes: When Does It Start?

Authors:

Abstract and Figures

Purpose We aimed to clarify the onset of diabetes. Methods Data from 27,392 non-diabetic health examinees was retrospectively analyzed for a mean of 5.3 years. Trajectories of fasting plasma glucose (FPG), body mass index (BMI) and the single point insulin sensitivity estimator (SPISE), an index of insulin sensitivity (Si), 10 years prior to diagnosis of prediabetes (n=4,781) or diabetes (n=1,061) were separately assessed by mixed effects model. Diabetes and prediabetes was diagnosed by the ADA definition on the basis of FPG and HbA1c values. Results In individuals who developed diabetes, mean FPG and BMI were significantly higher (respectively, P<0.01 each) and SPISE lower than those who did not at -10 years; FPG 101.5 mg/dL vs 94.5 mg/dL, BMI 24.0 kg/m² vs 22.7 kg/m² and SPISE 7.32 vs 8.34, P<0.01 each). These measurements in subjects who developed prediabetes were slightly but definitely different from those who did not, already at -10 years: FPG 91.8 mg/dl vs 89.6 mg/dl, BMI 22.6 kg/m² vs 22.1 kg/m² and SPISE 8.44 vs 8.82; P<0.01 each. In both cases, the differences were progressively greater toward year 0, the time of diabetes or prediabetes diagnosis. Conclusions FPG was significantly elevated in those developed diabetes at least 10 years before diagnosis of diabetes, and this was also the case in those developed prediabetes. Glucose dysregulation precedes diagnosis of diabetes at least for 20 years.
No caption available
… 
No caption available
… 
No caption available
… 
Content may be subject to copyright.
Type 2 Diabetes: When Does It Start?
Hiroyuki Sagesaka, Yuka Sato, Yuki Someya, Yoshifumi Tamura, Masanori Shimodaira,
Takahiro Miyakoshi, Kazuko Hirabayashi, Hideo Koike, Koh Yamashita, Hirotaka Watada,
and Toru Aizawa
Journal of the Endocrine Society
Endocrine Society
Submitted: March 06, 2018
Accepted: April 13, 2018
First Online: April 18, 2018
Advance Articles are PDF versions of manuscripts that have been peer reviewed and accepted but
not yet copyedited. The manuscripts are published online as soon as possible after acceptance and
before the copyedited, typeset articles are published. They are posted "as is" (i.e., as submitted by
the authors at the modification stage), and do not reflect editorial changes. No
corrections/changes to the PDF manuscripts are accepted. Accordingly, there likely will be
differences between the Advance Article manuscripts and the final, typeset articles. The
manuscripts remain listed on the Advance Article page until the final, typeset articles are posted.
At that point, the manuscripts are removed from the Advance Article page.
DISCLAIMER: These manuscripts are provided "as is" without warranty of any kind, either express
or particular purpose, or non-infringement. Changes will be made to these manuscripts before
publication. Review and/or use or reliance on these materials is at the discretion and risk of the
reader/user. In no event shall the Endocrine Society be liable for damages of any kind arising
references to, products or publications do not imply endorsement of that product or publication.
ADVANCE ARTICLE: JOURNAL OF
THE ENDOCRINE SOCIETY
JES
Downloaded from https://academic.oup.com/jes/advance-article-abstract/doi/10.1210/js.2018-00071/4975349
by guest
on 20 April 2018
ADVANCE ARTICLE
Journal of the Endocrine Society; Copyright 2018 DOI: 10.1210/js.2018-00071
1
Uncovering the onset of glucose dysregulation.
Type 2 Diabetes: When Does It Start?
Hiroyuki Sagesaka,
1
* Yuka Sato,
1
* Yuki Someya,
2
Yoshifumi Tamura,
2
Masanori
Shimodaira,
3
Takahiro Miyakoshi,
1
Kazuko Hirabayashi,
4
Hideo Koike,
4
Koh Yamashita,
1
Hirotaka Watada,
2
and Toru Aizawa
1
*These authors contributed equally to this work.
1
Diabetes Center,
4
Health Center, Aizawa Hospital, Matsumoto 390-8510, Japan;
2
Department of Metabolism & Endocrinology, Sportology Center, Juntendo University Graduate School of
Medicine, Tokyo 113-8421, Japan; and
3
Department of Internal Medicine, Iida Municipal Hospital, Iida 395-8502, Japan
Received 06 March 2018. Accepted 13 April 2018.
Purpose: We aimed to clarify the onset of diabetes.
Methods: Data from 27,392 non-diabetic health examinees was retrospectively analyzed
for a mean of 5.3 years. Trajectories of fasting plasma glucose (FPG), body mass index
(BMI) and the single point insulin sensitivity estimator (SPISE), an index of insulin
sensitivity (Si), 10 years prior to diagnosis of prediabetes (n=4,781) or diabetes (n=1,061)
were separately assessed by mixed effects model. Diabetes and prediabetes was diagnosed
by the ADA definition on the basis of FPG and HbA1c values.
Results: In individuals who developed diabetes, mean FPG and BMI were significantly
higher (respectively, P<0.01 each) and SPISE lower than those who did not at -10 years;
FPG 101.5 mg/dL vs 94.5 mg/dL, BMI 24.0 kg/m
2
vs 22.7 kg/m
2
and SPISE 7.32 vs 8.34,
P<0.01 each). These measurements in subjects who developed prediabetes were slightly but
definitely different from those who did not, already at -10 years: FPG 91.8 mg/dl vs 89.6
mg/dl, BMI 22.6 kg/m
2
vs 22.1 kg/m
2
and SPISE 8.44 vs 8.82; P<0.01 each. In both cases,
the differences were progressively greater toward year 0, the time of diabetes or prediabetes
diagnosis.
Conclusions: FPG was significantly elevated in those developed diabetes at least 10 years
before diagnosis of diabetes, and this was also the case in those developed prediabetes.
Glucose dysregulation precedes diagnosis of diabetes at least for 20 years.
FPG already increased at 10 years before diagnosis of diabetes, and also at 10 years before
diagnosis of prediabetes. Diabetes may begin at least > 20 years before its diagnosis.
Abbreviations: ALT, alanine aminotransferase; BIC, Bayesian information criterion; BMI, body
mass index; DM, diabetes mellitus; FPG, fasting plasma glucose; HbA1c, glycosylated haemoglobin
A1c; HDL-c, high-density lipoprotein cholesterol; HOMA-IR, homeostasis model assessment of
ADVANCE ARTICLE: JOURNAL OF
THE ENDOCRINE SOCIETY
JES
Downloaded from https://academic.oup.com/jes/advance-article-abstract/doi/10.1210/js.2018-00071/4975349
by guest
on 20 April 2018
ADVANCE ARTICLE
Journal of the Endocrine Society; Copyright 2018 DOI: 10.1210/js.2018-00071
2
insulin resistance; LDL-c, low-density lipoprotein cholesterol; NGR, normal glucose regulation;
PDM, prediabetes; Rd, rate of glucose disappearance; SBP, systolic blood pressure; Si, insulin
sensitivity; SPISE, Single Point Insulin Sensitivity Estimator; TG, triglycerides; T2DM, type 2
diabetes mellitus.
Introduction
It has been well established that a long-lasting prodromal stage exists before clinical
diagnosis of type 2 diabetes (T2DM), which consists of progressive elevation of plasma
glucose within non-diabetic range, weight gain and attenuation of insulin sensitivity (Si) [1-
5]. In general, such abnormalities may be detected already 10 years before diagnosis of
diabetes [1-8]. Increase in glucose-stimulated insulin secretion (GSIS), which may well be a
compensation for attenuated Si during this period, was demonstrated in some [2,8], but not
in other studies [1,9]. Variability in GSIS is likely due to ethnic diversity of Si [10] and in
part due to variable degree of obesity [8].
Japanese people are relatively lean and the average body mass index (BMI) in the
general population is approximately 22 kg/m
2
[11] while that of patients with T2DM in a
representative cohort was slightly over 23 kg/m
2
[12]. Increase in insulin resistance before
clinical diagnosis of diabetes was reported to be modest irrespective of the participants’
body weight in the Japanese population [8]. Despite the low degree of obesity accompanied
with increased insulin sensitivity in the Japanese population, the trajectory of glucose before
diabetes [6,8] and the prevalence of T2DM are not substantially different between Japanese
[13] and Caucasians [2,14]. Assuming that attenuated Si and β-cell dysfunction are the two
primary drivers for the development of diabetes, these data are compatible with a significant
role of β−cell dysfunction in T2DM causation [15,16] in Japanese individuals.
Despite accumulation of data, the timeline of T2DM has not been fully understood.
Particularly, the onset of glucose dysregulation leading to diabetes has not been clarified,
i.e., the trajectories before diagnosis of diabetes have been assessed for 10-15 years, and the
patients destined to develop T2DM exhibited significant elevation of plasma glucose
already at the earliest time points in all studies [1-8]. In this regard, the time point when
progressors to T2DM and nonprogressors first becomes significantly different from each
other is currently unknown. It was hypothesized that β-cell dysfunction starts 12 years
before the clinical diagnosis of diabetes [17]. However, such hypothesis is not necessarily
consistent with a more recent epidemiological study [2]. Therefore, we assessed the
trajectories of fasting plasma glucose (FPG), BMI and Si before development of diabetes or
prediabetes (PDM) separately. Si was quantified by a new index, the single point insulin
sensitivity estimator (SPISE) [18].
Materials and Methods
ADVANCE ARTICLE: JOURNAL OF
THE ENDOCRINE SOCIETY
JES
Downloaded from https://academic.oup.com/jes/advance-article-abstract/doi/10.1210/js.2018-00071/4975349
by guest
on 20 April 2018
ADVANCE ARTICLE
Journal of the Endocrine Society; Copyright 2018 DOI: 10.1210/js.2018-00071
3
Study participants and study design
The main dataset was obtained at the Health Center of the Aizawa Hospital, Matsumoto,
Japan, which was designated as the Aizawa Cohort. Another data set was obtained at
Juntendo University, Tokyo, Japan. Written informed consent was obtained from all
participants and the review board of Aizawa Hospital and Juntendo University approved the
study protocol. This study was performed in accordance with the principles outlined in the
Declaration of Helsinki.
Aizawa Cohort. A total of 49,781 participants received health examination including
FPG and glycosylated hemoglobin A1c (HbA1c) between July 2005 and May 2016. Of
those, 22,389 were excluded because they were newly diagnosed with diabetes at baseline
or they did not receive follow-up examinations during the study period. The difference
between the characteristics of the non-diabetic subjects who were followed-up and not
followed-up was minimal (data not shown). Thus, the data from 27,392 eligible individuals
were analyzed. The endpoint of the follow-up was the development of PDM or diabetes.
For the analysis of subjects developed PDM, data of 15,778 participants with normal
glucose regulation (NGR) were collected at baseline and until participants developed
prediabetes or until the last examination (whichever occurred first).
For the analysis of subjects who developed diabetes, data were collected from the entire
non-diabetic participant cohort (n = 27,392, NGR and PDM combined) until participants
developed diabetes or until the last examination (whichever occurred first). Participants who
developed diabetes during the observation period were defined as DM-Progressors and
those who did not develop diabetes until the last examination were defined as NonDM
(NDM)-Nonprogressors.
Trajectories were assessed for FPG, BMI and a new index of Si, SPISE [18]. The
following formula was used to calculate SPISE:
(
)
(
)
0.185 0.2 1.338
SPISE 600 HDL -c TG BMI= × ×
HDL-c: high-density lipoprotein cholesterol (mg/dL)
TG: triglycerides (mg/dL).
BMI: Body mass index (kg/m
2
)
SPISE is a quantitative index of Si suited for the health examination because of its low
cost and derivation from the ordinary data. We used it after validation of it in the Japanese
population because it is originally developed and validated in Caucasians [18].
Juntendo Cohort. This cohort was used for verification of SPISE [18] in the Japanese
adults. The characteristics of this cohort were reported elsewhere [19]. Nondiabetic
Japanese men aged between 30 and 50 years were recruited through posters at major
companies and internet advertisements. Subjects being treated for hypertension, lipid
disorders, diabetes, cardiovascular disease, chronic lung disease, cancer, renal failure,
ADVANCE ARTICLE: JOURNAL OF
THE ENDOCRINE SOCIETY
JES
Downloaded from https://academic.oup.com/jes/advance-article-abstract/doi/10.1210/js.2018-00071/4975349
by guest
on 20 April 2018
ADVANCE ARTICLE
Journal of the Endocrine Society; Copyright 2018 DOI: 10.1210/js.2018-00071
4
serious hepatic dysfunction, hepatitis B and hepatitis C were excluded. Blood samples after
overnight fasting were withdrawn for measurement of TG and HDL-c, and BMI
determined. 236 subjects volunteered to participate in the study, and after exclusion or
refusal, euglycemic hyperinsulinemic glucose clamp test with PG clamped at 95 mg/dL was
performed in 111.We employed rate of disappearance (Rd) of glucose during 180 to 360
min as an index of muscle sensitivity. For further detail of the clamp study is provided
elsewhere [19].
Diagnosis of glucose metabolism
Diabetes was diagnosed when FPG 126 mg/dL or HbA1c 6.5% [20]. Diagnosis of
diabetes was also made based on information by the participants who they had been
diagnosed with diabetes at a medical facility. Prediabetes was diagnosed when FPG was
between 100-125 mg/dL and/or HbA1c 5.7-6.4%. Participants with FPG <100 mg/dL and
HbA1c <5.7% were diagnosed as NGR.
Variables
Sex, age, BMI, systolic blood pressure (SBP), FPG, HbA1c, HDL-c, low-density
lipoprotein cholesterol (LDL-c), TG and alanine aminotransferase (ALT) were recorded.
SPISE (18] was also recorded as an index of Si. For analysis of trajectories before diabetes,
the date of examination was rounded to the nearest year by setting the date of diagnosis of
diabetes as day 0. For assessment of trajectories before prediabetes, the date of diagnosis of
prediabetes was taken as day 0. The date of last examination was taken as day 0 for those
who did not develop prediabetes or diabetes. It should be noted that the data from
individuals with NGR at baseline were used for the trajectory assessment before
prediabetes, and the data from those with NGR and/or PDM at baseline used for the
trajectory analysis before diabetes.
Statistics
The trajectories were assessed using the mixed effects model with adjustment for sex and
age, and the data shown in the figures were the estimated marginal means and 95%
confidence interval at each year. The number of subjects who received a health examination
at -9, -10 and -11 years were 94, 41 and 3, respectively. It was rather small and therefore the
subjects in the three year ranges were combined, and this group, containing the data from -
9, -10 and -11 years, was designated simply as -10 years in the figures. The correlation
between the clamp-based Rd and SPISE was examined using Spearman’s rank correlation.
Mann-Whitney U test and x
2
test were used as required. Comparison of the estimated
marginal means was performed by online calculator
(https://www.medcalc.org/calc/comparison_of_means.php). For the linear and cubic
weighted minimum square regression, Bayesian information criterion (BIC) and r
2
values
were determined to compare fitness of the regression.
ADVANCE ARTICLE: JOURNAL OF
THE ENDOCRINE SOCIETY
JES
Downloaded from https://academic.oup.com/jes/advance-article-abstract/doi/10.1210/js.2018-00071/4975349
by guest
on 20 April 2018
ADVANCE ARTICLE
Journal of the Endocrine Society; Copyright 2018 DOI: 10.1210/js.2018-00071
5
JMP
®
12.2.0, SAS Institute or Statistical Package for Social Sciences (SPSS
®
) 21.0,
IBM, statistical software was used, and P < 0.05 (two tailed) was considered significant.
Results
Baseline characteristics of the Aizawa Cohort
Baseline anthropometric and laboratory data in PDM-Progressors showed slightly but
significantly atherogenic or metabolic characteristics compared with NGR-NonProgressors
except for plasma HDL-c which was not significantly different between the two groups
(Table 1A). Such trend was unequivocal in DM-Progressors compared with NonDM-
Nonprogressors (Table 1B).
Correlation between SPISE and clamp-based Rd
Correlation between clamp-based index of Si and SPISE appears to be better in Juntendo
Cohort than in the original adult cohort: Spearman rank correlation coefficient 0.688 in the
former and Pearson correlation coefficient 0.474 in the latter.
SPISE was positively and robustly correlated with clamp-based Rd adjusted for body
weight (Spearman rho = 0.688, P <0.01) (Figure 1).
Trajectories of FPG
FPG was significantly higher in PDM-Progressors than NGR-Nonprogressors already at 10
years before PDM (Figure 2A). FPG gradually rose toward year 0 (the time of PDM
diagnosis) in PDM-Progressors. Whereas FPG exhibited no significant rise in NGR-
Nonprogressors.
FPG was significantly higher in DM-Progressors than NonDM-Nonprogressors at year -
10 (Figure 2B). A gradual elevation of FPG occurred in DM-Progressors thereafter until
year -2, which was followed by an accelerated increase towards year 0 (the time of diabetes
diagnosis). There was no significant increase in FPG in NonDM-Nonprogressors during the
observation period (Figure 2B).
The FPG trajectory in PDM-Progressors fitted to weighted cubic regression clearly
better than linear regression (Figure 2A’). BIC was 97.11 and 113.36 for cubic and linear
regressions, respectively, and r
2
was 0.944 and 0.548, respectively. Similar results were
obtained for the FPG trajectory in DM-Progressors (Figure 2B’): BIC for cubic and linear
regression was 108.57 and 125.42, respectively, and r
2
was 0.956 and 0.623, respectively.
Trajectories of BMI
BMI was significantly greater in PDM-Progressors than NGR-Nonprogressors already at
year -10 (P < 0.01) (Figure 3A), and, in the former, BMI progressively increased toward
year 0. BMI was also significantly greater in DM-Progressors than NonDM-Nonprogressors
at year -10 (Figure 3B). It gradually increased thereafter in DM-Progressors. At the time of
diabetes diagnosis, BMI was 25.6 kg/m
2
and 22.7 kg/m
2
, in DM-Progressors and NonDM-
ADVANCE ARTICLE: JOURNAL OF
THE ENDOCRINE SOCIETY
JES
Downloaded from https://academic.oup.com/jes/advance-article-abstract/doi/10.1210/js.2018-00071/4975349
by guest
on 20 April 2018
ADVANCE ARTICLE
Journal of the Endocrine Society; Copyright 2018 DOI: 10.1210/js.2018-00071
6
Nonprogressors, respectively (P < 0.01). BMI did not significantly change during the
observation period in the two Nonprogressor groups (Figure 3A and B, open symbols).
Trajectories of SPISE
SPISE was significantly lowered in PDM-Progressors compared to NonDM-
Nonprogressors already at year -10 (Figure 4A). SPISE values in PDM-Progressors, but not
in NGR-Nonprogressors, were progressively small thereafter (Figure 4A). Similarly, SPISE
in DM-Progressors showed an unequivocal lowering, compared with NonDM-
Nonprogressors, at 10 years before diagnosis of diabetes. There was no significant time-
dependent change of SPISE in NonDM-Nonprogressors (Figure 4B).
Discussion
Glucose trajectory before development of T2DM has been studied by many groups [1-8].
Consistent with these previous studies, we showed that FPG in individuals destined to
develop diabetes is already elevated at 10 years before diagnosis, compared to those who
did not develop diabetes. In individuals who developed diabetes, a relatively slow elevation
of FPG occurred until -3 to -5 years, which was followed by an accelerated escalation of
FPG towards the time of diagnosis of diabetes. Thus, the onset of T2DM has not been
identified. In Japanese people, the data was obtained in the cohorts with exclusively [6, 7]
or mostly [8] males in the previous studies. We analyzed the data of the cohort with an
approximately equal sex distribution. Nonetheless, our data on the trajectories in subjects
developed diabetes was mostly confirmative of the previous results. In other words, the
onset of glucose dysregulation leading to diabetes could not be identified in Aizawa Cohort
with this length of observation.
SPISE is a surrogate measure of Si developed and validated in Caucasians [18], and
therefore, we needed to confirm its validity in the Japanese people using the data from
Juntendo Cohort [19]. Knowing that SPISE is a reliable index of Si in the Japanese people,
we applied it to Aizawa Cohort.
In an attempt to uncover the onset of dysglycemia preceding diabetes, we assessed
the trajectories of FPG, as well as BMI and SPISE before PDM diagnosis, at the earliest
stage of diabetes evolution [21]. We hypothesized that, until a certain time point, FPG may
be indistinguishable between individuals who developed PDM and those who did not. To
our knowledge, this is the first study in which glucose trajectory before diagnosis of PDM
was investigated. The results were clear. Contrary to our hypothesis, the individuals
destined to develop PDM (PDM-Progressors) had significantly higher FPG value already at
-10 years, compared to those who did not develop PDM (NGR-Nonprogressors). In
addition, BMI and Si were greater and attenuated decreased, respectively, already at -10
years. Therefore, the primary abnormalities of T2DM, dysglycemia, increased body weight
and attenuated Si had started >10 years before diagnosis of PDM. The deviation from
ADVANCE ARTICLE: JOURNAL OF
THE ENDOCRINE SOCIETY
JES
Downloaded from https://academic.oup.com/jes/advance-article-abstract/doi/10.1210/js.2018-00071/4975349
by guest
on 20 April 2018
ADVANCE ARTICLE
Journal of the Endocrine Society; Copyright 2018 DOI: 10.1210/js.2018-00071
7
Nonprogressors was highly significant, although the degree of abnormality was smaller
compared to that seen in those destined to develop DM. Taken together, we consider
dysglycemia leading to T2DM begins even >10 years before diagnosis of PDM, so that it
would be > 20 years before diagnosis in majority of patients with T2DM, if not all.
We noticed that the trajectories of FPG, before both PDM and diabetes, fitted nicely to
the cubic regression (Figure 2A’ and B’), which suggested a time-dependent
pathophysiology. The most likely interpretation would be as follows. At the initial stage of
development of PDM or diabetes, a minute elevation of PG may occur due to modest
weight gain with a minimum attenuation of Si. This may cause increased insulin secretion
and stabilization of PG, at the slightly elevated levels. Eventually, as Si attenuates further,
β-cells cannot meet the increased demand of insulin secretion, and a relatively sharp rise of
PG ensues. Of note, the well fit cubic regression was not a product of setting a threshold
value for the diagnosis, because the fitness of cubic regression was present even after
omission of the value at the diagnosis of diabetes or PDM (year 0) (data not shown).
There were limitations in this study. First, our study population was a group of
potentially health-conscious individuals. Therefore, the timeline of T2DM in the general
population may be steeper than the Aizawa Cohort. Second, reliability of SPISE in the
Japanese subjects was confirmed. Nonetheless slight over- or under-estimation of Si by
SPISE cannot be completely ruled out. Third, the duration between diagnosis of PDM and
that of diabetes is currently unknown, so that entire timeline of diabetes evolution still
remains to be clarified. Finally, the insulin level was not determined in the Aizawa Cohort,
therefore the trajectory of β-cell function was not ascertained.
In conclusion, we assessed trajectories of FPG, BMI and Si, before diagnosis of diabetes
and PDM, separately. These measurements were apparently abnormal at least -10 years of
diagnosis of not only diabetes, but also PDM. Type 2 diabetes may start as early as 10 years
before development of prediabetes, which means > 20 years before diagnosis of diabetes in
majority of patients.
Acknowledgments
Address all correspondence and requests for reprints to: Toru Aizawa, MD, PhD,
Diabetes Center, Aizawa Hospital, 2-5-1 Honjo, Matsumoto, Japan. E-mail:
taizawax@ai-hosp.or.jp
Corresponding author: Toru Aizawa, Diabetes Center, Aizawa Hospital,
Matsumoto, Japan, 2-5-1 Honjo, Matsumoto 390-8510, Japan. Tel.: +81263338600;
Fax: +81263338609. E-mail address: taizawax@ai-hosp.or.jp
Disclosure Summary:
The authors have nothing to disclose.
Disclosure Summary:
ADVANCE ARTICLE: JOURNAL OF
THE ENDOCRINE SOCIETY
JES
Downloaded from https://academic.oup.com/jes/advance-article-abstract/doi/10.1210/js.2018-00071/4975349
by guest
on 20 April 2018
ADVANCE ARTICLE
Journal of the Endocrine Society; Copyright 2018 DOI: 10.1210/js.2018-00071
8
The authors have nothing to disclose.
References
1. Weyer C, Bogardus C, Mott DM, Pratley RE. The natural history of insulin
secretory dysfunction and insulin resistance in the pathogenesis of type 2 diabetes mellitus.
J Clin Invest. 1999;104:787-794.
2. Tabák AG, Jokela M, Akbaraly TN, Brunner EJ, Kivimäki M, Witte DR.
Trajectories of glycaemia, insulin sensitivity, and insulin secretion before diagnosis of type
2 diabetes: an analysis from the Whitehall II study. Lancet. 2009;373:2215-2221.
3. Færch K, Witte DR, Tabák AG, Perreault L, Herder C, Brunner EJ, Kivimäki M,
Vistisen D. Trajectories of cardiometabolic risk factors before diagnosis of three subtypes
of type 2 diabetes: a post-hoc analysis of the longitudinal Whitehall II cohort study. Lancet
Diabetes Endocrinol. 2013;1:43-51.
4. Ferrannini E, Nannipieri M, Williams K, Gonzales C, Haffner SM, Stern MP. Mode
of onset of type 2 diabetes from normal or impaired glucose tolerance. Diabetes.
2004;53:160-165.
5. Looker HC, Knowler WC, Hanson RL. Changes in BMI and weight before and after
the development of type 2 diabetes. Diabetes Care. 2001;24:1917-1922.
6. Heianza Y, Arase Y, Fujihara K, Hsieh SD, Saito K, Tsuji H, Kodama S, Yahagi N,
Shimano H, Yamada N, Hara S, Sone H. Longitudinal trajectories of HbA1c and fasting
plasma glucose levels during the development of type 2 diabetes: the Toranomon Hospital
Health Management Center Study 7 (TOPICS 7). Diabetes Care. 2012;35:1050-1052.
7. Heianza Y, Arase Y, Kodama S, Tsuji H, Tanaka S, Saito K, Hara S, Sone H.
Trajectory of body mass index before the development of type 2 diabetes in Japanese men:
Toranomon Hospital Health Management Center Study 15. J Diabetes Investig. 2015;6:289-
294.
8. Kuwahara K, Honda T, Nakagawa T, Yamamoto S, Hayashi T, Mizoue T. Body
mass index trajectory patterns and changes in visceral fat and glucose metabolism before
the onset of type 2 diabetes. Sci Rep. 2017;7:43521.
9. Aizawa T, Yamauchi K, Yamada M. Longitudinal changes in insulin sensitivity,
insulin secretion, beta cell function and glucose effectiveness during development of non-
diabetic hyperglycemia in a Japanese population. Springerplus. 2014;3:252.
10. Arakaki RF. Ethnic differences and β-cell changes. J Clin Endocrinol Metab.
2013;98:3595–3597.
11. Tanizaki Y, Kiyohara Y, Kato I, Iwamoto H, Nakayama K, Shinohara N, Arima H,
Tanaka K, Ibayashi S, Fujishima M. Incidence and risk factors for subtypes of cerebral
infarction in a general population: the Hisayama study. Stroke. 2000;31:2616-2622.
12. Tanaka S, Tanaka S, Iimuro S, Yamashita H, Katayama S, Ohashi Y, Akanuma Y,
Yamada N, Sone H; Japan Diabetes Complications Study Group. Cohort profile: The Japan
ADVANCE ARTICLE: JOURNAL OF
THE ENDOCRINE SOCIETY
JES
Downloaded from https://academic.oup.com/jes/advance-article-abstract/doi/10.1210/js.2018-00071/4975349
by guest
on 20 April 2018
ADVANCE ARTICLE
Journal of the Endocrine Society; Copyright 2018 DOI: 10.1210/js.2018-00071
9
diabetes complications study: a long-term follow-up of a randomised lifestyle intervention
study of type 2 diabetes. Int J Epidemiol. 2014;43:1054-1062.
13. Mukai N, Doi Y, Ninomiya T, Hirakawa Y, Nagata M, Yoshida D, Hata J, Fukuhara
M, Nakamura U, Kitazono T, Kiyohara Y. Trends in the prevalence of type 2 diabetes and
prediabetes in community-dwelling Japanese subjects: The Hisayama Study. J Diabetes
Investig. 2014;5:162-169.
14. Menke A, Casagrande S, Geiss L, Cowie CC. Prevalence of and trends in diabetes
among adults in the united states, 1988-2012. JAMA. 2015;314:1021-1029.
15. Seike M, Saitou T, Kouchi Y, Ohara T, Matsuhisa M, Sakaguchi K, Tomita K,
Kosugi K, Kashiwagi A, Kasuga M, Tomita M, Naito Y, Nakajima H. Computational
assessment of insulin secretion and insulin sensitivity from 2-h oral glucose tolerance tests
for clinical use for type 2 diabetes. J Physiol Sci. 2011;61:321-330
16. Katakura M, Komatsu M, Sato Y, Hashizume K, Aizawa T. Primacy of beta-cell
dysfunction in the development of hyperglycemia: a study in the Japanese general
population. Metabolism. 2004;53:949-953.
17. Lebovitz HE Management of hyperglycemia with oral antihyperglycemic agents in
type 2 diabetes. In: Kahn RC, Weir GC, King GL, Jacobson AM, Moses AC, eds. Joslin
Diabetes Mellitus. 14th ed. Boston: Lippincott Williams & Wilkins; 2005: 687-710.
18. Paulmichl K, Hatunic M, Højlund K, Jotic A, Krebs M, Mitrakou A, Porcellati F,
Tura A, Bergsten P, Forslund A, Manell H, Widhalm K, Weghuber D, Anderwald CH;
Beta-JUDO Investigators; RISC Investigators. Modification and validation of the
triglyceride-to-hdl cholesterol ratio as a surrogate of insulin sensitivity in white juveniles
and adults without diabetes mellitus: The Single Point Insulin Sensitivity Estimator
(SPISE). Clin Chem. 2016;62:1211-1219.
19. Takeno K, Tamura Y, Kawaguchi M, Kakehi S, Watanabe T, Funayama T,
Furukawa Y, Kaga H, Yamamoto R, Kim M, Nishitani-Yokoyama M, Shimada K, Daida H,
Aoki S, Taka H, Fujimura T, Sawada SS, Giacca A, Kanazawa A, Fujitani Y, Kawamori R,
Watada H. Relation between insulin sensitivity and metabolic abnormalities in Japanese
men with BMI of 23-25 kg/m
2
. J Clin Endocrinol Metab. 2016;101:3676-3684.
20. American Diabetes Association. Classification and diagnosis of diabetes. Diabetes
Care. 2016;39(Suppl.1):S13-22.
21. Cefalu WT. "Prediabetes": Are there problems with this label? No, We need
heightened awareness of this condition! Diabetes Care. 2016;39:1472-1477.
Figure 1. Validation of the single point insulin sensitivity estimator (SPISE). The clamp-
based rate of glucose disappearance (Rd) values (adjusted for body weight) strongly
correlated with SPISE: Spearman rho = 0.668, P < 0.01.
ADVANCE ARTICLE: JOURNAL OF
THE ENDOCRINE SOCIETY
JES
Downloaded from https://academic.oup.com/jes/advance-article-abstract/doi/10.1210/js.2018-00071/4975349
by guest
on 20 April 2018
ADVANCE ARTICLE
Journal of the Endocrine Society; Copyright 2018 DOI: 10.1210/js.2018-00071
10
Figure 2. Trajectories of fasting plasma glucose before prediabetes (A) and diabetes (B)
(upper panels), and weighted cubic regression of the estimated marginal means of FPG (A’,
trajectory before prediabetes; B’, trajectory before diabetes) (lower panels). Upper panels.
Values in the progressors and nonprogressors at each time point were all significantly
different (P < 0.01). Yrs, years; Dx, diagnosis. Black squares in A, prediabetes (PDM)-
Progressors; white squares in A, Normal glucose regulation (NGR)-Nonprogressors; closed
circles in B, DM-Progressors; open circles in B, NonDM-Nonprogressors. n, the number of
participants examined each year. The axis scale was intentionally maintained the same in A
and B to facilitate visual comparison. In the lower panels, the size of the dots is proportional
to the number of individuals. The lines in the lower panels are the best fit cubic regression,
and broken lines indicate 95% confidence intervals.
Figure 3. Trajectories of body mass index before diagnosis of prediabetes (A) and diabetes
(B). Symbols are the same as in Figure 2. Values in the progressors and nonprogressors at
each time point were significantly different both in A and B (P < 0.01 for each). The axis
scale was intentionally maintained the same in A and B to facilitate visual comparison. See
the upper panels of Figure 2 for the number of individuals examined each year.
Figure 4. Trajectories of the single point insulin sensitivity estimator (SPISE) before
prediabetes (A) and diabetes (B). The axis scale was intentionally maintained the same in A
and B to facilitate visual comparison. See the upper panels of Figure 2 for the number of
individuals examined each year.
Table 1. Characteristics of the participants used for trajectory assessment before prediabetes
(A) and diabetes (B)
Variable
A. Cohorts used for trajectory assessment
before prediabetes B. Cohorts used for trajectory assessment before
diabetes
PDM-Progressors (n
= 4,781) NGR-Nonprogressors
(n = 10,994) DM-Progressors (n
=1,061) NonDM-Nonprogressors (n =
26,331)
Males, n (%) 2,554 (53.4%) 6,094 (55.4%) 743 (70.0%) 15,154 (57.6)
Age (years) 49 (42-55) 44 (38-52) 53 (46-60) 48 (41-56)
BMI (kg/m
) 22.5 (20.6-24.6) 21.8 (20.1-23.8) 24.8 (22.5-27.3) 22.5 (20.6-24.6)
SBP (mmHg) 119 (109-130) 116 (106-127) 127 (117-138) 119 (109-131)
FPG (mg/dL) 92 (89-96) 90 (86-94) 106 (99-114) 93 (89-99)
HbA1c (%) 5.5 (5.2-5.6) 5.2 (5.1-5.5) 6.0 (5.7-6.2) 5.5 (5.2-5.7)
HDL-c (mg/dL) 60 (50-71) 60 (51-71) 53 (44-63) 59 (49-69)
LDL-c (mg/dL) 118 (100-139) 111 (92-131) 127 (108-151) 117 (98-139)
TG (mg/dL) 84 (60-121) 76 (55-110) 121 (84-169) 85 (61-126)
ALT (U/L) 19 (14-27) 18 (14-25) 26 (18-38) 19 (15-27)
SPISE 8.15 (6.73-9.81) 8.71 (7.20-10.38) 6.43 (5.40-7.82) 8.10 (6.67-9.82)
Follow-up (examination
No./year) 5.5/6.2 4.4/5.1 4.2/4.2 4.8/5.2
PDM, prediabetes; NGR, normal glucose regulation; DM, diabetes mellitus. PDM-Progressors and NGR-
Nonprogressors, individuals who developed prediabetes or remained normal glucose regulation, respectively.
DM-Progressors and NonDM-Nonprogressors, individuals who developed or did not develop diabetes,
respectively. All variables for Progressors and Nonprogressors in A and B, respectively, were significantly
different (P <0.01) except for HDL-c in A. Values are median (25%-75%), except for categorical data, which
ADVANCE ARTICLE: JOURNAL OF
THE ENDOCRINE SOCIETY
JES
Downloaded from https://academic.oup.com/jes/advance-article-abstract/doi/10.1210/js.2018-00071/4975349
by guest
on 20 April 2018
ADVANCE ARTICLE
Journal of the Endocrine Society; Copyright 2018 DOI: 10.1210/js.2018-00071
11
are shown as number and percent. Values for follow-up represent the mean. BMI, body mass index; SBP,
systolic blood pressure; FPG, fasting plasma glucose; HbA1c, glycosylated hemoglobin; HDL-c, high-density
lipoprotein cholesterol; LDL-c, low-density lipoprotein cholesterol; TG, triglycerides; ALT, alanine
aminotransferase; SPISE, the single point insulin sensitivity estimator (18).
ADVANCE ARTICLE: JOURNAL OF
THE ENDOCRINE SOCIETY
JES
Downloaded from https://academic.oup.com/jes/advance-article-abstract/doi/10.1210/js.2018-00071/4975349
by guest
on 20 April 2018
ADVANCE ARTICLE: EndocrinologyADVANCE ARTICLE: Endocrinology
ADVANCE ARTICLE
ADVANCE ARTICLE: JOURNAL OF
THE ENDOCRINE SOCIETY
JES
Downloaded from https://academic.oup.com/jes/advance-article-abstract/doi/10.1210/js.2018-00071/4975349
by guest
on 20 April 2018
ADVANCE ARTICLE: EndocrinologyADVANCE ARTICLE: Endocrinology
ADVANCE ARTICLE
ADVANCE ARTICLE: JOURNAL OF
THE ENDOCRINE SOCIETY
JES
Downloaded from https://academic.oup.com/jes/advance-article-abstract/doi/10.1210/js.2018-00071/4975349
by guest
on 20 April 2018
ADVANCE ARTICLE: EndocrinologyADVANCE ARTICLE: Endocrinology
ADVANCE ARTICLE
ADVANCE ARTICLE: JOURNAL OF
THE ENDOCRINE SOCIETY
JES
Downloaded from https://academic.oup.com/jes/advance-article-abstract/doi/10.1210/js.2018-00071/4975349
by guest
on 20 April 2018
ADVANCE ARTICLE: EndocrinologyADVANCE ARTICLE: Endocrinology
ADVANCE ARTICLE
ADVANCE ARTICLE: JOURNAL OF
THE ENDOCRINE SOCIETY
JES
Downloaded from https://academic.oup.com/jes/advance-article-abstract/doi/10.1210/js.2018-00071/4975349
by guest
on 20 April 2018
... In particular, the risk factors for type 2 diabetes and their contributions in the initial phases of the disease remain uncertain [1,[3][4][5][6][7][8][9][10][11]. Specifically, the trajectory of plasma glucose level before clinical diagnosis of diabetes and prediabetes reveal that a stable, long-lasting, slow elevation is followed by an accelerated rise for several years before the diagnosis [7,[12][13][14][15]. This so-called multistage model strongly suggests unfavorable interactions between minimally elevated glucose per se and the glucose regulatory mechanism. ...
... In Caucasians and Pima Indians, insulin resistance that evolves during the development of type 2 diabetes induces insulin hypersecretion and increased insulin synthesis [1,[4][5][6]. However, such compensatory hyperinsulinemia during the development of type 2 diabetes has not been shown in Japanese people who are generally nonobese and insulin-sensitive [3,[8][9][10][11][12]. ...
... In a sense, the issue is semantics regarding "what is the normal range?" If we permit the inclusion of people with the possibility of developing diabetes or prediabetes in the future [7,11,12] as "normal," the upper limit of "the normal range" naturally goes up. However, if we completely exclude such people from the normal, the upper limit of "the normal range" goes down. ...
Article
Full-text available
Objective To clarify the impact of hepatic steatosis (HS) indexed by Fatty Liver Index (FLI) and high normal fasting plasma glucose (FPG) as risk factors for incident prediabetes in a non-obese cohort. Methods Data from 1,125 participants with ADA-defined normal glucose metabolism (NGM) (median age and BMI, 52 years and 23.1 kg/m 2, respectively) were used for retrospective analysis. In the entire population, correlation between normal FPG and FLI was evaluated by multiple regression with adjustment for age and sex. Follow-up data from 599 participants in whom 75 g OGTT was repeated 3.7 years later showed that 169 developed prediabetes. This was analyzed by the multivariate Cox proportional hazards model. Results In the entire population, FLI was positively correlated with FPG (P <0.01): mean FLI increased from 15.8 at FPG 4.2 mmol/L to 31.6 at FPG 5.5 mmol/L. Analysis of the 599 participants (2,061 person-years) by Cox model, adjusted for sex, age, family history of diabetes, ISIMATSUDA and Stumvoll-1, clarified an increased risk of prediabetes with high normal FPG and FLI. In in participants with FLI≥16.5, as compared with FLI <16.5, P<0.001. The risk was also increased (2.1 times) in participants with FPG ≥5.3 mmol/L, P<0.001. The cutoff values (unadjusted) were obtained by ROC at the point of the largest Youden’s index using the entire range of the variables. Conclusions Even among non-obese individuals, HS indexed by FLI and a high-normal FPG (≥5.3 mmol/L) are risk factors for prediabetes, independently from insulin.
... Despite the RDSN findings, the Diabetes Heart Study demonstrated that QTc interval predicted all-cause and cardiovascular disease mortality in participants with type 2 diabetes mellitus [53], confirming the results previously obtained by Ewing et al [50]. In addition, in 2010, Pop-Busui et al [54] evaluated the mortality risk in participants with CAN and reported that CAN participants had a twofold all-cause mortality risk compared to individuals without CAN. ...
... The Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial demonstrated that participants with CAN had similar mortality rates when following both standard and intensive treatments for glycemic control, suggesting that severe glycemic control could promote hypoglycemia and increase the probability of mortality in diabetic patients [54]. Another study developed by Tang et al [51] based on the ACCORD trial evaluated the effects of intensive treatment of hyperglycemia, hypertension, and dyslipidemia as a prevention strategy to reduce cardiovascular events. ...
Article
Full-text available
Cardiovascular autonomic neuropathy (CAN) is a debilitating condition that mainly occurs in long-standing type 2 diabetes patients but can manifest earlier, even before diabetes is diagnosed. CAN is a microvascular complication that results from lesions of the sympathetic and parasympathetic nerve fibers, which innervate the heart and blood vessels and promote alterations in cardiovascular autonomic control. The entire mechanism is still not elucidated, but several aspects of the pathophysiology of CAN have already been described, such as the production of advanced glycation end products, reactive oxygen species, nuclear factor kappa B, and pro-inflammatory cytokines. This microvascular complication is an important risk factor for silent myocardial ischemia, chronic kidney disease, myocardial dysfunction, major cardiovascular events, cardiac arrhythmias, and sudden death. It has also been suggested that, compared to other traditional cardiovascular risk factors, CAN progression may have a greater impact on cardiovascular disease development. However, CAN might be subclinical for several years, and a late diagnosis increases the mortality risk. The duration of the transition period from the subclinical to clinical stage remains unknown, but the progression of CAN is associated with a poor prognosis. Several tests can be used for CAN diagnosis, such as heart rate variability (HRV), cardiovascular autonomic reflex tests, and myocardial scintigraphy. Currently, it has already been described that CAN could be detected even during the subclinical stage through a reduction in HRV, which is a non-invasive test with a lower operating cost. Therefore, considering that diabetes mellitus is a global epidemic and that diabetic neuropathy is the most common chronic complication of diabetes, the early identification and treatment of CAN could be a key point to mitigate the morbidity and mortality associated with this long-lasting condition. Key Words: Cardiovascular autonomic neuropathy, Cardiac autonomic neuropathy, Diabetes mellitus, Heart rate variability, Sympathetic autonomic nervous system, Parasympathetic autonomic nervous system
... It precedes disease manifestation for up to 20 years and, therefore, is an early sign of metabolic dysfunction. 1 Thus, understanding insulin sensitivity remains important to improve T2DM prevention. Insulin sensitivity is mainly determined by a crosstalk between the liver, the adipose tissue, and skeletal muscle. 2 Skeletal muscle plays a particularly important role, because, in healthy individuals, it is responsible for approximately 80% of insulinstimulated whole-body glucose uptake and disposal. ...
Article
Full-text available
Introduction Skeletal muscle contributes significantly to insulin sensitivity in humans. However, which non-invasive measurement best reflects this contribution remains unknown. Consequently, this paper compares morphologic and functional measurements. Research methods and design We conducted a cross-sectional analysis of 144 premenopausal women enrolled in the “Prediction, Prevention, and Sub-classification of Type 2 Diabetes” (PPSDiab) cohort study. For the analysis, we quantified insulin sensitivity by oral glucose tolerance testing and, in a subgroup of 30 women, euglycemic clamp. To assess skeletal muscle, we measured volume by magnetic resonance imaging, intramyocellular lipid content by magnetic resonance spectroscopy, and physical fitness by cardiopulmonary exercise testing. Results The mean age of the cohort was 35.7 ± 4.1 years and 94 participants (65%) had a history of gestational diabetes mellitus. Of the morphologic and functional muscle parameters, the maximum workload achieved during cardiopulmonary exercise testing associated most closely with insulin sensitivity (standardized beta = 0.39; p < .001). Peak oxygen uptake also demonstrated significant associations, whereas muscle volume and intramyocellular lipid content displayed none. Conclusion Functional measurements provided a better assessment of the muscular contribution to insulin sensitivity than morphologic measurements in premenopausal women. In particular, exercise testing rendered an easy and cost-effective method applicable in clinical settings and other human studies.
... reported that glucose dysregulation precedes the actual diagnosis of T2D by >10 years (45) in adults, while Lebovitz et al. reported that b-cell dysfunction in adults precedes clinical diagnosis of T2D by 12 years (46). In contrast, the diagnosis of T1D is often followed by the honeymoon phase or PR which largely determines the risks for early-phase dyslipidemia (6), mid-term microvascular disease risk (7), and long-term CVD risk (8). ...
Article
Full-text available
Literature Search Criteria A literature search was conducted to identify publications addressing the early phases of lipid phenotypes in children and adults with either type 1 diabetes or type 2 diabetes. Medline, EMBASE, and Ovid were searched using the following search terms: clinical remission, partial remission, partial clinical remission, honeymoon phase, C-peptide, type 1 or 2 diabetes, children, pediatric type 1 or 2 diabetes, and paediatrics type 1 or 2 diabetes, adults, adult type 1 or type 2 diabetes. Partial clinical remission (PR) of type 1 diabetes (T1D) is characterized by continued endogenous production of insulin and C-peptide following the diagnosis and the introduction of exogenous insulin therapy. PR is associated with improved glycemic control and reduced prevalence of diabetes complications. The theory of hyperglycemic memory was proposed to explain this concept of improved glycemic outcomes in remitters (those who experienced PR) versus non-remitters (those who did not experience PR). However, this theory is incomplete as it does not explain the dichotomy in early lipid phenotypes in T1D based on PR status, which is an understudied area in diabetology and lipidology. To fill this knowledge gap, we propose the Theory of Hyperlipidemic Memory of T1D. This theory is premised on our 5-year research on early post-diagnostic dichotomy in lipid phenotypes between remitters and non-remitters across the lifespan. It provides a more rigorous explanation for the differences in lifelong atherosclerotic cardiovascular disease (ASCVD) risk between remitters and non-remitters. We conducted 4 clinical studies in pediatric and adult subjects with diabetes mellitus to characterize the particulars of the hyperlipidemic memory. In the first investigation, we explored the impact of the presence or absence of PR on lipid parameters in children and adolescents with T1D. In the second, we investigated whether pubertal maturation influenced our findings in T1D; and whether these findings could be replicated in healthy, non-diabetic children and adolescents. In the third, we leveraged our findings from T1D and controls to investigate the mechanisms of early lipid changes in T2D by comparing the earliest lipid phenotype of subjects with type 2 diabetes (T2D) to those of remitters, non-remitters, and controls. In the fourth, we investigated the impact of PR on the earliest lipid phenotypes in adults with T1D and compared these early lipid data to those of T2D subjects and controls. This body of work across the lifespan in children, adolescents, and adults supports the Theory of Hyperlipidemic Memory. This new theory clarifies why PR largely determines the risks for early-phase dyslipidemia, mid-term microvascular disease risk, and long-term ASCVD risk in subjects with T1D.
... Moreover, it has been reported that higher fasting plasma glucose levels can be observed at least 10 years before the diagnosis of T2DM. 191 Although migraine has been associated with some factors implicated in diabetes, such as obesity and insulin resistance, to date little is known about the relationship between migraine and T2DM. Interestingly, Fagherazzi et al. recently reported 59 a linear decrease in the prevalence of migraine during the 24 years prior to T2DM diagnosis. ...
Article
Full-text available
Increasing evidence suggests that migraine may be the result of an impaired brain glucose metabolism. Several studies have reported brain mitochondrial dysfunction, impaired brain glucose metabolism and gray matter volume reduction in specific brain areas of migraineurs. Furthermore, peripheral insulin resistance, a condition demonstrated in several studies, may extend to the brain, leading to brain insulin resistance. This condition has been proven to downregulate insulin receptors, both in astrocytes and neurons, triggering a reduction in glucose uptake and glycogen synthesis, mainly during high metabolic demand. This scoping review examines the clinical, epidemiologic and pathophysiologic data supporting the hypothesis that abnormalities in brain glucose metabolism may generate a mismatch between the brain's energy reserve and metabolic expenditure, triggering migraine attacks. Moreover, alteration in glucose homeostasis could generate a chronic brain energy deficit promoting migraine chronification. Lastly, insulin resistance may link migraine with its comorbidities, like obesity, depression, cognitive impairment and cerebrovascular diseases. Perspective: Although additional experimental studies are needed to support this novel “neuroenergetic” hypothesis, brain insulin resistance in migraineurs may unravel the pathophysiological mechanisms of the disease, explaining the migraine chronification and connecting migraine with comorbidities. Therefore, this hypothesis could elucidate novel potential approaches for migraine treatment.
... Among these, the SPISE was developed as an easy and affordable tool for the evaluation of whole-body insulin sensitivity, which is comparable to clamp-derived M-value in sensitivity as well as specificity (19). Several studies have evaluated the SPISE in adult as well as juvenile populations (20,(41)(42)(43)(44)(45)(46). Correa-Burrows et al. assessed SPISE for its validity in diagnosing cardiometabolic risks, namely IR and metabolic syndrome, in post-pubertal Hispanic adolescents. ...
Article
Full-text available
Background Attenuated insulin-sensitivity (IS) is a central feature of pediatric non-alcoholic fatty liver disease (NAFLD). We recently developed a new index, single point insulin sensitivity estimator (SPISE), based on triglycerides, high-density-lipoprotein and body-mass-index (BMI), and validated by euglycemic-hyperinsulinemic clamp-test (EHCT) in adolescents. This study aims to assess the performance of SPISE as an estimation of hepatic insulin (in-)sensitivity. Our results introduce SPISE as a novel and inexpensive index of hepatic insulin resistance, superior to established indices in children and adolescents with obesity. Materials and Methods Ninety-nine pubertal subjects with obesity (13.5 ± 2.0 years, 59.6% males, overall mean BMI-SDS + 2.8 ± 0.6) were stratified by MRI (magnetic resonance imaging) into a NAFLD (>5% liver-fat-content; male n=41, female n=16) and non-NAFLD (≤5%; male n=18, female n=24) group. Obesity was defined according to WHO criteria (> 2 BMI-SDS). EHCT were used to determine IS in a subgroup (n=17). Receiver-operating-characteristic (ROC)-curve was performed for diagnostic ability of SPISE, HOMA-IR (homeostatic model assessment for insulin resistance), and HIRI (hepatic insulin resistance index), assuming null hypothesis of no difference in area-under-the-curve (AUC) at 0.5. Results SPISE was lower in NAFLD (male: 4.8 ± 1.2, female: 4.5 ± 1.1) than in non-NAFLD group (male 6.0 ± 1.6, female 5.6 ± 1.5; P< 0.05 {95% confidence interval [CI]: male NAFLD 4.5, 5.2; male non-NAFLD 5.2, 6.8; female NAFLD 4.0, 5.1, female non-NAFLD 5.0, 6.2}). In males, ROC-AUC was 0.71 for SPISE (P=0.006, 95% CI: 0.54, 0.87), 0.68 for HOMA-IR (P=0.038, 95% CI: 0.48, 0.88), and 0.50 for HIRI (P=0.543, 95% CI: 0.27, 0.74). In females, ROC-AUC was 0.74 for SPISE (P=0.006), 0.59 for HOMA-IR (P=0.214), and 0.68 for HIRI (P=0.072). The optimal cutoff-level for SPISE between NAFLD and non-NAFLD patients was 5.18 overall (Youden-index: 0.35; sensitivity 0.68%, specificity 0.67%). Conclusion SPISE is significantly lower in juvenile patients with obesity-associated NAFLD. Our results suggest that SPISE indicates hepatic IR in pediatric NAFLD patients with sensitivity and specificity superior to established indices of hepatic IR.
... Material, part 6) (15,23,75). For T1D, adult deaths from diabetic ketoacidosis, 800 in the U.S. in 2017, emphasize the importance of earlier diagnosis and prevention (76,77). ...
Article
As the world endures a viral pandemic superimposed on a diabetes pandemic, the latter incorporates most of the comorbidities associated with the former, thereby exacerbating risk of death in both. An essential approach to both pandemics is prevention and unrealized earlier treatment. Thus, in this Perspective relating to diabetes, we emphasize a paradigm of, first, reversible β-cell organ dysfunction and then irreversible β-cell organ failure, which directly indicate the potential for earlier prevention, also unrealized in current guidelines. Four pillars support this paradigm: epidemiology, pathophysiology, molecular pathology, and genetics. A substantial worldwide knowledge base defines each pillar and informs a more aggressive preventive approach to most forms of the disorder. This analysis seeks to clarify the temporal and therapeutic relationships between lost β-cell function and content, illuminating the potential for earlier diagnoses and, thus, prevention. We also propose that myriad pathways leading to most forms of diabetes converge at the endoplasmic reticulum, where stress can result in β-cell death and content loss. Finally, genetic and nongenetic origins common to major types of diabetes can inform earlier diagnosis and, potentially, prevention, with the aim of preserving β-cell mass.
... Current evidence suggests that constant positive energy balance in the modern obesogenic environment leads initially to hyperinsulinemia [31] in an effort to maintain normoglycemia. Indeed, it is known that insulin levels rise almost a decade before diabetes is detected [32][33][34][35] and are sometimes referred to as Stage 1 of diabetes associated with compensation [36]. ...
Article
Full-text available
Non-alcoholic fatty liver disease (NAFLD) is a fast-spreading epidemic across the globe and has serious implications far beyond that of a "benign" liver condition. It is usually an outcome of ectopic fat storage due to chronic positive energy balance leading to obesity and is associated with multiple health problems. While association with cardiovascular disease and hepatocellular cancer is well recognized, it is becoming clear the NAFLD carries with it an increased risk of cancers of extrahepatic tissues. Studies have reported a higher risk for cancers of the colon, breast, prostate, lung, and pancreas. Fatty liver is associated with increased mortality; there is an urgent need to understand that fatty liver is not always benign, and not always associated with obesity. It is, however, a reversible condition and early recognition and intervention can alter its natural history and associated complications.
... Thus, our results may not be widely generalizable to other settings or other new diabetes patients. However, we used 3 years cut-off to define newly diagnosed T2DM due to the long natural progression of T2DM [22,23] and the potential delay in receiving T2DM diagnosis among our study population, of which the majority came from lower socioeconomic levels [24,25]. Second, our study was designed to assess the association between LTBI and the risk of T2DM. ...
Article
Full-text available
Objective The purpose of this study is to compare the prevalence of latent TB infection (LTBI) among patients with type-2 diabetes mellitus (T2DM) to healthy controls without T2DM. To achieve this objective, we conducted a case-control study in a large hospital in Atlanta from 2016 to 2019. Results We enrolled 98 cases; 119 potential controls were screened, 84 of which had HbA1c ≥ 5.7% and one did not have QFT result, leaving 34 (28.6%) individuals enrolled as controls. LTBI prevalence was 9.2% among cases and 14.7% among controls (crude odds ratio 0.59, 95% CI 0.19–2.04). After adjusting for age and sex, the adjusted odds of LTBI among patients with T2DM was 0.45 (95% CI 0.13, 1.71) times the controls. We did not observe a statistically significant association between LTBI and T2DM. However, we reported a positive correlation between HbA1c level and nil count among individuals with LTBI (R ² = 0.55, p < 0.01). In addition, we reported a high prevalence of LTBI among adults with T2DM and family members without T2DM.
... Moreover, lower SPISE index significantly correlated in adults or adolescents with the presence of T2D [36], metabolic syndrome [37,39], risk of cardiovascular diseases [36], non-alcoholic fatty liver disease (NAFLD) [38], abdominal obesity, higher levels of C-reactive protein (CRP) and lower levels of adiponectin [24]. Finally, in line with our results obtained in youths, Sagesaka et al. demonstrated that basal SPISE index was significantly lower in adults who developed T2D 10 years later in comparison to those who did not progress to diabetes, in a longitudinal investigation on over 27,000 individuals without diabetes [40]. ...
Article
Full-text available
Purpose To investigate the relationship between the single-point insulin sensitivity estimator (SPISE) index, an insulin sensitivity indicator validated in adolescents and adults, and metabolic profile in overweight/obese children, and to evaluate whether basal SPISE is predictive of impaired glucose regulation (IGR) development later in life. Methods The SPISE index (= 600 × HDL 0.185 /Triglycerides 0.2 × BMI 1.338 ) was calculated in 909 overweight/obese children undergoing metabolic evaluations at University of Cagliari, Italy, and in 99 normal-weight, age-, sex-comparable children, selected as a reference group, together with other insulin-derived indicators of insulin sensitivity/resistance. 200 overweight/obese children were followed-up for 6.5 [3.5–10] years, data were used for longitudinal retrospective investigations. Results At baseline, 96/909 (11%) overweight/obese children had IGR; in this subgroup, SPISE was significantly lower than in normo-glycaemic youths (6.3 ± 1.7 vs. 7 ± 1.6, p < 0.001). The SPISE index correlated positively with the insulin sensitivity index (ISI) and the disposition index (DI), negatively with age, blood pressure, HOMA-IR, basal and 120 min blood glucose and insulin (all p values < 0.001). A correlation between SPISE, HOMA-IR and ISI was also reported in normal-weight children. At the 6.5-year follow-up, lower basal SPISE—but not ISI or HOMA-IR—was an independent predictor of IGR development (OR = 3.89(1.65–9.13), p = 0.002; AUROC: 0.82(0.72–0.92), p < 0.001). Conclusion In children, low SPISE index is significantly associated with metabolic abnormalities and predicts the development of IGR in life.
Article
Full-text available
We investigated BMI trajectory patterns before diabetes diagnosis and examined associated changes in visceral adiposity and glucose metabolism. 23,978 non-diabetic Japanese participants (2,789 women) aged 30–64 years were assessed with a mean follow-up of 7.6 years. Diabetes was diagnosed via fasting glucose, HbA1c, and self-report. Latent-class trajectory analyses were performed to identify BMI trajectories. Longitudinal changes in BMI, visceral adiposity, and glucose metabolism were estimated using mixed models. 1,892 individuals developed diabetes. Three distinct BMI trajectories were identified in adults developing and not developing diabetes, respectively. Among adults developing diabetes, 47.3% were classified as “medium BMI” (n = 895), and had increased mean BMI within the obesity category before diagnosis. The “low BMI” group (38.4%, n = 726) had an initial mean BMI of 21.9 kg/m2, and demonstrated small weight gain. The “high BMI” group (n = 271) were severely obese and showed greater increase in BMI until diagnosis. All groups which developed diabetes showed absolute and/or relative increase in visceral fat and impaired β-cell compensation for insulin resistance. All groups not developing diabetes showed measured variables were relatively stable during observation. These data suggest that visceral fat gain may induce β-cell failure in compensation for insulin resistance, resulting in diabetes regardless of obesity level.
Article
Full-text available
Aims/IntroductionWe aimed to investigate the long-term trajectory of general adiposity assessed by the body mass index (BMI) before the onset of type 2 diabetes in Japanese individuals.Materials and Methods We retrospectively examined data on 1553 Japanese men without diabetes. Mean BMI and incident cases of diabetes (diabetes indicated by fasting glucose concentrations ≥7.0 mmol/l, a self-reported history of clinician-diagnosed diabetes, or HbA1c ≥6.5% (≥48 mmol/mol) were assessed on an annual basis over a 10-year period after the baseline examination.ResultsMean (SD) BMI at the time of diagnosis was 24.4 (3.1) kg/m2 among cases of diabetes (n=191). An increasingly high BMI was associated with the early stage of the disease development such as an 8- to 10-year pre-diagnosis period; individuals who developed diabetes experienced a prolonged and stable elevated BMI of ≥24.4 kg/m2 over the 8 years prior to the diagnosis of diabetes. The mean BMI among the non-cases of diabetes did not exceed 23.2 kg/m2 throughout the period.Conclusions These results suggested that Japanese men who eventually developed diabetes during the 10-year observation period were not characterized as obese but had stable high-normal BMIs before the onset of diabetes. Previous evidence indicated that values for glycemic markers rapidly increased before the development of diabetes; however, the present study showed a slight gain in BMI in the earlier stage of the natural history of diabetes followed by a prolonged period of overweight.This article is protected by copyright. All rights reserved.
Article
Full-text available
Since there had been no previous studies of alterations in insulin sensitivity, glucose-stimulated insulin secretion, beta cell function and glucose effectiveness during the development of non-diabetic hyperglycemia in Asian populations, we conducted a longitudinal study of such changes in 244 Japanese adults with normal glucose tolerance (median BMI 23.3 kg/m2 and age 51 yrs). The median follow-up period was 3.3 yrs. One hundred and eighty-two subjects maintained normal glucose tolerance (nonprogressors). After excluding the 3 subjects who progressed to diabetes, we analyzed the 59 who developed non-diabetic hyperglycemia (progressors), of which 31 progressed to impaired fasting glucose and 28 to impaired glucose tolerance. Whole body insulin sensitivity was estimated by ISIMatsuda, glucose-stimulated insulin secretion by [δIRI0-30/δPG0-30] and Stumvoll indices, hepatic insulin sensitivity by quantitative insulin sensitivity check index (QUICKI) and 1/fasting IRI, beta cell function by oral disposition index (DIO) ([δIRI0-30/δPG0-30]∙[ISIMatsuda]), and glucose effectiveness by an OGTT-derived index (SgIO). ISIMatsuda (p <0.05), [δIRI0-30/δPG0-30], DIO and SgIO (both p <0.01), but not QUICKI, 1/fasting IRI, or Stumvoll-1st and -2nd phases, were lower in the progressors at baseline. This group was also characterized by the following: 1) ISIMatsuda, DIO and SgIO were reduced by 34%, 32% and 11%, respectively (all p <0.01); 2) QUICKI and 1/fasting IRI diminished by 21% and 5%, respectively (both p <0.01); and 3) no significant changes were found in [δIRI0-30/δPG0-30], Stumvoll-1st and -2nd phases or BMI during the follow-up. In the nonprogressors, no indices changed significantly during the follow-up. Our study concluded that during the transition from normal glucose tolerance to non-diabetic hyperglycemia in this non-obese population, whole body insulin sensitivity, hepatic insulin sensitivity, beta cell function, and glucose effectiveness were all attenuated, but no significant changes in glucose-stimulated insulin secretion occurred. Also of note is the fact that the transition took place without any accompanying increase in BMI. Electronic supplementary material The online version of this article (doi:10.1186/2193-1801-3-252) contains supplementary material, which is available to authorized users.
Article
Full-text available
Aims/IntroductionWe examined secular trends in the prevalence of type 2 diabetes and prediabetes in community-dwelling Japanese subjects.Materials and MethodsA total of 2,490 subjects in 1988 and 2,852 subjects in 2002 aged 40–79 years underwent a 75-g oral glucose tolerance test, and their glucose tolerance status was defined by the 1998 World Health Organization criteria.ResultsThe age-adjusted prevalence of type 2 diabetes increased significantly from 1988 to 2002 in men (14.6% in 1988 to 20.8% in 2002, P < 0.001) and women (9.1% in 1988 to 11.2% in 2002, P = 0.002). A significant rise in the age-adjusted prevalence of prediabetes was also observed in both sexes (26.2% in 1988 to 35.3% in 2002, P < 0.001 for men; 22.5% in 1988 to 25.1% in 2002, P = 0.04 for women). In age-stratified analysis, the prevalence of type 2 diabetes increased markedly over time in men aged 60–69 and 70–79 years (both P < 0.001) and women aged 70–79 years (P = 0.02). The prevalence of overall and central obesity increased significantly in men aged 60–69 and 70–79 years, and women aged 70–79 years from 1988 to 2002, whereas the frequency of regular exercise decreased significantly in men aged 70–79 years between the surveys.Conclusions Our findings suggest that the prevalence of type 2 diabetes and prediabetes increased significantly in both sexes from the 1980s to the 2000s in a general Japanese population, and that the increasing prevalence of obesity and the decline in physical activity exerted an influence on this rising trend.
Article
Full-text available
Most clinicians acknowledge that type 2 diabetes is multifactorial and has heterogeneous characteristics, but neither prevention nor treatment is systematically stratified. To address the heterogeneity of the disease, we examined whether patients diagnosed on the basis of fasting glucose concentrations, those diagnosed on the basis of 2 h concentrations, and those diagnosed on the basis of both criteria differed in terms of pathogenesis or cardiovascular risks. Retrospectively, we analysed trajectories of cardiometabolic risk factors and 10 year cardiovascular risks in the prospective Whitehall II study cohort by use of multilevel longitudinal modelling. Participants were diagnosed by 75 g oral glucose-tolerance tests. We classified those diagnosed with type 2 diabetes into three subgroups: diagnosed on the basis of fasting glucose concentrations, diagnosed on the basis of 2 h glucose concentrations, and diagnosed on the basis of both concentrations. We also developed a classification tree for identification of individuals who are likely to have high fasting and 2 h glucose concentrations, but for whom only fasting concentrations are available. Median follow-up was 14·2 years with 15 826 person-examinations (1991-2009). Of 10 308 individuals, 6843 were included and 6569 remained diabetes free. 274 cases of type 2 diabetes were identified: 55 had high fasting glucose concentrations only, 148 had high 2 h concentrations only, and 71 had high fasting and 2 h concentrations. At diagnosis, participants with high fasting and 2 h glucose concentrations had higher mean body-mass indices (30·9 kg/m(2) [SD 5·7]) than did those with high fasting concentrations (28·4 kg/m(2) [4·4]; p=0·0009) or 2 h concentrations (27·9 kg/m(2) [4·9]; <0·0001). Mean glycated haemoglobin A1c concentrations were also higher in the fasting and 2 h subgroup (7·4% [1·6]) than in the fasting (5·9% [0·5]; <0·0001) or 2 h (5·9% [0·6]; <0·0001) sugroups. Additionally, the fasting and 2 h subgroup had a higher proportion of individuals with moderate or high risk of cardiovascular disease than did the fasting subgroup (p=0·02). A classic pattern of β-cell decompensation before diagnosis was noted only in the fasting and 2 h subgroup. Additionally, glucose concentrations and insulin resistance accelerated more substantially before diagnosis in the fasting and 2 h subgroup than in the fasting subgroup or the 2 h subgroup. Patients with type 2 diabetes diagnosed on the basis of increased fasting glucose concentrations or 2 h glucose concentrations, or both, have distinct cardiometabolic risk development before diagnosis. UK Medical Research Council, UK Economic and Social Research Council, British Heart Foundation, UK Health and Safety Executive, UK Department of Health, US National Heart Lung and Blood Institute, US National Institute on Aging, US Agency for Health Care Policy Research, and John D and Catherine T MacArthur Foundation.
Article
The category of “prediabetes” defined by the American Diabetes Association comprises a range of intermediate hyperglycemia based on fasting or 2-h postload glucose or on HbA1c. Over the recent past, the “cut points” identifying this stage have changed, i.e., a lower fasting glucose level is used. On one hand, it can be argued that the change to a lower cut point identifies a group of individuals still at higher risk and provides heightened awareness for a condition associated with higher risk for cardiovascular disease. In addition, identification of individuals at this stage may represent a chance of earlier intervention in the disease. However, the argument against this definition of prediabetes is that it disguises the differences in the three subcategories and creates problems in interpreting observations on interventions and outcomes. In addition, it can be argued that the enormous numbers of people identified with the criteria far exceeds the capacity of health care systems to respond through individual care, particularly without evidence that interventions benefit any category other than impaired glucose tolerance. Thus, there does not appear to be consensus on the definition using the cut points identified. Controversy also remains as to whether there are glycemic metrics beyond HbA1c that can be used in addition to HbA1c to help assess risk of an individual developing diabetes complications. Given the current controversy, a Point-Counterpoint debate on this issue is provided herein. In the preceding point narrative, Dr. Yudkin provides his argument that there are significant problems with this label. In the counterpoint narrative below, Dr. Cefalu argues that the cut points are appropriate and do provide useful and important information in trying to reduce the future burden of diabetes. —William T. Cefalu Editor in Chief, Diabetes Care
Article
Context: Although the metabolic abnormalities are often developed in Asians with BMI of 23 to 25 kg/m(2), the characteristics of the non-obese Asians with metabolic abnormality have not been fully understood. Objective: The aim of this study was to investigate the clinical significance of insulin sensitivity in Japanese men with BMI of 23 to 25 kg/m(2). Design and participants: In this study, we defined that hypertension, hyperglycemia, and dyslipidemia are cardiometabolic risk factors (CMRF). We recruited the subjects who met the selection criteria as below; men with BMI of 21 to 23 kg/m(2) and no CMRF (n=24), men with BMI of 23 to 25 kg/m(2) and no CMRF (n=28), 1 CMRF (n=28), and ≥2 CMRF (n=14), and 20 overweight men with metabolic syndrome (OWMS). Insulin sensitivity (IS) and ectopic fat content in muscle and liver were measured by two-step hyperinsulinemic-euglycemic clamp and (1)H-magnetic resonance spectroscopy, respectively. Results: Among subjects with BMI of 23 to 25 kg/m(2), impaired IS in muscle, but not in liver, was found in those with even 1 CMRF, while impaired IS in both muscle and liver was observed in OWMS. Liver fat accumulation and elevated liver enzymes were associated with impaired IS in both muscle and liver in those subjects. Conclusions: Among Japanese men with BMI of 23 to 25 kg/m(2), muscle insulin resistance was present in those with even one CMRF. In this population, liver fat accumulation and/or elevated liver enzymes could be a good marker for impaired IS in both muscle and liver.
Article
Background The triglyceride-to-HDL-cholesterol (TG/HDL)-ratio was introduced as a tool to estimate insulin resistance, as circulating lipid measurements are available in routine settings. Insulin, C-peptide, and free fatty acids are components of other insulin-sensitivity indices, but expensive. Easier and more affordable tools are of interest for both pediatric and adult people. Methods Subjects from the “Relationship Between Insulin Sensitivity and Cardiovascular Disease” (43.9±8.3 years, n=1260) as well as the “Beta-Cell Function in Juvenile Diabetes and Obesity” study cohort (15±1.9 years, n=29) underwent oral-glucose-tolerance-tests and euglycemic clamp-tests for estimation of whole-body-insulin-sensitivity and calculation of insulin-sensitivity indices. To refine the TG/HDL-ratio, mathematical modeling was applied including body mass index (BMI), fasting triglycerides and HDL-cholesterol and compared to the clamp-derived M–value as an estimate of insulin sensitivity. Each modeling result was scored by identification of insulin resistance and correlation coefficient. The Single Point Insulin Sensitivity Estimator (SPISE) was compared to traditional insulin-sensivitity indices using area under the receiver-operating-characteristic curve (aROC) analysis and ChiSquare-test. Results The novel formula for SPISE was computed as follows: SPISE =600*HDL-C^0.185/(triglycerides^0.2*BMI^1.338), with fasting HDL-cholesterol (mg/dL), fasting triglyceride concentrations (mg/dL) and BMI (kg/m2). A cut-off value of 6.61 corresponds to an M-value smaller than 4.7 mg*kg-1*min-1 (aROC: M:0.797). SPISE showed a significantly better aROC than the TG/HDL-cholesterol-ratio. SPISE aROC was comparable to Matsuda’s ISI and equal to QUICKI and HOMA-IR when calculating with M-value. Conclusion The SPISE seems well suited to surrogate whole-body insulin-sensitivity from inexpensive fasting single-point blood draw and BMI in white adolescents and adults.
Article
Importance: Previous studies have shown increasing prevalence of diabetes in the United States. New US data are available to estimate prevalence of and trends in diabetes. Objective: To estimate the recent prevalence and update US trends in total diabetes, diagnosed diabetes, and undiagnosed diabetes using National Health and Nutrition Examination Survey (NHANES) data. Design, setting, and participants: Cross-sectional surveys conducted between 1988-1994 and 1999-2012 of nationally representative samples of the civilian, noninstitutionalized US population; 2781 adults from 2011-2012 were used to estimate recent prevalence and an additional 23 634 adults from 1988-2010 were used to estimate trends. Main outcomes and measures: The prevalence of diabetes was defined using a previous diagnosis of diabetes or, if diabetes was not previously diagnosed, by (1) a hemoglobin A1c level of 6.5% or greater or a fasting plasma glucose (FPG) level of 126 mg/dL or greater (hemoglobin A1c or FPG definition) or (2) additionally including 2-hour plasma glucose (2-hour PG) level of 200 mg/dL or greater (hemoglobin A1c, FPG, or 2-hour PG definition). Prediabetes was defined as a hemoglobin A1c level of 5.7% to 6.4%, an FPG level of 100 mg/dL to 125 mg/dL, or a 2-hour PG level of 140 mg/dL to 199 mg/dL. Results: In the overall 2011-2012 population, the unadjusted prevalence (using the hemoglobin A1c, FPG, or 2-hour PG definitions for diabetes and prediabetes) was 14.3% (95% CI, 12.2%-16.8%) for total diabetes, 9.1% (95% CI, 7.8%-10.6%) for diagnosed diabetes, 5.2% (95% CI, 4.0%-6.9%) for undiagnosed diabetes, and 38.0% (95% CI, 34.7%-41.3%) for prediabetes; among those with diabetes, 36.4% (95% CI, 30.5%-42.7%) were undiagnosed. The unadjusted prevalence of total diabetes (using the hemoglobin A1c or FPG definition) was 12.3% (95% CI, 10.8%-14.1%); among those with diabetes, 25.2% (95% CI, 21.1%-29.8%) were undiagnosed. Compared with non-Hispanic white participants (11.3% [95% CI, 9.0%-14.1%]), the age-standardized prevalence of total diabetes (using the hemoglobin A1c, FPG, or 2-hour PG definition) was higher among non-Hispanic black participants (21.8% [95% CI, 17.7%-26.7%]; P < .001), non-Hispanic Asian participants (20.6% [95% CI, 15.0%-27.6%]; P = .007), and Hispanic participants (22.6% [95% CI, 18.4%-27.5%]; P < .001). The age-standardized percentage of cases that were undiagnosed was higher among non-Hispanic Asian participants (50.9% [95% CI, 38.3%-63.4%]; P = .004) and Hispanic participants (49.0% [95% CI, 40.8%-57.2%]; P = .02) than all other racial/ethnic groups. The age-standardized prevalence of total diabetes (using the hemoglobin A1c or FPG definition) increased from 9.8% (95% CI, 8.9%-10.6%) in 1988-1994 to 10.8% (95% CI, 9.5%-12.0%) in 2001-2002 to 12.4% (95% CI, 10.8%-14.2%) in 2011-2012 (P < .001 for trend) and increased significantly in every age group, in both sexes, in every racial/ethnic group, by all education levels, and in all poverty income ratio tertiles. Conclusions and relevance: In 2011-2012, the estimated prevalence of diabetes was 12% to 14% among US adults, depending on the criteria used, with a higher prevalence among participants who were non-Hispanic black, non-Hispanic Asian, and Hispanic. Between 1988-1994 and 2011-2012, the prevalence of diabetes increased in the overall population and in all subgroups evaluated.