RESEARCH ARTICLE

A retrospective observational study of
glucocorticoid-induced diabetes mellitus withIgA nephropathy treated with tonsillectomy
plus methylprednisolone pulse therapy
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Yoshia Miyawaki, Takayuki Katsuyama, Ken-Ei Sada*, Sumie Hiramatsu, Keiji Ohashi,
Michiko Morishita, Eri Katsuyama, Haruki Watanabe, Mariko Takano-Narazaki,
Noriko Toyota-Tatebe, Katsue Sunahori-Watanabe, Tomoko Kawabata, Tatsuyuki Inoue,
Masaru Kinomura, Hitoshi Sugiyama, Jun Wada
Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Graduate
School of Medicine Dentistry and Pharmaceutical Sciences, Okayama, Japan* sadakenn@okayama-u.ac.jp

Abstract
OPEN ACCESS
Citation: Miyawaki Y, Katsuyama T, Sada K-E,
Hiramatsu S, Ohashi K, Morishita M, et al. (2017) A
retrospective observational study of glucocorticoidinduced diabetes mellitus with IgA nephropathy
treated with tonsillectomy plus methylprednisolone
pulse therapy. PLoS ONE 12(5): e0178018. https://doi.org/10.1371/journal.pone.0178018
Editor: Minoru Satoh, Kawasaki Ika Daigaku,
JAPAN

Aims
To evaluate the incidence of GC-DM among patients with immunoglobulin A nephropathy(IgAN) and to confirm the risk factors for the development of GC-DM.

Methods
The medical records of patients with IgAN newly treated with the protocol of tonsillectomy
combined with steroid pulse therapy were reviewed. The primary outcome was the development of GC-DM within the hospitalization period and during one year of follow-up.

Received: December 12, 2016
Accepted: April 10, 2017

Results

Published: May 31, 2017

Data Availability Statement: All relevant data arewithin the paper.

During hospitalization, 19 of the 95 patients developed GC-DM (20.0%), and the patientswith GC-DM were significantly older and had a higher rate of family history of diabetes andhigher HbA1c levels. The prevalence of hypertension was higher and the eGFR was numerically lower in patients with GC-DM than in those without. Older age (45 years) and a family
history of diabetes emerged as independent risk factors for the development of GC-DM(odds ratio [OR], 6.3 and 95% confidence interval [CI], 1.6–27.6; OR, 4.4 and 95% CI, 1.2–
16.6, respectively). No patients were newly diagnosed with GC-DM during 1-year observation period at out-patient clinic.

Funding: The authors received no specific funding
for this work.

Conclusions

Copyright: © 2017 Miyawaki et al. This is an open
access article distributed under the terms of theCreative Commons Attribution License, which
permits unrestricted use, distribution, andreproduction in any medium, provided the original
author and source are credited.

Competing interests: The authors declare thefollowing interests: JW received speaker honoraria(less than $10,000 each) from Astellas, Boehringer
Ingelheim, Novartis, and Tanabe Mitsubishi, andreceives grant support (more than $10,000 each)from Astellas, Bayer, Chugai, Daiichi Sankyo,

Among the patients with IgAN, 20% developed GC-DM during the hospitalization period,
confirming the family history of diabetes is clinically necessary before starting GC therapy.

PLOS ONE | https://doi.org/10.1371/journal.pone.0178018 May 31, 2017

1 / 11Glucocorticoid diabetes in IgAN patients

Kissei, Kyowa Hakko Kirin, MSD, Otsuka, Teijin,
Torii, Pfizer, Takeda, and Taisho Toyama. The
authors received no financial support for the
research, authorship, and/or publication of thisarticle. There are no patents, products indevelopment, or marketed products to declare.
This does not alter the authors’ adherence to all
PLOS ONE policies on sharing data and materials.

Introduction
Immunoglobulin A nephropathy (IgAN) is the most common primary glomerulonephritis(GN) worldwide [1, 2]. An exploration of the Japan-Renal Biopsy Registry database showed
that, for about 30% of patients, IgAN was the most frequent pathological diagnosis of thenative kidney [3, 4]. Regarding the definitive outcomes of IgAN, 30% to 40% of affectedpatients progress to end-stage kidney disease (ESKD) within 20 years [5]. The Kidney Disease
Improving Global Outcomes (KDIGO) Glomerulonephritis Work Group clinical practiceguidelines for GN recommend that patients with persistent proteinuria 1 g/day, despite 3–6
months of optimized supportive care (including ACE-I or ARB’s and blood pressure control)
and a glomerular filtration rate (GFR) <50 ml/min per 1.73 m2 receive a 6-month course ofsteroid therapy [6]. As an alternative treatment, tonsillectomy combined with steroid pulse(TSP) administration may be useful for inducing complete remission in patients with IgAN
who have persistent proteinuria, although its long-term effectiveness remains uncertain [7, 8].
Glucocorticoids (GCs) are an important component of therapy for IgAN, but their use frequently induces adverse effects, particularly GC-induced diabetes mellitus (GC-DM) [9–13], as
2% to 30% of patients treated with GCs develop GC-DM [10, 14]. Several risk factors for thedevelopment of GC-DM, including cumulative GC dose, age, body weight, BMI and family history of diabetes, have been identified among renal transplant recipients [15], but only an older
age has been repeatedly reported as a risk factor for the development of GC-DM along with primary renal diseases, neurologic diseases, inflammatory rheumatologic diseases and respiratory
diseases in other studies [15–19]. Cumulative GC dose was shown to be negatively associatedwith glucose tolerance and insulin sensitivity in patients with rheumatoid arthritis [20] or with arecent diagnosis of acute lymphoblastic leukemia or non-Hodgkin’s lymphoma on high-doseGC therapy [21]. Some studies have further reported that even low-dose GCs increase the plasma
glucose levels or risk of diabetes in patients with inflammatory rheumatologic diseases [22, 23].
Of note, the incidence and risk factors for the development of GC-DM in IgAN patients treatedwith TSP have not been clarified. Because DM is an important risk factor for end-stage renal disease in patients with IgAN [24], effectiveness of steroid treatment for IgAN may be attenuatedby GC-DM. In addition, treatment for GC-DM takes the additional cost. The patients with risk
factors could decide whether received steroid therapy or not considering these disadvantages.
We recently found that an older age, a higher hemoglobin A1c (HbA1c) level, and a lower
estimated glomerular filtration rate (eGFR) were independent risk factors for the developmentof GC-DM, and 78% of patients with any of these risk factors developed GC-DM among
patients with rheumatic or renal diseases [19]. However, whether or not a higher age in ayoung population (the 25 to 45-year-old age group), a higer hemoglobin A1c (HbA1c) level,
and a lower estimated glomerular filtration rate (eGFR) are also risk factors in relatively young
patient group with IgAN is unclear. Furthermore, the risk factors for the development of
GC-DM concerning a family history diabetes remains controversial, and whether or not thelong-term treatment of diabetes is necessary once GC-DM has developed is also unclear.
Therefore, in the present study, we evaluated the incidence of GC-DM among patients with
IgAN without other systemic inflammatory disorders both during hospitalization and after
one year of follow-up and identified the risk factors for the development of GC-DM.

Patients and methods
Patient population
From April 2006 to December 2013, we retrospectively reviewed the medical records of inpatients with IgAN who were fully treated according to the protocol of TSP therapy. At inclusion,

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all eligible patients were diagnosed with biopsy-proven IgA nephropathy and were not diabetic. DM was diagnosed as a fasting glucose level of 126 mg/dL or a postprandial glucose
level 200 mg/dL before pulse therapy, or a history of oral hypoglycemic agent use and/or
insulin injection therapy. Patients who had never had their fasting or blood glucose levels
measured during hospitalization and who had a history of using oral glucocorticoids were
excluded. Patients with IgA vasculitis were also excluded from the study.

Treatment protocol
Regarding the protocol of steroid pulse therapy after tonsillectomy, patients received methylprednisolone (mPSL) pulse (500 mg daily) administered intravenously for 3 consecutive days
followed by oral prednisolone (30 mg daily) on 4 consecutive days, with the course repeated 3
times during hospitalization. Oral prednisolone (30 mg) was then given on every alternate day
and gradually tapered and discontinued at 1 year (Fig 1). The duration of the TSP protocol is
17 days, so hospitalization for up to 28 days was permitted in this study. Tonsillectomy was
performed at least 10 days before starting steroid pulse therapy. DM during hospitalization
was diagnosed as a fasting glucose level of 126 mg/dL, or a postprandial glucose level 200
mg/dL twice except for during the pulse therapy, or a history of oral hypoglycemic agent use
and/or insulin injection therapy. GC-DM developing from the day of discharge to 1 year later
was diagnosed based on either a high HbA1c value (6.5%, NGSP) concomitant with a fasting
glucose level of 126 mg/dL, or a postprandial glucose level 200 mg/dL at least once, or theuse of oral hypoglycemic agents and/or insulin injection therapy.

Data collection
Baseline demographic characteristics were reviewed for the following data: age, gender, bodyweight, body mass index (BMI), family history of DM, hypertension, concomitant usage ofstatins and renin-angiotensin system inhibitors (RASI), fasting plasma glucose level, postprandial blood glucose level, HbA1c, immunoreactive insulin (IRI), high-density lipoprotein(HDL)-cholesterol, low-density lipoprotein (LDL)-cholesterol, triglycerides, serum creatinine(Cr), eGFR, urine protein creatinine ratio (UPCR), urinary protein, urinary occult blood,
urinary sediment including red blood cell casts or granular casts, immunoglobulin (Ig) A,
complement 3 (C3), and C-reactive protein (CRP) before starting the steroid pulse therapy.
Patients were also evaluated during the hospitalization period for the following data relating totreatments: vital status, fasting glucose level, postprandial glucose level, initial dosage of oral
PSL (per kilogram of body weight), duration until the development of GC-DM, developmentof GC-DM, and the usage of oral hypoglycemic agents and insulin. Body weight, BMI, blood
glucose levels, HbA1c levels, cumulative dosage of PSL, development of GC-DM, and theusage of oral hypoglycemic agents and insulin from the day of discharge to one year later werealso assessed. Family history of diabetes, defined by diabetes within second-degree relatives,
was collected medical records in the present study. Hypertension was defined as blood pressure (OBP) 140/90mmHg at admission and/or using of oral antihypertensive drugs at theadmission. Obesity was defined based on the definition of obesity established by the Japan
Society for the Study of Obesity (JASSO) as BMI 25 kg/m2, with BMI divided into 2 categories (<25 kg/m2 or 25 kg/m2) [25].

Outcome measures
The primary outcome of the study was the development of GC-DM during the hospitalization
period. The secondary outcomes of the study were as follows: the development of GC-DM
from starting the protocol until one year later, and the number of patients with concomitant

PLOS ONE | https://doi.org/10.1371/journal.pone.0178018 May 31, 20173 / 11Glucocorticoid diabetes in IgAN patientsuse of other oral hypoglycemic agents and/or insulin injection therapy during the hospitalization period and from the day of discharge to one year later.

Ethical considerations
This study was conducted in compliance with the principles of the Declaration of Helsinki,and the protocol was approved by the Ethics Committee of the Okayama University Graduate

Fig 1. Schematic illustration of the protocol. Patients received methylprednisolone (mPSL) pulse (500 mg daily) administeredintravenously for 3 consecutive days followed by oral prednisolone (30 mg daily) on 4 consecutive days, with the course repeated 3
times during hospitalization. Oral prednisolone (30 mg) was then given on every alternate day and gradually tapered and discontinued
at 1 year.
https://doi.org/10.1371/journal.pone.0178018.g001

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School of Medicine, Dentistry and Pharmaceutical Sciences (authorization number: No. 1609–
510).

Statistical analyses
The results were analyzed using the JMP 11 software package (SAS Institute, Cary, NC, USA).
The descriptive statistics are expressed as the median and interquartile range (IQR) unless otherwise specified. For the univariate analysis, Student’s t-test was used for continuous variables,
and Fisher’s exact tests were used for categorical variables to compare outcomes between the
GC-DM group and the non-GC-DM group. In the multivariate analysis, candidate risk factors
were selected according to the results of the univariate analysis and the findings of previous
reports. The continuous variables of age, HbA1c, and eGFR were changed to categorical variables using quartiles. To compare multiple categorical variables between the two groups, alogistic regression analysis was conducted. A p value <0.05 was considered to indicate a statistically significant difference.

Results
Patient background characteristics
Between April 2006 and December 2013, 95 of 123 candidate patients were enrolled in thisstudy. Regarding the 28 patients excluded from the study, the glucose level was not measured
in 23 (82%) patients. They were all discharged from the hospital within 28 days. The baselinecharacteristics of the eligible patients were as follows: 36 were men (37.9%), the median (25thand 75th percentiles, IQR) age was 33 years (25–45), the median BMI was 21.2 kg/m2 (19.4–
24.3), and the median hospitalization period was 17 days (16–17). Twenty patients (21.1%)
had family histories of diabetes, and 34 patients (35.8%) had concomitant hypertension. The
median fasting plasma glucose and postprandial blood glucose levels were 95 (88–102) mg/dL
and 99 (90–113) mg/dL, respectively. Only one patient had concomitant obesity-related glomerulopathy, and none of the eligible patients had concomitant inflammatory rheumatologic
diseases.

Risk factors for GC-DM during hospitalization
During the hospitalization period, 19 of the 95 patients developed GC-DM (20.0%) for a
median (IQR) of 7 (4–12) days. We compared the demographic characteristics of the patientswith and without GC-DM (Table 1).
The patients with GC-DM were significantly older (50 vs. 32 years, p <0.0001) and had ahigher rate of family history of diabetes (47.4 vs. 14.5%, p = 0.0037) and HbA1c (5.6 vs. 5.4%,
p = 0.0010) at the time of presentation than those without. The prevalence of hypertension was
higher and the eGFR was lower in patients with GC-DM than in those without (63.2% vs.
29.0%, p = 0.0077; 63.1 [52.9–75.4] vs. 82.0 [60.9–97.1]; p = 0.0071, respectively). Gender, BMI,
body weight, fasting blood glucose level, postprandial blood glucose level, IRI, triglyceride,
LDL-C, HDL-C, serum Cr, UPCR, urinary occult blood, urinary sediment, levels of IgA andC3, and CRP were comparable between the groups with no significant differences (p >0.05).
Nineteen patients were obese (20.0%), and the proportion of patients with obesity did not significantly differ between the GC-DM and non-GC-DM patients (26.3% vs. 18.4%, p = 0.5225).
For the multivariate analysis, the following candidate factors were selected: age, gender,
HbA1c level, eGFR, family history of diabetes and hypertension. Based on the quartiles, theage and HbA1c level were divided into two categories as follows: age <45 years or 45 years
and HbA1c <5.6% or 5.6%. From patients with or without chronic kidney disease, the eGFRPLOS ONE | https://doi.org/10.1371/journal.pone.0178018 May 31, 2017

5 / 11Glucocorticoid diabetes in IgAN patients

Table 1. Comparison of the baseline characteristics of the patients with and without GC-DM during hospitalization.
Without GC-DM(n = 76)

With GC-DM(n = 19)

P value

Age, years

32 [23–40]

50 [40–55]<0.0001

Male gender, n (%)

27 (35.5)

9 (47.4)

0.4294

Body weight, kg

56.1 [48.7–65.2]

56.4 [45.5–69.4]

0.4856

Initial dosage of oral PSL, mg/kg

0.54 [0.46–0.62]

0.53 [0.43–0.66]

0.5504

BMI, kg/m2

21.1 [19.5–24.3]

21.6 [18.4–25.0]

0.4103

Family history of diabetes, n (%)

11 (14.5)

9 (47.4)

0.0037Hypertension, n (%)

22 (28.9)

12 (63.2)

0.007720 (26.3)

10 (52.6)

0.0507

Concomitant RASI, n (%)
Concomitant statin, n (%)

6 (7.9)4 (21.1)

0.1089HbA1c, %5.4 [5.3–5.6]

5.6 [5.5–5.8]

0.0010

IRI, pmol/L

4.8 [3.9–11.1]

5.7 [3.7–7.7]

0.8480

Triglyceride, mg/dL

96.5 [68.8–153.0]

133 [101.0–165.0]

0.2203

LDL-C, mg/dL

103 [82.8–123.5]

117 [108.8–141.0]

0.1277

eGFR, ml/min/1.73 m2

82.0 [60.9–97.1]

63.1 [52.9–75.4]

0.0071

CRP, mg/dL

0.04 [0.02–0.08]

0.05 [0.03–0.09]

0.2159Urinary sediment, n (%)

30 (39.5)

10 (52.6)

0.3128

Data are presented median and numbers in brackets indicate interquartile range (IQR). BMI, body mass index; RASI, renin-angiotensin system inhibitor;
HbA1c, hemoglobin A1c; LDL-C, low-density lipoprotein cholesterol; eGFR, estimated glomerular filtration rate; CRP, C-reactive protein; UPCR, urine
protein creatinine ratio.
https://doi.org/10.1371/journal.pone.0178018.t001

was divided into >60 ml/min/1.73 m2 or 60 ml/min/1.73 m2. In a logistic regression analysis,
older age (45 years) and a family history of diabetes emerged as independent risk factors forthe development of GC-DM (odds ratio [OR], 6.3 and 95% confidence interval [CI], 1.6–27.6;
OR, 4.4 and 95% CI, 1.2–16.6, respectively) (Fig 2).

Outcome after one-year observation and comparison of the baselinecharacteristics of the patients with and without GC-DM at one year laterMedian (IQR) follow-up period of 95 patients was 359 (336–365) days and 77 patients (81.1%)
were followed up to one year. Among these 77 patients, 13 patients developed GC-DM. No
patient was diagnosed with GC-DM during the period from discharge to one year later. Thirteen of 19 patients with GC-DM were observed for 1 year after starting TSP therapy. At 1 year
later, 5 (38.5%) of 13 patients with GC-DM still had GC-DM and continued to take oral hypoglycemic agents. We compared the demographic and clinical features of the patients being
treated for GC-DM and those not being treated at one year later (Table 2). The body weight at
the start of TSP therapy was only significantly associated with the requirement of treatment of
GC-DM at one year later. All of the obese patients were included in the patient group with
GC-DM at one year, and no significant differences were noted in the body weight or BMI at
one year after starting therapy, even after excluding the obese patient’s data.

Discussion
In the present study, we found that 20% of the patients with IgAN newly treated with TSP therapy developed GC-DM during their hospitalization period, and about 40% of them continued
to require treatment for their diabetes at 1 year later. The independent risk factors for the

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Fig 2. Risk factors for GC-DM. The multivariate analysis revealed an older age (45 years) and a family history of diabetes to be independent risk factors
for the development of GC-DM during hospitalization. In a logistic regression analysis, older age (45 years) and a family history of diabetes emerged as
independent risk factors for the development of GC-DM (odds ratio [OR], 6.3 and 95% confidence interval [CI], 1.6–27.6; OR, 4.4 and 95% CI, 1.2–16.6,
respectively).
https://doi.org/10.1371/journal.pone.0178018.g002

Table 2. Comparison of the baseline characteristics of the patients with and without GC-DM treatment at one year.
Without treatment(n = 8)With diabetic treatment(n = 5)

P value

Age, years

53 [46–60]

52 [42–60]

0.7493

Male gender, n (%)

3 (37.5%)

3 (60.0%)

0.5921

Body weight, kg

52.5 [44.5–59.6]

69.4 [54.0–73.6]

0.0246

BMI, kg/m2

20.3 [18.3–22.7]

23.1 [19.3–30.2]

0.1096

Family history of diabetes, n (%)

4 (50.0%)

3 (60.0%)

1.0000Hypertension, n (%)

5 (62.5%)

3 (60.0%)

1.0000HbA1c, %5.7 [5.5–6.0]

5.6 [5.5–5.8]

0.3700HbA1c at one year later, %5.7 [5.6–6.0]

5.5 [5.5–5.9]

0.4425

IRI, pmol/L

4.1 [2.3–13.9]

5.7 [4.2–8.2]

0.8113

Triglyceride, mg/dL

107.0 [95.8–151.8]

122.0 [101.5–148.5]

0.6583

LDL-C, mg/dL

119.0[109.0–127.0]

112.0 [93.0–152.0]

0.9739eGFR, ml/min/1.73 m2

59.5 [49.5–71.7]

62.5 [49.1–76.6]

0.9106

CRP, mg/dL

0.05 [0.04–0.10]

0.07 [0.02–0.96]

0.2350

Accumulative dosage of PSL at one year, mg

3787.0 [3780.0–3840.0]

3825 [3772.5–3869.4]

0.4614

Urinary sediment, n (%)

3 (37.5%)

3 (60.0%)

0.5921

UPCR, g/gCr

0.36 [0.10–0.65]

0.68 [0.31–0.78]

0.5620

Data are presented median and numbers in brackets indicate interquartile range (IQR). BMI, body mass index; HbA1c, hemoglobin A1c; LDL-C, low-density
lipoprotein cholesterol; eGFR, estimated glomerular filtration rate; CRP, C-reactive protein; UPCR, urine protein creatinine ratio.
https://doi.org/10.1371/journal.pone.0178018.t002

PLOS ONE | https://doi.org/10.1371/journal.pone.0178018 May 31, 20177 / 11Glucocorticoid diabetes in IgAN patientsdevelopment of GC-DM in patients with IgAN were older age (45 years) and a family historyof diabetes.
The characteristics of the patients at risk of developing GC-DM have been identified [15–19]. Using a multivariate analysis, our previous study showed that an older age (65 years), ahigher HbA1c level (6.0%), and a lower eGFR (<40 ml/min/1.73 m2) were independent risk
factors for the development of GC-DM [18]. However, that study included patients with various rheumatic or renal diseases and with a varied dose of GCs. In the present study, because of
the single disease and fixed protocol of GC administration, we were able to perform a more
precise analysis of the risk factors among patients’ background data for the development of
GC-DM. As in the previous study, an older age was again identified as a risk factor for thedevelopment of GC-DM. However, the eGFR and HbA1c levels were not extracted because
the eGFR at baseline was close to normal, with a median eGFR of 77.6 ml/min/1.73 m2 in thisstudy population, and the HbA1c level was lower than in our past study. There was only one
patient (1.1%) whose eGFR was <40 ml/min/1.73 m2, and 8 patients (8.4%) had an HbA1clevel 6.0%. Therefore, a higher HbA1c level (6.0%) and a lower eGFR (<40 ml/min/1.73m2) were not found to be independent risk factors for the development of GC-DM in the present study. Even though the average age of the group was 36 years old, surprisingly, older age
was still shown to be a risk factor.
In this study, a family history of diabetes was an independent risk factor for the development of GC-DM. In our previous study, although a family history of diabetes tended to be arisk factor, there were no significant differences between groups [19]. Similarly, in anotherstudy with rheumatic diseases, there was no significant difference in the family history of diabetes between groups with and without GC-DM [26]. Previous studies have shown the predictors of developing “diabetes” to be a high BMI and a family history of GC-DM (men only) andhypertension (both men and women) in a Japan-specific longitudinal study [27, 28]. Few
reports, though, are available on the family history of diabetes as an independent risk factor forthe development of “GC-DM” [15]. The patients with evident diabetes were excluded in ourprevious study. Because the population in the present study was relatively young, the patientswith a family history of diabetes may not have yet developed diabetes. Therefore, it may still be
important to consider the risks and benefits of administering GCs in young patients with afamily history of diabetes.
Five of 13 GC-DM patients still required pharmacological interventions at 1 year later,
despite the termination of GCs, but no patients were newly diagnosed with GC-DM after the
initial hospitalization. The patients still being treated with GC-DM at one year later had a significantly higher body weight than those not being treated. All obese patients were included in
the GC-DM groups at one year. No statistically significant difference was observed, but thismay be due to the small sample size of the patients. Even after excluding the obese patients’data, there were no significant differences in the family history of diabetes between the twogroups at one year later. Obesity is known to contribute to both insulin resistance and areduced pancreatic β cell function [29]. Therefore, several studies have reported that obesity is
an independent risk factor for the development of diabetes during GC therapy [30–32]. These
present and previous results suggest that obese patients require continuous treatment for diabetes once they develop GC-DM.
We acknowledge that our retrospective study has several limitations. First, some patients inthe present study may have had impaired glucose tolerance, as the oral glucose tolerance test
was not performed to exclude patients who already had diabetes. Second, 6 of 19 patients with
GC-DM were lost to follow-up at 1 year, so we may have understimated the proportion ofpatients who still required treatment for diabetes at 1 year.

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In conclusion, our study revealed that 20% of patients with IgAN developed GC-DM during the hospitalization period, and 38.5% of the GC-DM patients were still being treated fordiabetes at 1 year later. The independent risk factors for the development of GC-DM were anolder age (45 years) and a family history of diabetes. Obese patients treated with GC-DM
may require continuous treatment for diabetes once they develop GC-DM. On the otherhands, patients without risk factors may be able to be reduced frequency of glucose monitoringsince the patients developed GC-DM up to 17 days from starting TSP. Furthermore, risk factors in the present study could help to raise the feasibility of future clinical trials for treatment
or prevention of GC-DM.

Acknowledgments
We would like to thank our colleagues at Okayama University Hospital, Akifumi Onishi,
Toshio Yamanari, Masashi Kitagawa, Hiroshi Morinaga, Katsuyuki Tanabe, Haruhito Adam
Uchida, and Shinji Kitamura for their valuable contributions to this work.

Author Contributions
Conceptualization: YM T. Katsuyama KS.
Data curation: YM T. Katsuyama KS TI MK HS.
Formal analysis: YM T. Katsuyama KS.
Investigation: YM T. Katsuyama.
Methodology: YM T. Katsuyama KS.
Project administration: YM T. Katsuyama KS SH KO MM EK HW MN NT KW T. Kawabata
TI MK HS JW.
Resources: YM T. Katsuyama KS SH KO MM EK HW MN NT KW T. Kawabata TI MK HS
JW.
Software: YM T. Katsuyama KS SH KO MM EK HW MN NT KW T. Kawabata TI MK HS
JW.
Supervision: YM T. Katsuyama KS SH KO MM EK HW MN NT KW T. Kawabata TI MK HS
JW.
Validation: YM T. Katsuyama KS SH KO MM EK HW MN NT KW T. Kawabata TI MK HS
JW.
Visualization: YM T. Katsuyama KS SH KO MM EK HW MN NT KW T. Kawabata TI MK
HS JW.
Writing – original draft: YM T. Katsuyama KS.
Writing – review & editing: YM T. Katsuyama KS SH KO MM EK HW MN NT KW T.
Kawabata TI MK HS JW.

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