Identifikasi Struktur Jurnal

Tugas Ini Disusun Untuk Memenuhi Tugas Mata Kuliah Metodologi Riset

Keperawatan

Dosen Pembimbing :

Abdurahman Wahid, Ns.,M.Kep

Oleh

Nama : Mildawati

NIM : 1710913420014

FAKULTAS KEDOKTERAN

PROGRAM STUDI ILMU KEPERAWATAN ALIH JENJANG

UNIVERSITAS LAMBUNG MANGKURAT

BANJARBARU

2018
Tugas 1

Jurnal 1
Gambaran Pengetahuan Masyarakat Tentang Resiko Penyakit Diabetes Mellitus Di
Kacamatan Pakisaji Kabupaten Malang

NO. STRUKTUR JURNAL PENJELASAN

Berisi gambaran konsep atau variabel yang diteliti,
kepada siapa dan dimana penelitian dilakukan.

Jurnal 1
1. Judul
Gambaran Pengetahuan Masyarakat Tentang Resiko
Penyakit Diabetes Mellitus Di Kacamatan Pakisaji
Kabupaten Malang

Bayu Jaya Noor Arisma, Moch Yunus, Erianto

2. Penulis
Fanani
Abstrak dari jurnal berisi latar belakang, tujuan,
3. Abstrak
metode, hasil, dan kesimpulan
Berisi tentang pentingnya masalah yang akan diteliti.
Masalah penelitian harus didukung oleh data
menurut waktu dan tempat.

4. Pendahuluan
Jurnal 1
Menjelaskan bagaimana gambaran pengetahuan yang
ada di masyarakat tentang resiko penyakit diabetes
mellitus
Tinjauan pustaka memuat landasan teori yang
menunjang masalah atau variabel yang diteliti
5. Tinjauan Pustaka
Jurnal 1
Menjelaskan teori tentang pengetahuan masyarakat
 tentang resiko penyakit diabetes mellitus
Menjelaskan tentang rancangan penelitian, teknik
pengambilan sampel, lokasi dan waktu dan serta
populasi penelitian yang di gunakan
Jurnal 1
6. Metode Analisis data penelitian ini menggunkan analisis
deskriptif analitik, menggunakan metode rapid
survey atau survei cepat. Populasi adalah masyarakat
usia > 40 tahun di Kecamatan Pakisaji Kabupaten
Malang 2017
Menjelaskan gambaran karakteristik responden.
pembahasan berisi tentang penalaran hasil penelitian
dengan memakai teori yang sudah ditulis pada
Hasil Penelitian dan
7. tinjauan pustaka dan hasil penelitian terkait sehingga
Pembahasan
dapat menjawab rumusan masalah yang diajukan
seperti pengetahuan masyarakat pada resiko diabetes
mellitus
Isi kesimpulan berupa temuan yang relevan maupun
tidak relevan, menjawab tujuan khusus penelitian dan
Mengacu pada manfaat penelitian dan bersifat
8. Kesimpulan dan Saran operasional, berisi pemecahan masalah atau
rekomendasi penelitian lebih lanjut. Kesimpulan
penelitian ini yaitu gambaran pengetahuan
masyarakat tentang resiko penyakit diabetes mellitus
Penulisan daftar pustaka terdiri dari nama belakang,
tahun penerbitan, judul, edisi, penerbit dan tempat
9. Daftar Pustaka
terbit sesuai dengan aturan yang berlaku, daftar
pustaka berasal dari buku dan jurnal-jurnal.
Jurnal 2
Relationship between frequency of hypoglycemic episodes and changes in carotid
atherosclerosis in insulin-treated patients with type 2 diabetes mellitus

No STRUKTUR JURNAL PENJELASAN

Berisi gambaran konsep atau variabel yang diteliti
dan siapa objek penelitian.

Jurnal 2
1. Title
Relationship between frequency of hypoglycemic
episodes and changes in carotid atherosclerosis in
insulin-treated patients with type 2 diabetes mellitus

Tomoya Mita, Naoto Katakami, Toshihiko Shiraiwa,

Hidenori, Yoshii, Nobuichi Kuribayashi, Takeshi
2. Author Osonai, Hideaki Kaneto, Keisuke Kosugi, Yutaka
Umayahara, Masahiko Gosho, Licihiro Shimomura,
& Hirotaka Watada
Menjelaskan secara singkat dari latar belakang,
3. Abstract
tujuan, metode, hasil, dan kesimpulan penelitian.
Menjelaskan variabel yang akan diteliti dan
gambaran permasalahan tentang frekuensi episode
4. Introduction
hipoglikemi dan perubahan aterosklerosis karotis
yang akan diteliti.
Hasil penelitian dapat menjawab rumusan masalah
yang di ajukan. Jumlah pasien sebanyak 104 dari 274
pasien mengalami hipoglikemia. analisis data dari
5. Result
keseluruhan populasi menunjukkan bahwa terdapat
hubungan antara peningkatan frekuensi episode
hipoglikemi dengan perubahan aterosklerosis karotis.
Pembahasan berisi penjelasan dari hasil penelitian.
6. Discussion
Dimana kejadian frekuensi hipoglikemia yang
 meningkat dikaitkan dengan meningkatnya
aterosklerosis karotis
kesulitan-kesulitan metodologis atau prosedural
7. Study limitations tertentu sehingga tidak dapat dicakup di dalam
penelitian dan di luar kendalikan peneliti.
Kesimpulan adalah Temuan yang relevan maupun
tidak relevan untuk menjawab tujuan khusus
penelitian. Pada penelitian ini terdapat hubungan
antara peningkatan frekuensi episode hipoglikemi
Conclusions and dengan perubahan aterosklerosis karotis
8.
suggestion
Saran Berisi pemecahan masalah seperti pada
penelitian ini yaitu dr harus lebih peduli pada
kejadian hipoglikemi di rumah sakit untuk
menurunkan proses penyakit ateroskeloris
Menjelaskan tentang desain penelitian yang
digunakan, teknik pengambilan sampel dan analisa
9. Methods yang digunakan. Dimana Analisis data penelitian ini
menggunakan analisis post hoc dengan di uji secara
acak.
Susunan daftar pustaka sudah baku dan sesuai
10. References dengan aturan yang berlaku, daftar pustaka berasal
dari buku dan jurnal-jurnal.
 GAMBARAN PENGETAHUAN MASYARAKAT TENTANG
RESIKO PENYAKIT DIABETES MELLITUS DI
KECAMATAN PAKISAJI KABUPATEN MALANG

Bayu Jaya Noor Arisma

Moch Yunus
Erianto Fanani
Universitas Negeri Malang
bayujayanoor72@gmail.com

Abstract: Diabetes mellitus cases in Indonesia by Riskesdas (2007) is the sixth cause of death
disease (5.8%) and by Depkes (2012) in Indonesia there were 102,399 cases. In 2030 Indonesian
people with diabetes mellitus estimated as much as 21.3 million. The incidence of diabetes mellitus
in Pakisaji’s Puskesmas is 1164 incidents. The purpose of this research is to know the overview of
public knowledge about the risks of diabetes mellitus at Pakisaji, Malang. This research method is
a descriptive analytical research. The research using rapid survey method. The population is the
society with the age of >40 years old in district Pakisaji. The number of samples are taken from
254 of 12 villages in the Sub-District of Pakisaji with the cluster random sampling technique and
random sampling technique as the appropriate rules of rapid survey. The results of the research is
the percentage of public knowledge about the risks of diabetes mellitus in District of Pakisaji like
eating patterns the percentage of peopole who know about 63%, physical activity (56,5%), stress
(50%), smoking (45%), alcohol (56%), hypertension (60%), obesity (51%), age (64.5%),
generation (78%), and gender (64.5%). The average result value of the public knowledge in
district Pakisaji Malang about the risk of diabetes mellitus disease is less.

Keywords: diabetes mellitus, knowledge, risk

Abstrak: Data diabetes mellitus di Indonesia menurut Riskesdas (2007) menempati urutan
keenam penyakit penyebab kematian (5,8%) dan di Indonesia menurut Depkes (2012) terdapat
102.399 kasus diabetes mellitus. Diperkirakan pada tahun 2030 angka diabetes mellitus (diabetisi)
adalah sebanyak 21,3 juta jiwa. Angka kejadian diabetes mellitus di Puskesmas Pakisaji sejumlah
1164 kejadian. Penelitian ini bertujuan untuk mengetahui gambaran pengetahuan masyarakat
tentang resiko penyakit diabetes mellitus di Kecamatan Pakisaji Kabupaten Malang. Metode
penelitian ini adalah penelitian deskriptif analitik. Penelitian ini menggunakan metode rapid
survey atau survei cepat. Populasi adalah masyarakat usia >40 tahun di kecamatan Pakisaji
kabupaten Malang. Jumlah sampel sebesar 254 diambil dari 12 desa di kecamatan Pakisaji dengan
teknik cluster random sampling dan random sampling sesuai kaidah rapid survey. Hasil penelitian
dari 254 responden persentase pengetahuan masyarakat yang tahu tentang resiko penyakit diabetes
mellitus seperti pola makan, masyarakat yang tahu bahwa pola makan merupakan faktor resiko
diabetes mellitus sebanyak 63%, aktivitas fisik 56,5%, stres 50%, merokok 45%, alkohol 56%,
hipertensi 60%, obesitas 51%, usia 64,5%, keturunan 78%, dan jenis kelamin 64,5%. Sehingga
dari nilai pengetahuan masyarakat di Kecamatan Pakisaji Kabupaten Malang tentang resiko
penyakit diabetes mellitus masuk kategori kurang.

Kata kunci: diabetes mellitus, pengetahuan, resiko

2 Jurnal Preventia, Vol ... No ... April 2017
Menurut Riset Kesehatan
Dasar (Riskesdas) tahun 2007
diabetes di Indonesia menempati
urutan keenam penyakit penyebab
kematian (5,8%) setelah stroke,
tuberkulosis, hipertensi, cedera, dan
perinatal. Diabetes juga sebagai
penyebab kematian pada kelompok
usia 45-54 di daerah perkotaan
menduduki peringkat ke-2 yaitu
14,7% dan daerah pedesaan diabetes
menduduki peringkat ke-6 yaitu
5,8% (PERKENI, 2011).
Global status report on NCD
World Health Organization (WHO)
tahun 2010 melaporkan bahwa 60%
penyebab kematian semua umur di
dunia karena penyakit tidak menular,
salah satunya adalah diabetes
mellitus yang menduduki peringkat
ke-6 sebagai penyebab kematian.
Berdasarakan data Departemen
Kesehatan Republik Indonesia
(2012) terdapat 102.399 kasus
diabetes mellitus. Indonesia
diperkirakan pada tahun 2030 akan
memiliki penyandang diabetes
mellitus (diabetisi) sebanyak 21,3
juta jiwa (Depkes RI, 2013).
Diabetes mellitus merupakan
masalah global yang insidennya
semakin meningkat. Diabetes
mellitus menyebabkan 1,5 juta
kematian pada tahun 2012 yang
mana glukosa darah tinggi dari angka
normal bertanggung jawab terhadap
2,2 juta kematian tambahan sebagai
akibat dari peningkatan risiko
penyakit kardiovaskular dan lainnya,
dengan total 3,7 juta kematian terkait
dengan kadar glukosa darah pada
tahun 2012. Banyak dari kematian
(43%) terjadi di bawah usia 70. Pada
tahun 2014, 422 juta orang di dunia
menderita diabetes mellitus dengan
prevalensi 8,5% di antara populasi
orang dewasa. Prevalensi diabetes
mellitus terus meningkat selama 3
dekade terakhir dan tumbuh paling
cepat di negara-negara
berpenghasilan rendah dan
menengah (WHO, 2016).
Prevalensi diabetes mellitus
di kabupaten Malang pada tahun
2015 terdapat sejumlah 1684 kasus,
yang angka terbanyak terdapat pada
rentang usia 40-69 tahun yaitu 943
kasus. Diabetes mellitus secara
keseluruhan menjadi penyakit
terbanyak nomer 2 dari yang tercatat
dari semua puskesmas di kabupaten
Malang (Dinkes Kabupaten Malang,
2016).
Data rekapitulasi dari
Puskesmas Pakisaji tahun 2015
angka kejadian diabetes mellitus di
Kecamatan Pakisaji Kabupaten
Malang masuk dalam 10 besar
kejadian penyakit terbanyak yaitu
sejumlah 1164 kejadian, dimana
angka kejadian paling tinggi terjadi
di bulan November yaitu 131
kejadian. (Puskesmas Pakisaji,
2016).
Pengetahuan merupakan
salah satu variabel penting yang
menunjang insiden dan prevalensi
kasus penyakit diabetes mellitus di
kecamatan Pakisaji. Salah satu faktor
yang mempengaruhi pengetahuan
menurut Notoatmojo (2010) adalah
tingkat pendidikan, di kecamatan
Pakisaji tingkat pendidikan rata-rata
paling banyak adalah SD dengan
kisaran 35%, SMP dengan kisaran
persentase 27%, SMA dengan
kisaran persentase 23% dan 10%
terbagi dalam lulusan pendidikan
tinggi (Diploma dan Sarjana) serta
sisanya merupakan yang tidak
sekolah atau tidak tamat SD, Angka
tersebut merupakan jumlah
penduduk usia lebih dari 25 tahun
dari total populasi di kecamatan
Pakisaji yang berjumlah 84.964 jiwa
(BPS Kabupaten Malang, 2015).
 Pengetahuan adalah hasil dari
tahu yang terjadi melalui proses
sensoris khususnya mata dan telinga
terhadap suatu objek tertentu. Proses
adopsi perilaku, menurut Rogers
(dalam Notoatmodjo, 2007) adalah
sebelum seseorang mengadopsi
sesuatu di dalam diri orang tersebut
suatu proses yang berurutan yaitu:
Awareness (kesadaran), Interest
(tertarik), Evaluating (menimbang-
nimbang), Trial (mencoba),
Adaptation (adaptasi).
Diabetes mellitus adalah
penyakit dengan gangguan
metabolisme (metabolic syndrome)
dari distribusi gula oleh tubuh.
Penderita diabetes mellitus tidak
mampu memproduksi hormon
insulin dalam jumlah cukup, atau
tubuh tidak dapat menggunakannya
secara efektif sehingga terjadi
kelebihan gula di dalam darah
(Irianto, 2014).
Faktor resiko menurut
American Diabetes Association
(ADA) adalah karakteristik, tanda
atau kumpulan gejala pada penyakit
yang diderita individu yang secara
statistik berhubungan dengan
peningkatan kejadian kasus baru
berikutnya (beberapa individu lain
pada suatu kelompok masyarakat).
Karakteristik, tanda atau kumpulan
gejala pada penyakit yang diderita
individu dan ditemukan juga pada
individu-individu yang lain bisa
dirubah dan ada juga yang tidak
dapat bisa dirubah atau tepatnya)
Faktor resiko yang tidak dapat
dimodifikasi misalnya umur dan
genetik, 2) Faktor resiko yang dapat
dimodifikasi misalnya kebiasaan
merokok atau latihan olahraga.
Faktor resiko diabetes
mellitus terbagi menjadi 2 yaitu
faktor resiko yang tidak dapat
dimodifikasi dan faktor resiko yang
dapat dimodifikasi. Faktor resiko
yang tidak dapat dimodifikasi: umur,
jenis kelamin, bangsa dan etnik,
faktor keturunan, riwayat menderita
diabetes gestasional, dan riwayat
melahirkan bayi dengan berat badan
lahir lebih dari 4000 gram.
Sedangkan faktor resiko yang dapat
dimodifikasi: obesitas, aktifitas fisik
yang kurang, hipertensi, stres, pola
makan, penyakit pada pankreas:
pankreatitis, neoplasma, fibrosis
kistik, dan alkohol (Tjokroprawiro,
2006).
Tujuan dari penelitian ini
adalah untuk mengetahui gambaran
pengetahuan masyarakat tentang
resiko penyakit diabetes mellitus di
kecamatan Pakisaji kabupaten
Malang.
METODE
Penelitian ini merupakan
penelitian epidemiologi deskriptif
analitik. Rancangan penelitian
menggunakan metode Rapid Survey
atau survei cepat. Lokasi
pengambilan data di semua desa
yang ada di Kecamatan Pakisaji
Kabupaten Malang dan pengambilan
data dilakukan pada bulan Januari-
Februari tahun 2017.
Populasi adalah masyarakat
usia >40 tahun di kecamatan Pakisaji
kabupaten Malang. Jumlah sampel
sebesar 254 diambil dari 12 desa di
kecamatan Pakisaji dengan teknik
cluster random sampling dan
random sampling sesuai kaidah
rapid survey. Teknik analisis dalam
penelitian ini adalah analisis statistik
deskriptif dengan software komputer.
Analisis instrumen
menggunakan aspek aspek yang
mempengaruhi pengetahuan dan
hasil akan di analisis dengan
menggunakan pembagian tingkatan
pengetahuan menurut Erlinawati
4

8 Jurnal Preventia, Vol ... No ... April 2017

(2007) tingkat pengetahuan ada HASIL

beberapa kategori sebagai berikut: 1) Berikut adalah tabel skor dan
Pengetahuan baik: rata-rata nilai 85- hasil pengetahuan berdasarkan Desa
100, 2) Pengetahuan cukup baik: di Kecamatan Pakisaji Kabupaten
rata-rata nilai 70-84, 3) Malang:
Pengetahuan
kurang: rata-rata nilai 50-69, 4)
Pengetahuan sangat kurang: rata-rata
nilai kurang dari 50.

Tabel 1 Skor dan Hasil Pengetahuan berdasarkan Desa

Hasil
Skor
No Nama Desa Jumlah Responden (rata-rata)
1 Permanu 16 68,37 Kurang
2 Karangpandan 15 57,14 Kurang
3 Glanggang 14 69,52 Kurang
4 Sutojayan 14 65,71 Kurang
5 Wonokerso 14 52,55 Kurang
6 Karangduren 21 61,36 Kurang
7 Pakisaji 23 61,22 Kurang
8 Jatisari 18 61,5 Kurang
9 Wadung 18 61,11 Kurang
10 Genengan 24 63,18 Kurang
11 Kebonagung 50 61,37 Kurang
12 Kendalpayak 27 65,6 Kurang
Total 254 61,9 Kurang

Tabel 1 menunjukkan bahwa pengetahuan masyarakat di

dari 12 desa di kecamatan Pakisaji kecamatan Pakisaji masuk kategori
desa dengan skor tertinggi ada pada kurang.
desa Glanggang sedangkan skor Berikut ini merupakan
terendah ada pada desa Wonokerso. persentase hasil pengetahuan
Rata-rata skor pengetahuan masyarakat di Kecamatan Pakisaji
masyarakat di kecamatan Pakisaji Kabupaten Malang:
adalah 61,9. Sehingga hasil
Pengetahuan

Sangat Kurang Kurang Cukup Baik

7% 14%
29%

50%

Gambar 1 Pengetahuan Masyarakat di Kecamatan Pakisaji Kabupaten Malang

Gambar 1 dapat disimpulkan sebanyak 14% dari 254 responden,

yaitu jumlah responden dengan kategori kurang 50% dari 254
pengetahuan kategori sangat kurang responden, kategori cukup 29% dari
254 responden, dan kategori baik ada
9% dari 254 responden. Sehingga
tingkat pengetahuan tentang
pengetahuan resiko penyakit diabetes
mellitus di kecamatan Pakisaji
masuk dalam kategori kurang (50%).
Pendidikan
Pendidikan masyarakat dari
kecamatan Pakisaji sebanyak 35%
adalah Sekolah Dasar, dan 27%
adalah Sekolah Menengah Pertama,
23% adalah Sekolah Menengah Atas
dan 10% Pendidikan tinggi. Hasil
pengetahuan masyarakat tentang
resiko diabetes mellitus berbanding
lurus dengan tingkat pendidikan,
skor tertinggi yaitu 70,6 (kategori
cukup) ada pada masyarakat dengan
pendidikan tinggi.
Usia
Rata-rata usia penduduk di
kecamatan Pakisaji Kabupaten
Malang adalah usia 40-49 tahun.
Hasil pengetahuan masyarakat
tentang resiko diabetes mellitus
dengan usia 40-49 tahun memiliki
skor 61,8 (kategori kurang).
Pekerjaan
Sekitar 8.024 orang di
kecamatan Pakisaji Kabupaten
Malang bekerja sebagai karyawan
(Swasta). Hasil pengetahuan
masyarakat tentang resiko diabetes
mellitus dengan pekerjaan Swasta
memiliki skor 61,4 (kategori kurang).
Jenis Kelamin
Jenis Kelamin penduduk di
Kecamatan Pakisaji Kabupaten
Malang sebanyak 59% adalah
perempuan dan 41% laki-laki. Hasil
pengetahuan masyarakat tentang
resiko diabetes mellitus dengan jenis
kelamin laki-laki memiliki skor 61,2
dan perempan memiliki skor 62
(kategori kurang).
PEMBAHASAN
Pendidikan
Pendidikan masyarakat dari
kecamatan Pakisaji sebanyak >30%
adalah Sekolah Dasar, dan >20%
adalah Sekolah Menengah Pertama,
sehingga berbanding lurus dengan
hasil pengetahuan yang menyatakan
kurang dan nilai skor antara
masyarakat yang berpendidikan
tinggi lebih tinggi daripada
masyarakat yang berpendidikan
SMA, SMP, dan SD. Menurut Hary
(dalam Hanifah, 2010) menyebutkan
bahwa tingkat pendidikan turut pula
menentukan mudah tidaknya
seseorang menyerap dan memahami
pengetahuan yang mereka peroleh
pada umumnya semakin tinggi
pendidikan seseorang makin baik
pula pengetahuannya. Pendidikan
merupakan jenjang pendidikan
formal terakhir yang pernah diikuti
oleh seseorang. Orang yang tingkat
pendidikannya tinggi biasanya akan
memiliki pengetahuan tentang
kesehatan (Legumen, 2013). Dengan
adanya pengetahuan tersebut orang
akan memiliki kesadaran dalam
menjaga kesehatannya (Irawan,
2010). Pembagian tingkat pendidikan
antara lain (Notoatmodjo, 2007):
Pendidikan Dasar (SD,
SMP/Sederajat), Pendikan Menengah
(SMA/Sederajat), dan Pendidikan
Tinggi (Akademik/Perguruan
Tinggi). Tingkat pendidikan memiliki
pengaruh terhadap pengetahuan
masyarakat terhadap resiko kejadian
diabetes mellitus dan atau kejadian
diabetes mellitus, Pendidikan
responden sebanyak 39% adalah
sekolah dasar (SD) sehingga
pengetahuan masyarakat masuk
kategori kurang.
8 Jurnal Preventia, Vol ... No ... April 2017
Usia Menurut Nursalam (dalam
Hanifah, 2010) usia individu
terhitung mulai dilahirkan sampai
saat ini (dalam tahun). Semakin
cukup usia, tingkat kematangan
seseorang akan lebih matang dalam
berfikir dan bekerja. Dari segi
kepercayaan masyarakat, seseorang
yang lebih dewasa akan lebih dewasa
akan lebih dipercaya dari orang
belum cukup kedewasanya.
Ahmadi (dalam Hanifah,
2010) juga mengemukakan bahwa
memang daya ingat itu salah satunya
dipengaruhi oleh usia. Usia
masyarakat 40-49 tahun merupakan
masa dimana seharusnya sudah
masuk kategori matang tetapi secara
skor usia 50-59 tahun memiliki nilai
lebih tinggi daripada usia 40-49
dikarenakan masyarakat usia 50-59
memiliki pengalaman lebih karena
usia 50-59 tahun terdapat jumlah
penderita diabetes mellitus lebih
banyak daripada usia 40-49 tahun.
Sedangkan usia >60 juga sama
banyaknya dengan usia 50-59 tahun
akan tetapi secara kognitif dan
penerimaan informasi sangat kurang
daripada usia 40-49 tahun dan 50-59
tahun sehingga memiliki skor
kurang.
Penelitian antara usia dengan
kejadian diabetes mellitus
menunjukan adanya hubungan yang
signifikan. Kelompok usia < 45
tahun merupakan kelompok yang
kurang berisiko menderita diabetes
mellitus. Resiko pada kelompok ini
72 persen lebih rendah dibanding
kelompok umur ≥45 tahun. Menurut
Iswanto (dalam Legumen, 2013) juga
menemukan bahwa ada hubungan
yang signifikan antara usia dengan
kejadian diabetes mellitus. Studi
yang dilakukan Sanjaya (2009) juga
menemukan bahwa kelompok usia
yang paling banyak menderita
diabetes mellitus adalah kelompok
usia 45-55 (47,5%). Peningkatan
diabetes risiko diabetes seiring
dengan usia. Adanya proses penuaan
menyebabkan berkurangnya
kemampuan sel β pankreas dalam
memproduksi insulin (Sanjaya,
2009). Sehingga usia 50-59 tahun
dan >60 tahun memiliki resiko lebih
besar terkena diabetes mellitus dan
atau memiliki riwayat terkena
diabetes mellitus.
Pekerjaan
Jenis pekerjaan erat kaitannya
dengan kejadian diabetes mellitus.
Pekerjaan seseorang mempengaruhi
tingkat aktivitas fisiknya. Misalnya
IRT yang secara aktivitas tidak
rendah karena melakukan perkerjaan
seperti menyapu, mencuci, memasak
dan lain-lain. Berdasarkan analisis
hubungan antara pekerjaan dengan
kejadian diabetes mellits tipe 2,
didapatkan bahwa tidak ada
hubungan yang signifikan antara
pekerjaan dengan kejadian diabetes
mellitus tipe 2 (Fatimah, 2015).
Pekerjaan dalam pemenuhan hasil
pengetahuan dapat diukur dari
bidang pekerjaan yang ditekuni oleh
seseorang. Pengetahuan baik ada
pada kelompok responden yang
bekerja sebagai PNS. Hal ini sesuai
dengan yang diuraikan Situmorang
(2009) bahwa lingkungan pekerjaan
dapat menjadikan seseorang
memperoleh pengalaman dan
pengetahuan baik secara langsung
maupun secara tidak langsung,
demikian juga yang terlihat dalam
kelompok responden pekerjaan PNS.
PNS 80-90% pekerja PNS
merupakan mereka yang memiliki
dasar pendidikan minimal SMA dan
rata-rata pendidikan tinggi berbeda
dengan buruh yang dasar
pendidikannya SD dan SMP,
sehingga skor pekerja PNS lebih baik
daripada buruh. Pekerjaan lain selain
PNS dasar pendidikan lebih
bervariasi dan 70% lebih banyak
pendidikan SD dan SMP sehingga
pekerja swasta, wiraswasta, buruh,
dan IRT memiliki skor lebih rendah.
Pekerjaan terbanyak sebesar 42%
responden adalah IRT, sehingga hasil
pengetahuan rata-rata di kecamatan
Pakisaji kurang.
Jenis Kelamin
Jenis kelamin di masyarakat
pakisaji menunjukkan 64%
perempuan dan 36% laki-laki dan
diketahui skor perempuan lebih
tinggi daripada laki-laki.
Berdasarkan analisis antara jenis
kelamin dengan kejadian diabetes
mellitus tipe 2, prevalensi kejadian
diabetes mellitus tipe 2 pada wanita
lebih tinggi daripada laki-laki.Wanita
lebih berisiko mengidap diabetes
karena secara fisik wanita memiliki
peluang peningkatan indeks masa
tubuh yang lebih besar. Sindroma
siklus bulanan (premenstrual
syndrome), pasca-menopouse yang
membuat distribusi lemak tubuh
menjadi mudah terakumulasi akibat
proses hormonal tersebut sehingga
wanita berisiko menderita diabetes
mellitus tipe2 (Irawan, 2010).
Perempuan 90% bekerja
sebagai Ibu Rumah Tangga (IRT)
sehingga media informasi dari
perempuan lebih banyak seperti
menonton televisi dan aktivitasnya
dalam bidang sosial lebih banyak
sehingga proses diskusi dan
pertukaran informasi dan pikiran
lebih banyak daripada laki-laki.
KESIMPULAN
Berdasarkan hasil penelitan
menunjukkan pengetahuan
masyarakat di kecamatan Pakisaji
kabupaten Malang tentang resiko
penyakit diabetes mellitus masuk
kategori kurang dengan karakteristik
masyarakat adalah masyarakat yang
memiliki usia >40 tahun. Faktor
resiko diabetes mellitus dibagi
menjadi 2 yaitu faktor resiko yang
dapat dimodifikasi dan faktor resiko
yang tidak dapat dimodifikasi. Faktor
resiko yang dapat dimodifikasi antara
lain pola makan, aktivitas fisik, stres,
merokok, alkohol, hipertensi, dan
obesitas, sedangkan faktor resiko
yang tidak dapat dimodifikasi yaitu
usia, keturunan dan jenis kelamin.
Pengetahuan masyarakat yang
mengetahui tentang resiko penyakit
diabetes mellitus di kecamatan
Pakisaji kabupaten Malang yaitu pola
makan, masyarakat yang tahu
bahawa pola makan merupakan
resiko diabetes mellitus sebanyak
63%, sedangkan aktivitas fisik
56,5%, Stres 50%, merokok 45%,
alkohol 56%, hipertensi 60%,
obesitas 51%, usia 64,5%, keturunan
78%, dan jenis kelamin 64,5%.
Hasil skor dari 254 responden
memiliki rentang skor 28 (benar 4)
adalah skor paling rendah atau
minimum dan skor 100 (benar 14)
adalah skor paling tinggi atau
maksimum. Jumlah skor paling
banyak (modus) ada pada skor 57
dan 64 (benar 8 dan 9), sedang nilai
rata-rata (mean) secara keseluruhan
adalah 61,9 (kurang). Persentase
hasil pengetahuan dari 254
responden sebanyak 127 responden
atau 50% yang memiliki
pengetahuan kurang.
Ketidakselarasan hasil
pengetahuan terjadi karena selain
daripada faktor-faktor yang telah
disebutkan dalam mempengaruhi
pengetahuan seperti usia, pekerjaan,
pendidikan, yaitu kembali kepada
proses terbentuknya pengetahuan
pada setiap individu di luar dari
tingkat pendidikannya seperti yang
diuraikan dalam Notoatmodjo (2010)
yaitu pengetahuan adalah hasil
penginderaan manusia, atau hasil
tahu seseorang terhadap objek
melalui indra yang dimilikinya
(mata, hidung, telinga, dan
sebagainya). Artinya sangat
dipengaruhi oleh intensitas perhatian
dan persepsi terhadap objek.
SARAN
Saran dari penelitian skripsi
yang berjudul Gambaran
Pengetahuan Masyarakat tentang
Resiko Penyakit Diabetes Mellitus di
Kecamatan Paksiaji Kabupaten
Malang” ini, antara lain:
Bagi Kecamatan dan atau
Puskesmas Pakisaji
Dengan ditulisnya skripsi dan
penelitian ini diharapkan mampu
menjadi acuan yang dapat
menggambarkan kondisi masyarakat
di kecamatan Pakisaji tentang
pengetahuan terhadap resiko
penyakit diabetes mellitus sehingga
dapat dilakukan upaya pencegahan
dan promosi kesehatan dalam bentuk
program atau sebuah kebijakan untuk
memperbaiki dan meningkatkan
derajat kesehatan masyarakat di
kecamatan Pakisaji.
Bagi Jurusan Ilmu Kesehatan
Masyarakat
Dengan ditulisnya skripsi dan
penelitian ini diharapkan mampu
menjadi salah satu rujukan untuk
para mahasiswa jurusan ilmu
kesehatan masyarakat baik di
Universitas Negeri Malang dan atau
Universitas lain dalam pemenuhan
tugas kuliahnya.
Bagi Peneliti Selanjutnya
Dengan ditulisnya skripsi dan
penelitian ini diharapkan mampu
menjadi sumber ide kepada peneliti-
peneliti selanjutnya untuk
meneruskan membuat penelitian
terkait penyakit diabetes mellitus
akan tetapi lebih dikupas secara luas
dan mendalam dengan variabel-
variabel lain seperti sikap, tindakan
dan perilaku.
DAFTAR RUJUKAN
Badan Pusat Statistik Kabupaten
Malang. 2016. Kecamatan
Pakisaji Dalam Angka 2015.
Malang.
Departemen Kesehatan. 2008.
Kurikulum & Modul Diabetes
Mellitus. Jakarta.
Departemen Kesehatan. 2009.
Pedoman Teknis Penemuan
dan Tatalaksana Penyakit
Diabetes Mellitus. Jakarta.
Departemen Kesehatan. 2013.
Pedoman Teknis Penemuan
dan Tatalaksana Penyakit
Diabetes Mellitus. Jakarta.
Dinas Kesehatan Kabupaten Malang.
2016. Profil Kesehatan
Kabupaten Malang. Malang.
Erlinawati. 2007. Buku Ajar Ilmu
Penyakit Dalam Jilid I.
Jakarta: Balai Pustaka.
Fatimah, Restyana Noor. 2015.
Diabetes Mellitus Tipe 2.
Jurnal Majority Volume 4
Nomor.
Hanifah, Maryam. 2010. Hubungan
Usia dan Tingkat Pendidikan
dengan Pengetahuan Wanita
Usia 20-50 Tahun 2010
tentang Periksa Payudara
Sendiri
(SADARI).
 Universitas Islam Negeri
Syarif Hidayatullah. Skripsi
Hastuti. 2008. Faktor Risiko
Kejadian Diabetes Mellitus
Tipe 2 Pasien Rawat Jalan
(Studi Kasus di Rumah Sakit
Umum Daerah Sunan
Kalijaga Demak. Tesis
Universitas
Negeri
Semarang).
(online)
[http:/lib.unnes.ac.id/2428/]
diunduh pada 19 November
2016.
Irawan, Dedi. 2010. Prevalensi dan
Faktor Risiko Kejadian
Diabetes Melitus Tipe 2 di
Daerah Urban Indonesia
(Analisa Data Sekunder
Riskesdas 2007). Universitas
Indonesia. Thesis (tidak
diterbitkan).
Irianto, Koes. 2014. Epidemiologi
Penyakit Menular dan Tidak
Menular:Panduan Klinis.
Bandung: Alfabeta.
Kementrian Kesehatan RI. 2007.
Hasil Riskesdas Tahun 2007.
Banlitbangkes.
Kementrian Kesehatan RI. 2013.
Hasil Riskesdas Tahun 2013.
Banlitbangkes.
Notoatmojo, S. 2007. Promosi
Kesehatan dan Ilmu Perilaku.
Jakarta: Rineka Cipta.
Notoatmodjo, S. 2010. Ilmu
Perilaku Kesehatan.
Jakarta: Rineka Cipta.
PERKENI. 2011. Konsensus
Pengelolaan dan Pencegahan
Diabetes Mellitus Tipe 2 di
Indonesia. Jakarta: PB.
PERKENI
Puskesmas Pakisaji. 2016. Profil &
Data Kesehatan Kecamatan
Pakisaji tahun 2015. Malang.
Sanjaya, I Nyoman. 2009. Pola
Konsumsi Makanan
Tradisional Bali sebagai
Faktor Risiko Diabetes
Melitus Tipe 2 di Tabanan.
Jurnal Skala Husada Vol. 6
No.1 hal: 75-81
Siregar, Sofyan. 2012. Statistik
Deskriptif untuk Penelitian.
Depok. Rajagrafino Persada.
Situmorang, Siska dkk. 2009.
Gambaran Pengetahuan
Masyarakat Kota Medan
Mengenai Penggunaan Obat
Antijamur Topikal. E-Journal
FK USU Vol.1 No.1.
Tjokroprawiro, Askandar. 2006.
Diabetes Mellitus Klasifikasi,
Diagnosis, dan Terapi.
Jakarta: Gramedia Pustaka
Utama.
World Health Organization. 2016.
Global Report on Diabetes.
Geneva.
 OPE Relationship between frequency of
N
hypoglycemic episodes and
changes in carotid atherosclerosis
received: 03 June
in insulin-treated patients with type
2 diabetes mellitus
2016
Accepted: 29 November 2016
Published: 09 January 2017
Tomoya Mita1, Naoto Katakami2,3, Toshihiko Shiraiwa4, HidenoriYoshii5, Nobuichi
Kuribayashi6, Takeshi Osonoi7, Hideaki Kaneto2, Keisuke Kosugi8, Yutaka
Umayahara9, Masahiko Gosho10, Iichiro Shimomura2 & Hirotaka Watada1
The effect of hypoglycemia on the progression of atherosclerosis in patients with type 2 diabetes mellitus
(T2DM) remains largely unknown. This is a post hoc analysis of a randomized trial to investigate the
relationship between hypoglycemic episodes and changes in carotid intima-media thickness (IMT). Among
274 study subjects, 104 patients experienced hypoglycemic episodes. Increases in the mean IMT and left
maximum IMT of the common carotid arteries (CCA) were significantly greater in patients with
hypoglycemia compared to those without hypoglycemia. Classification of the patients into three groups
according to the frequency of hypoglycemic episodes showed that high frequency of hypoglycemic events
was associated with increases in mean IMT-CCA, and left max-IMT-CCA and right max-IMT-CCA. In addition,
repetitive episodes of hypoglycemia were associated with a reduction in the beneficial effects of sitagliptin
on carotid IMT. Our data suggest that frequency of hypoglycemic episodes was associated with changes in
carotid atherosclerosis.

While type 2 diabetes mellitus (T2DM) is a risk factor for cardiovascular disease (CVD), which is one of the
major causes of morbidity and mortality in these patients 1, large randomized clinical trials did not show the
benefits of strict glycemic control on CVD in patients with established atherosclerosis or longstanding
T2DM2–4. On the other hand, a recent study reported that the occurrence of hypoglycemia was associated with
increased risk of CVD and all-cause mortality in insulin-treated patients with type 1 diabetes mellitus (T1DM)
and T2DM5.
Hypoglycemia is a common adverse effect of management for diabetes, especially insulin therapy, and
a bar- rier to optimal glycemic control. Hypoglycemia affects blood constituents6,7, inflammatory cytokine
levels8,9, and coagulation and fibrinolysis factors10,11, all of which might promote the progression of
atherosclerosis. Indeed, the acute effects of hypoglycemia, such as sympatho-adrenal activation,
catecholamine release on inflammation, endothelial injury, and pro-atherothrombotic biomarkers12,13, are
well known in patients with T1DM. Also, a cross sectional study demonstrated that repeated episodes of
hypoglycemia were associated with preclinical ath- erosclerosis evaluated by carotid and femoral
echography and measurement of flow-mediated brachial dilatation

1
Department of Metabolism & Endocrinology, Juntendo University Graduate School of Medicine, Hongo 2-1-1,
Bunkyo-ku, Tokyo 113-8421, Japan. 2Department of Metabolic Medicine, Osaka University Graduate School of
Medicine, 2-2,Yamadaoka, Suita, Osaka 565-0871, Japan. 3Department of Metabolism and Atherosclerosis, Osaka
University Graduate School of Medicine, 2-2, Yamadaoka, Suita, Osaka 565-0871, Japan. 4Shiraiwa Medical Clinic,
4-10-24 Houzenji, Kashiwara, Osaka 582-0005, Japan. 5Department of Medicine, Diabetology & Endocrinology,
Juntendo Tokyo Koto Geriatric Medical Center, Shinsuna 3-3-20, Koto-ku, Tokyo 136-0075, Japan. 6Misaki Naika
Clinic, 6-44-9 Futawahigashi, Funabashi, Chiba 274-0805, Japan. 7Naka Memorial Clinic, 745-5, Nakadai, Naka City,
Ibaraki 311-0113, Japan. 8Osaka Police Hospital, 10-31 Kitayamacho, Tennoji-ku, Osaka 543-0035, Japan. 9Osaka
General Medical Center, 3-1-56 Bandai-Higashi, Sumiyoshi-ku, Osaka 558-8558, Japan. 10Department of Clinical
Trial and Clinical Medicine, University of Tsukuba, 1-1-1, Tennodai, Tsukuba, Ibaraki 305-8575, Japan. Correspondence and requests
Epidemiology, Faculty of for materials should be addressed to T.M. (email: tom-m@juntendo.ac.jp)

Scientific RepoRts | 7:39965 | DOI: 10.1038/srep39965 1

www.nature.com/scientificreports/

in patients with T1DM14. However, the long-term effect of hypoglycemia on the progression of atherosclerosis
remains largely unknown in patients with T2DM.
Sitagliptin, a dipeptidyl peptidase-4 (DPP-4) inhibitor, improves glycemic control without increasing the
risk of hypoglycemia15,16. Recently, we reported that sitagliptin treatment attenuated the increases in carotid
intima-media thickness (IMT) in insulin-treated patients with T2DM compared with the conventional treat-
ment17. In the same study, we demonstrated that sitagliptin treatment was superior to conventional treatment in
terms of HbA1c reduction without increasing the incidence of hypoglycemic episodes, consistent with previous
studies18–20. However, we have not investigated whether hypoglycemic events are associated with a reduction
in the beneficial effects of sitagliptin on the changes in carotid atherosclerosis.
The aim of the present post hoc-analysis was to investigate the relationship between hypoglycemic
events and changes in carotid IMT in insulin-treated patients with T2DM.
Results
Participants. In the original study, 104 of 274 patients experienced hypoglycemia (52 of the sitagliptin
group and 52 of the conventional group) over the 104 week follow-up. There was no significant
differences in the mean number of hypoglycemic events between the two groups (0.34 ± 0.85
episodes/month/person in the sitagliptin group vs 0.36 ± 0.80 in the conventional group). One episode of
severe hypoglycemic event occurred in each group. Subgroup analysis according to the occurrence of
hypoglycemia showed that patients with hypoglycemia were older, had lower estimated glomerular
filtration rate (eGFR) level, lower C-peptide level and had more fre- quent use of sulfonylurea and α-
glucosidase inhibitors, but were more lean, less likely to be smokers, had lower HbA1c, total-cholesterol,
triglyceride, hs-CRP (high-sensitivity C-reactive protein) and interleulin-6, and few use of glinides (Table
1).

Occurrence of hypoglycemia is associated with the changes in carotid IMT. Of the 274
patients in the original study, 243 patients with available carotid IMT data at baseline and 104 weeks were
included in this post hoc analysis. Among them, 98 patients experienced hypoglycemia (49 of the sitagliptin
group and 49 of the conventional group). In the analysis of covariance models that included the occurrence of
hypoglycemia, age, gen- der, baseline IMT and the original treatment group (model 1), the changes in mean
IMT of the common carotid arteries (mean-IMT-CCA) and left maximum IMT of the common carotid artery
(max-IMT-CCA), but not right max-IMT-CCA, were significantly higher in patients with hypoglycemia than
those without (Table 2). Similar findings were noted even in the adjusted models, including model 2 (model
1+ body mass index (BMI) + current smoking), model 3 (model 2 + HbA1c, total cholesterol, high density
lipoprotein-cholesterol, triglyceride and systolic blood pressure), model 4 (model 3+ eGFR + angiotensin-
converting enzyme inhibitors/angiotensin II receptor blocker, statins and anti-platelets), model 5 (model 4 +
sulfonylurea+ glinides+ α-glucosidase inhibi- tors), and model 6 (model 5 + C-peptide+ hsCRP+
interleukin 6).
Next, we performed subgroup analysis according to type of treatment. As shown in Table 3, the
mean-IMT-CCA was significantly increased relative to baseline in patients with hypoglycemia, but not in
those without hypoglycemia in the conventional group. In addition, the changes in mean-IMT-CCA and
left max-IMT-CCA tended to be greater in patients with hypoglycemia compared to those without. More
impor- tantly, in patients without hypoglycemia, the changes in mean-IMT-CCA and left max-IMT-CCA,
but not right max-IMT-CCA, were significantly smaller in the sitagliptin treatment group than those in
the conventional treat- ment group, while these findings were not observed in patients with hypoglycemia
(Table 3). These data showed that hypoglycemia was associated with a reduction in the beneficial effects
of sitagliptin.

Frequency of hypoglycemia is associated with changes in carotid IMT. Next, to investigate

the relationship between the frequency of hypoglycemia and changes in carotid IMT, we divided patients with
the occurrence of hypoglycemia into three groups; patients without hypoglycemia, patients with less than 1
times/month hypoglycemia, and patients with more than 1 times/month hypoglycemia. Trend asso- ciations
across three groups and changes in IMT were evaluated by univariate and multivariate linear regres- sion
analyses (Table 4). The frequency of hypoglycemia was associated with changes in mean-IMT-CCA and left
max-IMT-CCA, but not right max-IMT-CCA in unadjusted model (model 1). Almost similar findings were
noted even in the adjusted models, including model 2 (model 1 + baseline IMT), model 3 (model 2+ age +
gender + the original treatment group), model 4 (model 3+ BMI + current smoking), model 5 (model 4 +
HbA1c, total cholesterol, high density lipoprotein-cholesterol, triglyceride and systolic blood pressure), model
6 (model 5 + eGFR + angiotensin-converting enzyme inhibitors/angiotensin II receptor blockers, stat- ins
and anti-platelets), model 7 (model 6 + sulfonylurea + glinides + α-glucosidase inhibitors), and model 8
(model 7 + C-peptide+ hsCRP+ interleukin 6). In addition, analysis of data of the entire population showed
that increased frequency of hypoglycemia was associated with changes in mean-IMT-CCA (P for difference
among the three groups= 0.002), right max-IMT-CCA (P= 0.032), and left max-IMT-CCA (P= 0.02) (Fig.
1).

Changes in other parameters. The change in HbA1c (value at end of study - value at baseline) was
compa- rable between the hypoglycemia group (−0.2 ± 0.9%) and no-hypoglycemia group (−0.4 ± 1.1%)
(Supplementary Table 1). Similarly, there were no differences in changes in other risk factors for
atherosclerosis such as hyperten- sion and lipid parameters during the observation period (Supplementary
Table 1).
Discussion
Hypoglycemia is a common adverse effect of insulin treatment for T2DM 21. Previous studies demonstrated that
the frequency of hypoglycemic episodes remains unacceptably high even when DPP-4 inhibitors are added to
insulin therapy, although they did not increase the incidence of hypoglycemic episodes 18–20. The same appears
to be true in the present study. Indeed, the high frequency of hypoglycemic events is associated with increases

Scientific RepoRts | 7:39965 | DOI: 10.1038/srep39965 2

 Parameters Hypoglycemia group No-Hypoglycemia group P
(n= 104) (n= 170) value
Mean number of hypoglycemic events (n/month/person) 0.93 ± 1.13 0.00 ± 0.00 <0.001
Age (years) 65.6 ± 9.4 62.6 ± 10.0 0.014
Gender (males) (%) 59 (57) 106 (62) 0.38
Body Mass Index 24.3 ± 3.7 25.5 ± 4.2 0.021
Systolic blood pressure (mmHg) 130 ± 15 132 ± 15 0.24
Diastolic blood pressure (mmHg) 74 ± 10 75 ± 12 0.32
Current smoking 30 (22) 29 (21) 0.22
Hypertension 60 (58) 101 (59) 0.80
Dyslipidemia 61 (59) 114 (67) 0.19
Duration of diabetes (years) 18.6 ± 8.5 16.5 ± 8.5 0.053
HbA1c (%) 7.8 ± 0.8 8.2 ± 1.1 0.011
HbA1c (mmol/mol) 62.2 ± 8.9 65.8 ± 12.3 0.011
C-peptide (ng/ml) 0.32 ± 0.24 0.44 ± 0.25 <0.001
Total cholesterol (mmol/l) 4.79 ± 0.76 5.10 ± 0.94 0.005
LDL cholesterol (mmol/l) 2.67 ± 0.66 2.90 ± 0.78 0.014
HDL cholesterol (mmol/l) 1.47 ± 0.42 1.39 ± 0.35 0.09
Triglyceride (mmol/l) 1.04 (0.69, 1.69) 1.21 (0.97, 1.74) 0.008
eGFR (mL/min/1.73 m2) 73.9 ± 17.6 81.7 ± 24.9 0.006
UAE (mg/g creatinine ) 18.7 (7.1, 59.8) 19.7 (9.3, 88.2) 0.52
hsCRP (ng/dl) 380 (209, 911) 523 (264, 1340) 0.042
IL-6 (ng/dl) 1.5 (1.1, 2.2) 2.1 (1.4, 3.4) <0.001
ICAM-1 (ng/ml) 229 (193, 278) 228 (181, 265) 0.59
VCAM-1 (ng/ml) 736 (634, 920) 774 (662, 977) 0.22
Mean IMT-CCA (mm) 0.85 ± 0.20 0.83 ± 0.19 0.35
Right maximum IMT-CCA (mm) 1.10 ± 0.36 1.02 ± 0.34 0.073
Left maximum IMT-CCA (mm) 1.11 ± 0.35 1.10 ± 0.38 0.82
Use of oral glucose-lowering agents
Metformin 41 (39) 56 (33) 0.3
Sulfonylurea 21 (20) 11 (6) <0.001
Glinides 1(1) 20 (12) <0.001
Thiazolidinediones 9 (9) 15 (9) 1.00
α-glucosidase inhibitors 44 (42) 39 (23) 0.001
Use of anti-hypertensive agents
Angiotensin-converting enzyme inhibitors 4 (4) 8 (5) 1.00
Angiotensin II receptor blockers 50 (48) 72 (42) 0.38
Calcium channel blocker 30 (29) 54 (32) 0.69
Diuretic drugs 10 (10) 15 (9) 0.83
α-adrenergic receptor antagonist 2 (2) 2 (1) 0.64
β-adrenergic receptor antagonist 2 (1) 1 (1) 0.56
Use of lipid-lowering agents
Statins 46 (44) 83 (49) 0.53
Ezetimibe 8 (8) 6 (4) 0.16
Fibrates 3 (3) 4 (2) 1.00
Use of anti-thrombotic agents
Antiplatelet agents 23 (22) 36 (21) 0.88

Table 1. Clinical characteristics of patients of the two groups. Data are number (%) of
patients or mean± SD values or median (range) values. Differences in parameters between groups were
analyzed by the Student’s
t-test or Wilcoxon’s rank sum test for continuous variables and Fisher’s exact test for categorical variables.
CCA, common carotid artery; estimated glomerular filtration rate; ICAM-1, intercellular adhesion molecule 1;
IMT, intima-media thickness; ICAM-1, intercellular adhesion molecule 1; VCAM-1, vascular cell adhesion
molecule 1; IL-6, interleukin 6; hs-CRP, high-sensitivity C-reactive protein; UAE, urinary albumin excretion.

in carotid atherosclerosis. Previous studies identified several factors, such as BP, BMI22 and lipid parameters23,
but not hypoglycemic events, to be associated with the changes in carotid artery atherosclerosis in patients
with T2DM. Thus, this was the first study to demonstrate that frequent episodes of hypoglycemia are
associated with changes in carotid artery atherosclerosis in insulin-treated patients with T2DM.
While most clinical data showing associations between hypoglycemia and adverse CV risk/mortality risk
have derived from “serious hypoglycemic” episodes24–26, the effect of mild hypoglycemia on adverse CV
outcomes

Scientific RepoRts | 7:39965 | DOI: 10.1038/srep39965 3

 remains still unknown. On the other hand, virtually, this study showed the relation between frequency of
mild hypoglycemia and changes in IMT because most of the hypoglycemic episodes were mild. In this
regard, further prospective large sample size studies are required to address whether mild hypoglycemia is
also associated with adverse CV risk/mortality risk
In this study, patients with hypoglycemia were older, suffered more severe renal dysfunction, had less
endog- enous insulin and more frequent use of sulfonylurea. Thus, it is possible that hypoglycemia is only a
maker of patients with advanced stages of T2DM and/or those prone to CVD. However, the occurrence of
hypoglycemia was still associated with the changes in carotid IMT even after adjustment for these
confounders. Furthermore, the control of atherosclerosis risk factors was not consistently worse in patients
with the occurrence of hypogly- cemia because they were less obese, were less likely to be smokers, achieved
better glycemic and lipid controls and had lower serum levels of inflammatory cytokines, reflecting patients
who were at lower risk for CVD. Indeed, almost similar findings were observed in analysis of covariance
models after adjustment for those confounding factors. These data support that hypoglycemia by itself seem to
be a contributing factor for atherosclerosis.
The mechanism of the deleterious effect of hypoglycemia on carotid vascular wall may be
multidimensional and possibly involves changes in blood constituents6,7, inflammation8,9, and coagulation
and fibrinolysis10,11, through counter-regulatory defense responses to hypoglycemia. While these
responses and changes are transient and play a crucial role in protecting vital organs, previous studies
demonstrated that acute insulin-induced hypo- glycemia can provoke inflammatory response, platelet
aggregation and endothelial dysfunction in patients with T1DM12,27. Thus, the progression of atherosclerosis
may be accelerated if hypoglycemic episodes occur frequently. However, repeated episodes of relatively mild
hypoglycemia have been shown to reduce the counter-regulatory defense responses to hypoglycemia in
intensive treatment of T2DM28. Nevertheless, at least in Goto-Kakizaki rats, diabetic model rats, these
responses never disappear and enhance monocyte adhesion to endothelial cells in the aorta, leading to
increased intimal thickening29. In agreement with this finding, our data demonstrated that changes in
carotid atherosclerosis increased with increased number of hypoglycemic events.
What is the precise mechanism through which repeated episodes of hypoglycemia promote the progression
of atherosclerosis? In the present study, we did not find any association between serum biomarkers of
inflammation or endothelial injury and frequency of hypoglycemia or carotid IMT changes (data not shown). It
is possible that this negative relationship may be due to several limiting features of such biomarkers. Indeed,
the amount of such biomarkers is known to be affected by both transient and chronic non-atherosclerotic
diseases and drug treatment within a relatively short time 30. In the future, it would be interesting to determine
whether repeated episodes of hypoglycemia could affect plaque characteristics of the carotid arteries evaluated
by sophisticated studies such as Computed Tomography and Magnetic Resonance Imaging. These studies
might shed light on pro-inflammatory effects of repetitive hypoglycemia on the vasculature. Another
possibility is that hypoglycemia directly induced hypercatecholaminemia by acting on the vascular wall 29,31.
However, it is difficult to evaluate serum catecholamine levels during hypoglycemia in clinical setting. Further
studies are required to clarify the mechanism of the influence of hypoglycemia on the vasculature.
It is reported that glucagon-like peptide-1 (GLP-1) attenuates hypoglycemia-induced oxidative stress,
inflam- mation and endothelial dysfunction in patients with T1DM 27. Therefore, there is a great interest in
determining whether DPP-4 inhibitors play an important role in protecting against hypoglycemia-induced
vascular damages. In this regard, our data suggest that repetitive episodes of hypoglycemia are associated with
a reduction in the beneficial effects of sitagliptin on the changes in carotid atherosclerosis. The different results
may be due to the different subjects (T1DM vs. T2DM) or different levels of GLP-1 (DPP-4 inhibitor vs. GLP-
1). In any case, when DPP-4 inhibitors are used as add-on therapy to insulin therapy, one should take
precaution against potential hypoglycemia by, for example, reducing the dose of insulin.

Study limitations. The present study has certain limitations. First, this was a post hoc and exploratory
anal- ysis of a randomized unblinded trial and the sample size was relatively small. The analysis is limited by
the study design and this make the significance of the findings less clear. Thus, the results should be
interpreted with cau- tion. Second, we evaluated self-reported hypoglycemic events through self-monitoring of
blood glucose (SMBG) levels and hypoglycemic symptoms. Thus, there may be a risk of underestimation of
the incidence of hypoglyce- mic episodes. In an effort to overcome possible recall bias, we confirmed the
occurrence of hypoglycemia at each visit of each patient. Third, we did not evaluate hypoglycemia awareness
status. Since some episodes of non-severe hypoglycemia could be asymptomatic, they were unreported by
patients. Thus, we could not rule out possible underestimation of the deleterious effects of hypoglycemia on
carotid atherosclerosis. Fourth, there were some discrepancies in the results of carotid IMT although the results
showed a similar pattern. These differences may be due to the underpowered sample and side difference in
IMT-CCA32.

Conclusions
Our data suggest that frequent episodes of hypoglycemia were associated with changes in carotid
atherosclerosis in insulin-treated patients with T2DM. Physicians need to take care in avoiding the occurrence
of hypoglycemic episodes in the clinical setting in order to minimize the process of atherosclerogenesis.

Methods
Study population. We performed a post hoc analysis from the Sitagliptin Preventive study of Intima-
media thickness Evaluation (SPIKE). The study design, inclusion and exclusion criteria, study schedule and
measure- ments were described in detail previously17,33. Briefly, insulin-treated Japanese T2DM patients free of
past history of apparent CVD who periodically attended the Outpatient Diabetes Clinics at 12 centers across
Japan were asked to participate in this study. A total of 282 participants were randomly allocated to either the
sitagliptin

Scientific RepoRts | 7:39965 | DOI: 10.1038/srep39965 4

 Hypoglycemia No-Hypoglycemia Adjusted mean difference P
group group between groups value
Mean IMT-CCA (mean change from baseline; SE)
Model 1 0.027 (0.015) −0.023 (0.012) −0.050 (−0.088, −0.013) 0.009
Model 2 0.027 (0.015) −0.023 (0.012) −0.050 (−0.088, −0.012) 0.010
Model 3 0.031 (0.015) −0.023 (0.012) −0.054 (−0.093, −0.015) 0.007
Model 4 0.030 (0.015) −0.023 (0.012) −0.052 (−0.092, −0.013) 0.010
Model 5 0.026 (0.016) −0.020 (0.012) −0.047 (−0.088, −0.005) 0.027
Model 6 0.027 (0.016) −0.021 (0.013) −0.048 (−0.090, −0.006) 0.027
Right maximum IMT-CCA (mean change from baseline; SE)
Model 1 0.041 (0.035) −0.007 (0.029) −0.048 (−0.139, 0.043) 0.30
Model 2 0.039 (0.036) −0.006 (0.029) −0.046 (−0.138, 0.046) 0.33
Model 3 0.042 (0.036) −0.007 (0.029) −0.049 (−0.143, 0.046) 0.31
Model 4 0.042 (0.036) −0.007 (0.029) −0.049 (−0.143, 0.046) 0.31
Model 5 0.045 (0.037) −0.009 (0.030) −0.054 (−0.153, 0.045) 0.28
Model 6 0.049 (0.037) −0.012 (0.030) −0.061 (−0.160, 0.038) 0.22
Left maximum IMT-CCA (mean change from baseline; SE)
Model 1 0.027 (0.029) −0.053 (0.024) −0.081 (−0.155, −0.007) 0.032
Model 2 0.032 (0.029) −0.057 (0.024) −0.089 (−0.164, −0.014) 0.020
Model 3 0.036 (0.029) −0.057 (0.024) −0.093 (−0.169, −0.016) 0.017
Model 4 0.033 (0.029) −0.055 (0.024) −0.088 (−0.164, −0.012) 0.024
Model 5 0.029 (0.030) −0.053 (0.024) −0.082 (−0.161, −0.002) 0.045
Model 6 0.024 (0.031) −0.049 (0.024) −0.074 (−0.155, 0.008) 0.075

Table 2. Changes in intima-media thickness from baseline by analysis of

covariance models. Differences in delta change in IMT from baseline between two groups were
analyzed with analysis of covariance models that included the presence of hypoglycemia, age, gender, baseline
IMT and the original treatment group (Model 1), model 1 plus body mass index and current smoking (Model
2), model 2 plus HbA1c, total cholesterol, high density lipoprotein-cholesterol, triglyceride and systolic blood
pressure (Model 3), model 3 plus estimated glomerular filtration rate, use of angiotensin-converting enzyme
inhibitors/angiotensin II receptor blockers, use of statins and use of anti-platelets (Model 4), model 4 plus the
use of sulfonylurea, the use of glinides and the use of α-glucosidase inhibitors (Model 5), model 5 plus C-
peptide, high-sensitivity C-reactive protein and interleukin (Model 6). CCA, common carotid artery; IMT,
intima-media thickness.

group (n = 142) or the conventional treatment group (using drugs other than the DPP-4 inhibitor) (n =
140). Finally, 137 in the sitagliptin group and 137 in the conventional treatment group were included in
the full analysis set. Each participant underwent ultrasonography of the carotid arteries including mean-
IMT-CCA and in the right and left max-IMT-CCA performed by expert sonographers at the start of the
study, and the procedure was repeated after 52 and 104 weeks.
All patients who agreed to participate were entered into the study. The protocol was approved by the
Institutional Review Board of each participating institution (Juntendo University Graduate School of Medicine,
Osaka University Graduate School of Medicine, Juntendo Tokyo Koto Geriatric Medical Center, Naka
Memorial Clinic, Osaka Police Hospital, Osaka General Medical Center, Kansai Rosai Hospital, Sasebo Chuo
Hospital, Jiyugaoka Medical Clinic, Ikeda Municipal Hospital) in compliance with the Declaration of Helsinki
and current legal regulations in Japan. Written informed consent was obtained from all the participants after
full explanation of the study. This study has been registered on the University Hospital Medical Information
Network Clinical Trials Registry, which is a non-profit organization in Japan and meets the requirements of
the International Committee of Medical Journal Editors (UMIN000007396).

Definition of hypoglycemia. All adverse events including hypoglycemia were recorded at each visit
during study, as described previously17. During the study, participants were asked to submit their records of
SMBG and whether they had a sign and symptoms of hypoglycemia. Hypoglycemia was defined based on
confirmation by measurement of plasma glucose of ≤3.9 mmol/L and/or self-reported probable hypoglycemic
symptom. Severe hypoglycemia was defined as events requiring aid of another person to administer treatment.

Measurement of carotid IMT. Ultrasonographic scans of the carotid artery were performed by
expert sonographers who were specifically trained to perform the prescribed study examination, as
reported previ- ously17,33. To avoid inter-sonographer variability, each participant was examined by the
same sonographer with the same equipment throughout all the visits. To avoid inter-reader variability, all
scans were electronically stored and emailed to the central office (IMT Evaluation Committee, Osaka,
Japan) to be read by a single experienced reader blinded to the clinical features of the patients, in a
random order, using automated digital edge-detection software (Intimascope; MediaCross, Tokyo,
Japan)17,33. The software system averages 200 points of IMT values in the segment 2 cm proximal to the
dilation of the carotid bulb (mean-IMT-CCA). In addition, the greatest

Scientific RepoRts | 7:39965 | DOI: 10.1038/srep39965 5

 Parameters Hypoglyce Sitagliptin group Conventional P
mia group value
No −0.057 ± 0.140 (n= 72)§ 0.012 ± 0.138 (n= 73) 0.003
Change in mean IMT-CCA
Yes 0.012 ± 0.201 (n= 49) 0.042 ± 0.135 (n= 49)* 0.38
No −0.039 ± 0.243 (n= 72) 0.041 ± 0.412 (n= 73) 0.16
Change in right max IMT-CCA
Yes 0.062 ± 0.470 (n= 48) −0.007 ± 0.295 (n= 49) 0.39
No −0.105 ± 0.298 (n= 72)# −0.003 ± 0.304 (n= 73) 0.042
Change in left max IMT-CCA
Yes −0.005 ± 0.393 (n= 49) 0.060 ± 0.266 (n= 49) 0.34

Table 3. Changes in IMT from baseline at 104 weeks in patients treated with or
without sitagliptin in subgroup analysis based on the occurrence of
hypoglycemia. Data are mean± SD. Differences in parameters from baseline to 104 weeks within group were
analyzed by one-sample t-test. Differences in parameters from baseline to 104 weeks between groups were
analyzed by the Student’s t-test. *P < 0.05, #P< 0.01, §P< 0.001.

Regression
Variable coefficient (95% P
Confidence value
Interval)
Change in mean IMT-CCA
Model 1 0.047 (0.019–0.075) <0.001
Model 2 0.048 (0.021–0.075) <0.001
Model 3 0.043 (0.016–0.070) 0.002
Model 4 0.050 (0.012–0.088) 0.01
Model 5 0.054 (0.015–0.093) 0.007
Model 6 0.052 (0.013–0.092) 0.01
Model 7 0.047 (0.005–0.088) 0.027
Model 8 0.044 (0.014–0.074) 0.005
Change in right max IMT-CCA
Model 1 0.052 (−0.014–0.118) 0.12
Model 2 0.064 (0.001–0.128) 0.045
Model 3 0.058 (−0.005–0.122) 0.073
Model 4 0.046 (−0.046–0.138) 0.33
Model 5 0.049 (−0.046–0.143) 0.31
Model 6 0.049 (−0.046–0.143) 0.31
Model 7 0.054 (−0.045–0.153) 0.28
Model 8 0.069 (−0.002–0.139) 0.058
Change in left max IMT-CCA
Model 1 0.077 (0.019–0.134) 0.009
Model 2 0.078 (0.026–0.130) 0.004
Model 3 0.070 (0.018–0.123) 0.009
Model 4 0.089 (0.014–0.164) 0.02
Model 5 0.093 (0.016–0.169) 0.017
Model 6 0.088 (0.012–0.164) 0.024
Model 7 0.082 (0.002–0.161) 0.045
Model 8 0.069 (0.011–0.127) 0.021

Table 4. Trend associations across groups divided by frequency of

hypoglycemia and changes in IMT. Model 1: Trend estimation for linear trends across
quintiles is based on linear regression analysis for continuous variables unadjusted (Model 1), adjusted for
model 1 plus baseline IMT (Model 2), model 2 plus age, gender, baseline IMT and the original treatment
group (Model 3), model 2 plus body mass index and current smoking (Model 4), model 4 plus HbA1c, total
cholesterol, high density lipoprotein-cholesterol, triglyceride and systolic blood pressure (Model 5), model 4
plus estimated glomerular filtration rate, use of angiotensin-converting enzyme inhibitors/angiotensin II
receptor blockers, use of statins and use of anti-platelets (Model 6), model 6 plus the use of sulfonylurea, the
use of glinides and the use of α-glucosidase inhibitors (Model 7), model 7 plus C-peptide, high-sensitivity C-
reactive protein and interleukin (Model 8). CCA, common carotid artery; IMT, intima-media thickness.

thicknesses of IMT, including plaque lesions in the common carotid arteries (max-IMT-CCA) were also meas-
ured separately. The reproducibility of IMT measurement was very high as described previously 17.

Statistical analysis. Data were reported as mean± SD. Statistical analysis was performed using analysis
of covariance models that included several variables in addition to occurrence of hypoglycemia, such as age,
gender and baseline IMT (see Table 2 for details). Baseline and follow-up group comparisons were assessed
with the

Scientific RepoRts | 7:39965 | DOI: 10.1038/srep39965 6

 Figure 1. Changes in IMT according to the frequency of hypoglycemic episodes. Data are
mean± SD.

Student’s t-test or Wilcoxon’s rank sum test for continuous variables and Fisher’s exact test for categorical
varia- bles. Changes from baseline to treatment visits were assessed with one-sample t-test and Wilcoxon’s
signed rank test within the group. We categorized patients into the following three groups according to the
number of hypo- glycemic episodes during follow-up: 1) those with no episodes, 2) those with less than
one episode per month, and 3) those with one or more episodes. Comparisons among the three groups
were performed by one-way anal- ysis of variance. Trend associations across the three groups and
changes in IMT were evaluated by univariate and multivariate linear regression analyses. All statistical tests
were two-sided with 5% significance level. All analyses were performed using the SAS software version 9.4
(SAS Institute, Cary, NC).

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Acknowledgements
The authors thank all the collaborators, the clinical staff and members of and members of the committee
(Yoshimitsu Yamasaki, Nishi-Umeda Clinic for Asian Medical Collaboration; Kazunori Shimada and Hirotoshi
Ohmura, Department of Neurology, Juntendo University Graduate school of Medicine; and Ryota Tanaka,
Department of Cardiovascular Medicine, Juntendo University Graduate school of Medicine) for their
assistance with the execution and completion of the clinical trial. Financial support for this study was provided
by the Japan Society for Patients Reported Outcome research fund from Mitsubishi Tanabe, Ono and Novo
Nordisk.
Author Contributions
The authors meet the criteria for authorship recommended by the International Committee of Medical
Journal Editors and take full responsibility for all contents of the manuscript and editorial decisions. All
authors (T.M., N.Ka., T.S., H.Y., N.K., T.O., H.K., K.K., Y.U., M.G., I.S. and H.W.) contributed to the
study design and were involved at all stages of the study and manuscript development. T.M. and N.Ka.
drafted the manuscript. M.G. contributed to analysis of research data. All authors (T.M., N.Ka., T.S., H.Y.,
N.K., T.O., H.K., K.K., Y.U., M.G., I.S. and H.W.) were involved in analysis and interpretation of data,
reviewed/edited the manuscript and approved the final manuscript. I.S. and H.W. are the principal
guarantors of this work and have full access to all the data and take responsibility for the integrity of the
data and accuracy of data analysis.
Additional Information
Competing Financial Interests: TM received research funds from MSD and Takeda Pharma
K.K. and has received lecture fees from AstraZeneca K.K., Boehringer Ingelheim, Eli Lilly, Kowa
Pharmaceutical Co., Mitsubishi Tanabe Pharma Co., MSD, Ono Pharmaceutical Co., and Takeda
Pharmaceutical Co. NKa is a staff member of the endowed chair (Department of Metabolism and
Atherosclerosis) established by funds from Kowa Pharmaceutical Co., has received research funds from
MSD and lecture fees from Astellas Pharma Inc., AstraZeneca K.K., Boehringer Ingelheim, Daiichi Sankyo
Inc., Dainippon Sumitomo Pharma Co., Eisai Co., Eli Lilly, Kowa Pharmaceutical Co., Mitsubishi Tanabe
Pharma Co., Novartis Pharmaceuticals, Novo Nordisk Pharma, Ono Pharmaceutical Co., Otsuka
Pharmaceutical, Shionogi & Co., Takeda Pharmaceutical Co., Sanofi-Aventis, and Shionogi & Co. TS has
received lecture fees from Boehringer Ingelheim, Sanofi-
Aventis, Novo Nordisk Pharma, Novartis Pharmaceuticals, Eli Lilly, Abbott Japan, Takeda Pharmaceutical Co.,
Sanwakagaku Kenkyusho, Mitsubishi Tanabe Pharma Co., Daiichi Sankyo Inc., Astellas Pharma Inc., Ono
Pharmaceutical Co., MSD, Shionogi, Pharma, and Taisho Toyama Pharmaceutical Co. NKu has received lecture
fees from Sanofi-Aventis and Novartis Pharmaceuticals. TOs has received lecture fees from Novo Nordisk,
Inc., Astellas Pharma, Inc., Mitsubishi Tanabe Pharma, Sanwakagaku Kenkyusho, Takeda Pharmaceutical
Co., Kowa Co. and research funds from Novo Nordisk, Inc., Astellas Pharma, Inc., Mitsubishi Tanabe
Pharma, Sanwakagaku Kenkyusho, Kowa Co. Novo Nordisk Pharma, Dainippon Sumitomo Pharma., Eli
Lilly Taisho
Pharmaceutical Co., Ltd., GlaxoSmithKline, Sumitomo Dainippon Pharma Co., Ltd., Astellas Pharma US,
Inc., Bayer HealthCare, and AbbVie GK. KK has received lecture fees from Boehringer Ingelheim, Sanofi-
Aventis, Novo Nordisk Pharma, Novartis Pharmaceuticals, Eli Lilly, Takeda Pharmaceutical Co., MSD, Kowa
Co., Mitsubishi Tanabe Pharma and research funds from Sysmex Co. HK has received lecture fees from
Boehringer Ingelheim, Sanofi-Aventis, Ono Pharmaceutical Co., MSD, Novo Nordisk Pharma, Novartis
Pharmaceuticals, Daiichi Sankyo Inc., Takeda Pharmaceutical Co., Kissei Pharmaceutical Co., Dainippon
Sumitomo Pharma Co., Mitsubishi Tanabe Pharma Co., Kyowa Kirin, Eli Lilly, Pfizer, Astrazeneca, Astellas
Pharma Inc. and research funds from Takeda Pharmaceutical Co., MSD, Mochida Pharmaceutical Co. Sanofi-
Aventis, Novartis Pharmaceuticals, Novo Nordisk Pharma, Eli Lilly, Daiichi Sankyo Inc., Shionogi Pharma,
Teijin Pharma, Dainippon Sumitomo Pharma Co., Otsuka Pharmaceutical, Kissei Pharmaceutical Co.,
Mitsubishi Tanabe Pharma Co., Ono Pharmaceutical Co., Astrazeneca, Astellas Pharma Inc., and Kyowa
Hakko Kirin Co.
KK has received lecture fees from Boehringer Ingelheim, Sanofi-Aventis, Novo Nordisk Pharma, Novartis
Pharmaceuticals, Eli Lilly, Takeda Pharmaceutical Co., MSD, Kowa Co., Mitsubishi Tanabe Pharma and
Scientific RepoRts | 7:39965 | DOI: 10.1038/srep39965 8
 research funds from Sysmex Co. MG received lecture fees from Novartis and Tiho Pharma K.K. and
received travel fees from Takeda Pharmaceutical Co. and writing fee from Kowa Co., Ltd. IS has received
lecture fees from Astellas Pharma Inc., AstraZeneca K.K., MSD K.K., Ono Pharmaceutical Co., Kyowa
Hakko Kirin Co., Kowa Pharmaceutical Co., Sanofi K.K., Sanwa Kagaku Kenkyusho Co., Daiichi Sankyo
Co., Takeda Pharma K.K., Mitsubishi Tanabe Pharma Co., Teijin Pharma, Eli Lilly Japan K.K., Nippon
Boehringer Ingelheim Co., Novartis Pharma K.K., Novo Nordisk Pharma, Bayer Yakuhin, Pfizer Japan Inc.,
Bristol-Myers K.K., Mochida Pharmaceutical Co., Shionogi & Co., Taisho Toyama Pharmaceutical Co.,
Shionogi & Co., and research
funds from Astellas Pharma Inc., AstraZeneca K.K., Eisai Co., MSD K.K, Otsuka Pharmaceutical Co., Ono
Pharmaceutical Co., Kaken Pharmaceutical Co., Kissei Pharmaceutical Co., Kyowa Hakko Kirin Co., Sanofi
K.K., Shionogi & Co., Daiichi Sankyo Co., Dainippon Sumitomo Pharma Co., Takeda Pharma K.K.,
Mitsubishi Tanabe Pharma Co., Teijin Pharma, Nippon Boehringer Ingelheim Co., Novartis Pharma K.K.,
Novo Nordisk Pharma, Pfizer Japan Inc., Bristol-Myers K.K., Mochida Pharmaceutical Co., Eli Lilly Japan
K.K, Kowa Co., Ltd., Kowa Pharmaceutical Co., and Taisho Toyama Pharmaceutical Co. HW has received
lecture fees from Novo Nordisk, Inc., Eli Lilly and Company, Sanofi, Dainippon Sumitomo Pharma Co.,
Fujifilm, Bayer Health Care, Kissei Pharmaceutical Company, Mochida Pharmaceutical Company, MSD,
Takeda Pharmaceutical Company, Boehringer Ingelheim Pharmaceuticals, Inc., Daiichi-Sankyo, Ono
Pharmaceutical Co., Ltd., Novartis Pharmaceuticals Corporation, Mitsubishi Tanabe Pharma Corporation,
AstraZeneca LP, Kyowa Hakko Kirin Comapany, Ltd, Sanwa Kagaku Kenkyusyo Company, Ltd., Kowa
Company Ltd, Astellas Pharma, Inc., advisory fees from Novo Nordisk, Inc., Mochida Pharma Company,
AstraZeneca LP, Kowa Company, Astellas Pharma, Inc., Sanofi, Boehringer Ingelheim Pharmaceuticals, Inc.,
MSD, Mitsubishi Tanabe Pharma Corporation, Novartis Pharmaceuticals Corporation, Dainippon Sumitomo
Pharma Co, Takeda Pharmaceutical Company, Ono Pharmaceutical Co, Pfizer, Inc., Kowa Company and
research funds from Boehringer Ingelheim, Pfizer, Mochida Pharmaceutical Co., Sanofi-Aventis, Novo
Nordisk Pharma, Novartis Pharmaceuticals, Sanwakagaku Kenkyusho, Terumo Corp. Eli Lilly, Mitsubishi
Tanabe Pharma, Daiichi Sankyo Inc., Takeda Pharmaceutical Co., MSD, Shionogi, Pharma, Dainippon
Sumitomo Pharma, Kissei Pharma, and Astrazeneca.
How to cite this article: Mita, T. et al. Relationship between frequency of hypoglycemic episodes
and changes in carotid atherosclerosis in insulin-treated patients with type 2 diabetes mellitus. Sci. Rep. 7,
39965; doi: 10.1038/ srep39965 (2017).
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Scientific RepoRts | 7:39965 | DOI: 10.1038/srep39965 9