China Diabetes Registry - a Prospective Cohort Study of Patients With Diabetes in National Metabolic Management Centers in China
Conditions: Type 2 Diabetes Mellitus, Type1 Diabetes Mellitus, Monogenetic Diabetes, Pancreatogenic Diabetes, Drug-Induced Diabetes Mellitus, Other Forms of Diabetes Mellitus
Sponsor: Guang Ning

Protocol
China Diabetes Registry - a Prospective Cohort Study of Patients
with Diabetes in National Metabolic Management Centers (MMC) in
China
Study Protocol
(Version 2.1)
Protocol Number：CCEMD-2018-1201
ClinicalTrials.gov Number: NCT03811470
Protocol Date:
1st March 2022
Sponsor: Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai,
PR China
Principle Investigator：
Prof. Guang Ning, MD, PHD, Shanghai National Research Centre for Endocrine and
Metabolic Diseases, State Key Laboratory of Medical Genomics, Shanghai Institute for
Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of
Medicine, Shanghai, China
Prof. Weiqing Wang, MD, PHD, Shanghai National Research Centre for Endocrine and
Metabolic Diseases, State Key Laboratory of Medical Genomics, Shanghai Institute for
Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of
Medicine, Shanghai, China

TABLE OF CONTENT
TABLE OF CONTENT
1.
Background.................................................................................................................................1
2.
the Principles of MMC...............................................................................................................2
3.
Data collection............................................................................................................................6
4.
Objective and Long-term Vison of the MMC............................................................................6
5.
Study Population........................................................................................................................ 7
6.
Questionnaires............................................................................................................................ 8
6.1 Questionnaire Overview.......................................................................................................8
6.2 Questionnaire Implementation.............................................................................................8
6.3 the Baseline Questionnaire...................................................................................................9
6.3.1 General Information................................................................................................ 10
6.3.2 Medical History.......................................................................................................10
6.3.3 Medication Use........................................................................................................12
6.3.4 Lifestyle Exposures.................................................................................................13
6.4 Follow-up Questionnaires.................................................................................................. 14
7.
Physical Measurements............................................................................................................ 15
7.1 Height and Weight..............................................................................................................16
7.2 Head, Neck, Waist and Hip Circumference....................................................................... 16
7.3 Blood Pressure....................................................................................................................17
7.4 Visceral and Subcutaneous Fat...........................................................................................17
8.
Clinical Examination................................................................................................................18
8.1 Baseline Laboratory Tests.................................................................................................. 18
8.1.1 HbA1c Measurements.............................................................................................18
8.1.2 Glucose Tolerance Test............................................................................................19
8.2 Baseline Examination of Diabetes-related Complications................................................ 19
8.2.1 Fundus Photography................................................................................................19
8.2.2 Screening for Diabetic Neuropathy.........................................................................20
8.2.3 Measurements of brachial-ankle pulse wave velocity (baPWV) and ankle-brachial
index (ABI).......................................................................................................................20
8.2.4 Carotid Ultrasonography.........................................................................................21
8.2.5 Electrocardiogram (ECG) and Echocardiogram.....................................................21
8.3 Clinical Examination at Follow-up Visits..........................................................................22
9.
Clinical Outcome Measures..................................................................................................... 22
9.1
Primary
outcome
measures:
The
primary
outcomes
include
incidence
of
all
diabetes-related clinical endpoints........................................................................................... 22
9.2 Secondary Outcome Measures...........................................................................................25
9.3 Safety measures..................................................................................................................26
9.4 Exploratory measures.........................................................................................................26
10. Quality assurance and quality control measures for clinical operation...................................26
11.
Geographical disparity............................................................................................................. 31
REFERENCES.................................................................................................................................32

Protocol Version 2.1 1/3/2022
1 / 35
1. Background
The prevalence of diabetes and its related disease burden was increased
dramatically in the past decades. It showed that, according to the report from World
Health Organization (WHO), the prevalence of diabetes was about 150 million around
the world in 2000. With 6% increase every year, it is estimated to reach 300 million
by the year 2025. This situation is worse in Asia, especially in China [1-3]. A general
population-based survey, involving data from 98,658 adult individuals in China, using
2010 criteria of the American Diabetes Association (ADA), indicated that the
prevalence of diabetes and prediabetes in Chinese adults was 11.6% and 50.1%,
respectively [1]. These findings indicated that China has the largest absolute diabetes
disease burden worldwide. This is followed by an increase in the country's economic
burden and health care expenses for diabetes and its related complications. And this
cost reached 30 billion and more every year, accounting for 8 percent of the health
care cost in total. What is more frightening is that the economic expenditure on
diabetes care is expected to increase in the future [4, 5].
The reasons behind were complicated. However, rapid changes of lifestyle, social
aging, and accelerated obesity might be the potential reasons for the increase in the
incidence of diabetes [1, 6]. Moreover, China now faces several challenges when
dealing with the problems in diabetes prevention and management. First, contrary to
the high prevalence of diabetes, the rate of awareness and control of diabetes were
relatively low and unsatisfactory. Extensive and efficient health education in the
whole population is insufficient. Moreover, with the serious imbalance in the

Protocol Version 2.1 1/3/2022
2 / 35
physician to patient ratio, it is difficult to achieve early diagnosis and adequate care of
diabetes and its complication. Second, the existing hospital facilities and management
system can hardly meet the requirement of the quick increase in diabetes population.
Inconvenient and time-consuming tests procedure make it difficult to diagnosis for
diabetes and its complications. Moreover, according to the Healthy China 2030
strategy, the management of chronic diseases like diabetes should be handled at
different levels, which was called a tiered medical services policy. However, there are
difficulties in the implementation of this policy which might be caused by the wide
variations in the economy, cultural, and medical service standards in different regions
all around the country. Therefore, it is necessary to form a pilot and standard system,
integrating with advanced technologies, which can be followed and copied in different
regions nationwide, so as to deal with the challenges in management of diabetes and
its related complications. Therefore, in 2016, the National Metabolic Management
Center (MMC) was firstly established and promoted nationwide.
2. ONE CENTER, ONE STOP, AND ONE STANDARD MODEL IN THE
MMC
All MMCs in China have the same structure in terms of facilities, layout, and
databases, as well as the same routine daily operations, aiming to establish a platform
with standardized diagnosis and treatment of metabolic diseases and their long-term
follow-up. This platform of treatment is called the ‘One Center, One Stop, and One
Standard Model’ (Figure 1). In the MMCs, patients can enjoy one-stop care to receive

Protocol Version 2.1 1/3/2022
3 / 35
a comprehensive series of services from registration, tests, evaluation, prescriptions,
appointment follow-up, to health education. Under the guidance of the MMC Experts
Committee, 492 stringent standard operational procedures (SOPs) are set up for
quality control of the MMC operation (Figure 2). And we have also published MMC
Guideline,
Metbolic
Disease
Management
Guideline
for
National
Metbolic
management Center which includes guidelines for diabetes diagnosis and treatment as
well as the the process of management in MMC [7]. Furthermore, with technological
innovations, for example, the “all-in-one machine” (Figure 1), by the ingenious
integration of the examination equipments, greatly shortens the process for the
screening of complications. In addition, the MMC has established an independent
digital medical record system integrating real-time information of patients in and
outside the hospital into a centralized medical data center that can be exported
through various Internet of Things (IoT) instruments, including apps, Wechat, and a
teleconsultation system, to enable patient care to be extended from the MMC to
anytime, anywhere outside the center (Figure 3).

Protocol Version 2.1 1/3/2022
4 / 35
Figure 1. MMC's typical equipment and layout
Figure 2. Displays of MMC's SOP

Protocol Version 2.1 1/3/2022
5 / 35
Figure 3. Internet-based electronic database management and patient care system for
MMC program

Protocol Version 2.1 1/3/2022
6 / 35
3. Data collection
We
encoded
four
metadata
categories
and
devised
numerous
of
data
cleaning/conversion rules to create a proprietary electronic medical record system
covering thousands of metabolic disease indicators. Leveraging HBee's intelligent
HIS data acquisition, we gathered data on more than 1,000 examination/test indicators.
Natural Language Processing (NLP) & Optical Character Recognition (OCR) in our
MDoc engine analyze imaging reports, enhancing data quality. For unequipped
MMCs, manual data entry and registration ensure complete data collection. During
our data analysis, we ensure the desensitization of sensitive information related to
patients' personal privacy.
4. OBJECTIVE AND LONG-TERM VISION OF THE MMC
The objective of the MMC is to launch a new metabolic disease management model
based on the Internet health information platform. Moreover, the MMC helps improve
adherence to and the effectiveness of treatment for patients, thus benefitting both
patients and doctors. The proprietary electronic medical database in the MMC will
make dynamic big-data analysis in diabetes epidemiology, prevention, diagnosis, and
treatment very efficient and effective. Furthermore, this nationwide standardized care
system also forms a collaborative research network for prospective interventional
studies on treatment and prevention. Therefore, in the long run, the MMC will offer
large amounts of data and evidence from hospital-based care to achieve long-term
optimal health outcomes, enabling a replicable standard care model across the entire
country that can form the base for future healthcare policy improvement.

Protocol Version 2.1 1/3/2022
7 / 35
Objective
1. To establish a multi-center nationwide prospective database of diabetes patients in
MMCs, including clinical data, biological samples library so as to explore the
epidemiology, genetics, new biomarkers, risk factors, and prognostic methods related
to diabetes and its complications, as well as other metabolic diseases.
2. To collect cross-sectional data from patients seen and treated at each MMC centers
so as to evaluate: the current status of care of patients with diabetes and its related
complications, as well as other risk factors treatment strategies at these centers.
Patients’ costs and quality of life (QoL) will also be evaluated.
3. To collect the prospective data of patients treated at each MMC centers in order to
evaluate the strategies for the achievement of treatment
goals, changes in
management, control of risk factors, incidence and progression of all-diabetes related
clinical endpoints (including mortality), behavioral changes, psychological well-being
as well as costs and QoL.
5. Study Population：
All the patients who are seen and treated at each MMC centers, and meet the
Inclusion/Exclusion Criteria will be included in this study.
Main Inclusion Criteria:

Age ≥18 years old

Diagnosis of diabetes according to the diagnostic criteria for diabetes at
the time of enrollment.

Gender: males and females

Fully understand the study and provide written informed consent

Protocol Version 2.1 1/3/2022
8 / 35

With satisfactory compliance
Main Exclusion Criteria:

Patients with significantly reduced life expectancy (less than 5 years)

With Drug abuse

With Acquired Immune Deficiency Syndrome (AIDS) or syphilis or
infectious diseases such as viral hepatitis or tuberculosis in active phase at
enrollment
6. Questionnaires
6.1 Questionnaire Overview
Both baseline and follow-up questionnaires were designed to comprehensively collect
metabolic diseases-related information. The questionnaires integrated the basic
history collection requirements with the routine items of cohort studies in the area of
diabetes [8, 9] and enabled us to examine modifiable and unmodifiable factors. All
these data were collected through a proprietary electronic medical record system in
MMC [10].
6.2 Questionnaire Implementation
All the questionnaire information can be collected by trained staff after informed
consent. Furthermore, part of the questionnaire can be filled in by the patients
themselves (patient-side) through downloading the MMC APP under guidance. The
completed patient-side questionnaire (e.g., general information, symptoms, part of the
medical history) needs to be checked and confirmed by the staff to guarantee the
accuracy and authenticity.

Protocol Version 2.1 1/3/2022
9 / 35
6.3 the Baseline Questionnaire
The required baseline questionnaire can be subdivided into the following sections:
general information, medical history, family history (cancer, diabetes, cardiovascular
diseases, obesity and hyperlipidemia), symptoms, medication use, menstrual and
reproductive history (e.g., for females, the menopausal history), birth and feeding
history, lifestyle exposures and pregnancy (for women of childbearing age). The
questions assessed in each required section are listed in Table 1. The other optional
chapters for the baseline questionnaire such as basic knowledge structure of diabetes,
diabetic psychology, diabetes skills and abilities (e.g., EuroQol Five Dimensions
Questionnaire [EQ-5D]) will also be obtained.
Table 1. Required questionnaire data collected in each MMC (according to follow-up
visits arranged within each year)
Variables
Arranged follow-up visits
Baseline
Month 3
Month 6
Month 9
Year 1
General information
Unique identifier
√
Birthdate
√
Sex
√
Ethnicity
√
Origin and birthplace
√
Blood type
√
Education level
√
Retirement status
√
Occupation
√
Economic level
√
Marital status
√
Whether the spouse has
joined MMC
√
Medical history
Diabetes mellitus
√

Protocol Version 2.1 1/3/2022
10 / 35
Hypertension
√
Hyperlipidemia
√
Coronary artery disease
√
Stroke
√
Heart failure
√
Tumor
√
Peripheral artery disease
√
History of trauma and
surgery
√
Other diseases
√
Symptoms
√
√
Family history
√
Medication use
√
√
√
√
√
Menstrual and reproductive
history (for females)
√
Birth and feeding history
√
Lifestyle exposures
Smoking
√
√
Alcohol consumption
√
√
Dietary habit
√
√
Physical activity
√
√
Sleep
√
√
Pregnancy (for females)
If
applicable
If
applicable
If
applicable
If
applicable
If
applicable
Adverse events
√
√
√
√
6.3.1 General Information
Multiple demographic and socioeconomic questions have been included (Table 1).
Education level is defined as below high school, or high school and above. The
unique identifier can be used not only to identify different patients, but also to capture
data. In addition, the telephone number is required for registration, which is essential
for telephone follow-up and access to the text message of appointment.
6.3.2 Medical History

Protocol Version 2.1 1/3/2022
11 / 35
The information collected in the section of medical history is shown in Table 1. The
diagnosis of diabetes is confirmed if the participant has a self-reported history of
diagnosed diabetes by professionals, and/or fasting blood glucose (FBG) ≥7.0
mmol/L, and/or 2h postprandial blood glucose (PBG) ≥11.1 mmol/L according to the
1999 World Health Organization (WHO) diagnostic criteria [11]. Since 2021,
glycated hemoglobin (HbA1c) ≥6.5% was added into the diagnostic criteria for
diabetes in accordance with 2020 guidelines for the prevention and treatment of type
2 diabetes in China. The duration of diabetes is determined by the following criterion:
1) the accurate time diagnosed with diabetes patients provided; 2) Newly diagnosed
with diabetes (patients reported never diagnosed with diabetes before), the duration of
diabetes is “0”; 3) if the information of whether diagnosed with diabetes before is not
available and the laboratory examination meets the criterion of diabetes, the
information of diabetic duration is missing.
1) Types of diabetes
At each MMC, a qualified medical practitioner was responsible for determining the
specific type of diabetes. Participants with type 1 diabetes (T1DM), gestational
diabetes mellitus (GDM), and other specific forms of diabetes were excluded from the
study. In cases where the type of diabetes was unclear, T1DM was diagnosed based
on the presence of glutamic acid decarboxylase antibodies (GADA) and low
C-peptide concentrations (<0.8 ng/mL). A comprehensive review of medical records
and laboratory tests, including thyroid and adrenal hormone profiles, and other

Protocol Version 2.1 1/3/2022
12 / 35
relevant parameters, was conducted to exclude rare or unusual cases of diabetes. For a
more detailed account of these diagnostic procedures, please refer to our previously
published article [12].
2) Other metabolic related disease
(1) Hypertension: Ever diagnosed by physicians; or when measuring the clinic blood
pressure on three different days without the use of antihypertensive medications,
systolic blood pressure (SBP) is ≥140mmHg and/or diastolic blood pressure (DBP)
is ≥90mmHg. If a patient has a history of hypertension and is currently taking
antihypertensive medications, even if their blood pressure is lower than 140/90mmHg,
they should still be diagnosed with hypertension.
(2) Hyperlipidemia: Ever diagnosed by physicians; or when enrolled in MMC,
laboratory tests showed LDL-C ≥3.4 mmol/L (130 mg/dl) and / or TG≥1.7
mmol/L (150 mg/dl).
(3) The prevalent cardiovascular diseases are defined as meeting any of these
conditions: (a) stroke or (b) myocardial infarction or other coronary heart disease or (c)
heart failure. Please refer to the “9. Clinical Outcome Measures” for details.
6.3.3 Medication Use
All medications which have been used regularly in the recent 3 months before
enrollment
are
required
to
be
registered,
which
include
glucose-lowering,
antihypertensive, and lipid -lowering drugs and other drugs. The staff record usage,
dosage, start date, end date, adjustment date of each agent in detail, which can meet

Protocol Version 2.1 1/3/2022
13 / 35
the wide range of needs for scientific research.
6.3.4 Lifestyle Exposures
The lifestyle information encompasses smoking, alcohol, dietary habits, physical
activities as well as sleep. The smoking and drinking sections contain questions
relating to smoking/drinking habits (at present and in the past), amount, type, as well
as duration. The current smoking and drinking status are defined as “yes” if the
frequency is daily (or almost daily) and weekly (or almost weekly), respectively. We
also define ideal smoking if the participant has never smoked or stopped smoking for
more than 12 months.[13] Definition about smoking and drinking habits may be
changed in certain analysis.
In the dietary part, we collect the usual dietary intake during the past 12 months.
The dietary questionnaire evaluated in China Noncommunicable Disease and Risk
Factor Surveillance and the Risk Evaluation of Cancers in Chinese Diabetic
Individuals (REACTION) study [8, 9] was simplified and adapted to be suitable for
real-world clinical settings. The diet components that have greater evidence regarding
their close association with metabolic diseases were retained, and a semi-quantitative
design was adopted. The questionnaire involves the following food items: fresh fruits,
fresh vegetables, fish, soy products, salt and sweets/sugar-sweetened beverages.
Adapted from the American Heart Association (AHA) 2020 Impact goals [13], a diet
score can be calculated based on the following five healthy diet components: more
intake for fruits and vegetables (≥4.5 cups/d), fish (≥two 3.5-oz servings/week), and
soy protein (≥25 g/d), less intake for salt (< 4g/d salt) and sweets/sugar-sweetened

Protocol Version 2.1 1/3/2022
14 / 35
beverages [14]. Other definitions for low salt intake (≤6g/d or ≤8g/d salt) are also
explored for their relation to clinical outcome measures. The U.S. Department of
Agriculture (USDA) nutrition plate is referred for details.
The level of physical activities at work and leisure time is obtained. With respect to
physical activity at leisure time, the International Physical Activity Questionnaire
(IPAQ) is adopted [15], which records physical activity in terms of intensity,
frequency and duration. It is a healthy lifestyle behavior if the participant performs
≥150
min/week
of
moderate-intensity
physical
activity,
≥75
min/week
of
vigorous-intensity physical activity, or ≥150 min/week of moderate-intensity and
vigorous-intensity physical activity. In addition, the quality and duration of sleep are
also surveyed.
6.4 Follow-up Questionnaires
Planned follow-up surveys will be conducted every 3 months from baseline. The
follow-up questionnaires are specified in standard operating procedures (SOPs) and
presented in Table 1 (taking one year as an example). Symptoms and lifestyle factors
will be collected at one-year interval. For each follow-up visit, patients' actual
medication use and adverse events (with pre-defined categories of diseases) needs to
be recorded repeatedly and registered in the electronic medical record system.
Adverse events refer to any adverse medical events that occur during the patient's
visit, which could be any unwell sign, symptom, disease, or laboratory abnormality.
The registered adverse events mainly include cardio-cerebrovascular events, severe
hypoglycemia, cancer, hospitalization, laser coagulation treatment for diabetic

Protocol Version 2.1 1/3/2022
15 / 35
retinopathy (DR), and other adverse events that local doctors judge necessary to
record. Details are formulated in the corresponding chapter ('Assessing and Recording
of Adverse Events').
For patients who have been lost to facility-based follow-up, the staff will be
proposed to make a telephone follow-up. If the call gets through and death is learned,
death registration (e.g., date, causes of death) will be completed by the staff. Hospital
records and death certificates will be supplemented if available.
7. Physical Measurements
Height, weight and blood pressure are recorded at each visit. Head circumference is
obtained at the baseline visit without repeated measurements later. Circumferences
of neck, waist and hip, visceral fat area (VFA) and subcutaneous fat area (SFA) are
recorded once a year. VFA and SFA measurements is required for regional MMC,
and optional for county and community MMC (Table 2).
Table 2. The required items for physical measurements and clinical examination in
different levels of MMC (according to follow-up visits arranged within each year)
Variables
Arranged follow-up visits
Baseline
Month 3*
Month 6
Month 9*
Year 1
Physical measurements
Height and weight
□○△
□○△
□○△
□○△
□○△
Blood pressure and heart rate
□○△
□○△
□○△
□○△
□○△
Head circumference
□○△
Neck, waist and hip
circumference
□○△
□○△
VFA and SFA
□
□
Laboratory tests
Blood and urine routine
□○△
□○△
Biochemical tests
□○△
□○△
□○△
□○△
□○△
HbA1c
□○△
□○△
□○△
□○△
□○△

Protocol Version 2.1 1/3/2022
16 / 35
FBG
□○△
□○△
□○△
□○△
□○△
PBG
□○△
□○△
Fasting serum
insulin/C-peptide
□○
□○
Postprandial insulin/C-peptide
□○
□○
UACR
□○△
□○△
□○△
Islet autoantibodies
□
Thyroid hormone
□
Examination of
diabetes-related
complications
Fundus examination
□○△
□○△
Screening for diabetic
neuropathy
□○
□○
Measurements of baPWV and
ABI
□○
ECG
□○
Echocardiogram
□○
Carotid Ultrasonography
□○
□,○,△: representing the requirements for regional, county, and community MMC, respectively;
* denotes the visits not required by quality control; VFA: visceral fat area; SFA: subcutaneous fat
area; HbA1c, glycated hemoglobin; FBG, fasting blood glucose; PBG, postprandial blood glucose;
UACR, urinary albumin-to-creatinine ratio; baPWV, brachial-ankle pulse wave velocity; ABI,
ankle-brachial index.
7.1 Height and Weight
Height and body weight will be measured by a height-weight scale with participants
removing shoes and heavy outer clothing. Several parameters which are accurate to
one decimal place including height in centimetres, weight in kilograms and BMI
calculated as the weight in kilograms divided by height in meters squared will be
displayed on the screen.
7.2 Head, Neck, Waist and Hip Circumference
In addition to height and weight, the patient's head, neck, waist, and hip

Protocol Version 2.1 1/3/2022
17 / 35
circumference should also be measured. Head circumference will be measured by a
measuring tape through superciliary arch (just above the eyebrows) and occipital
protuberance. Neck circumference will be recorded below the laryngeal prominence.
Waist circumference will be measured midway between lateral lower ribs and the
upper margin of the iliac crest for standing participants. Hip circumference is the
maximal width of the buttocks. The staff have been trained to ensure that the
measurements can be performed correctly. All measurements will be accurate to one
decimal place.
7.3 Blood Pressure
After at least a 5-minute rest, blood pressure and heart rate will be measured using an
automated electronic device in the seated position. The elbow of the arm used for
measurement need to be supported at heart level. The monitor will automatically
upload the systolic and diastolic blood pressure and heart rate readings to the MMC
electronic database system.
7.4 Visceral and Subcutaneous Fat
VFA and SFA will be measured by a dual bioelectrical impedance analyzer
(DUALSCAN, HDS2000, Omron Healthcare Co.). An abdominal measuring device
will be attached around the abdomen at the umbilical level to measure abdominal
shape, so as to calculate the total abdominal cross-sectional area. The fat-free area is
calculated by the axial abdominal impedance generated when the current flows
through the four limbs by four electrodes on hands and feet. When a current is applied
to eight electrodes placed at the level of umbilicus, the measured abdominal surface

Protocol Version 2.1 1/3/2022
18 / 35
impedance is used to calculate SFA. SFA and fat-free area is finally subtracted from
the total abdominal cross-sectional area to calculate VFA. The visceral fat increase is
defined as VFA ≥100 cm2 or otherwise specified.
8. Clinical Examination
The organizational structure of MMC consists of the MMC leading center, regional
centers, county centers, and community centers. Different setting standards for MMCs
at each level have been described in detail in the guide[16]. Overall, comprehensive
laboratory tests and examination of complications related to diabetes are carried out at
baseline and annual visits in regional or county MMC. It is proposed to refer the
patients at community MMCs to regional or county MMCs nearby at initial and
subsequent annual visits for comprehensive examination. Follow-up visits are
implemented to record patients’ clinical progress, thereby providing important
information for establishing and modulating treatment strategies. Schedules for
clinical examinations at each visit during one year can be found in Table 2.
8.1 Baseline Laboratory Tests
The required baseline laboratory tests at different levels of MMC are shown in Table
2.
Islet
autoantibodies
mainly
involve
insulin
cell
antibody
(ICA),
insulin
autoantibody (IAA) and glutamic acid decarboxylase antibody (GAD-Ab), and it is
proposed to detect GAD-Ab at least to help classify the type of diabetes. All
laboratory tests will be performed in local sites.
8.1.1 HbA1c Measurements
Local
HbA1c
for
regional
and
county
MMCs
should
be
measured
by

Protocol Version 2.1 1/3/2022
19 / 35
high-performance liquid chromatography (HPLC).
8.1.2 Glucose Tolerance Test
For the glucose tolerance test, participants will be required to fast overnight to
undergo a standard steamed bread meal test. First, at fasting, blood is drawn for
measuring fasting blood glucose (FBG), fasting serum C peptide and/or insulin, liver
and kidney function, blood lipid profiles and other laboratory tests. For postprandial
measurements, 100 g steamed bun will be given. After the first bite, the patients will
have blood drawn 2 hours later in order to measure postprandial blood glucose (PBG),
postprandial serum C peptide and insulin. Under certain circumstances, 3h oral
glucose tolerance test (OGTT) in five time points will be undertaken. Participants are
forbidden to smoke, drink or eat anything throughout the glucose tolerance test.
Patients who have been diagnosed with diabetes take their hypoglycemic and other
agents normally during the test.
8.2 Baseline Examination of Diabetes-related Complications
8.2.1 Fundus Photography
Fundus examination is performed for all diabetic patients by an experienced and
trained technician. One color macula-centered fundus image will be acquired from
each eye. Fundus images are taken without pupil dilation and with a 45-degree field
of view. The worse diabetic retinopathy (DR) classification of the two eyes will be
chosen as the final patient-level DR grade. The status of DR is defined as “yes” if
mild non-proliferative DR (NPDR) or above is present. We describe DR grade by

Protocol Version 2.1 1/3/2022
20 / 35
following definitions: referable DR (moderate NPDR or above); vision-threatening
DR (VTDR, severe NPDR or above and/or clinically significant macular edema
[CSME])[12]. The definition for VTDR may be modulated and specified in certain
studies.
8.2.2 Screening for Diabetic Neuropathy
To assess diabetic peripheral neuropathy (DPN), electromyography is prioritized in
hospitals where conditions are available. The instrument (NC-stat® DPN Check™)
can also be used to measure the amplitude and conduction velocity (CV) of the sural
nerve in legs of the patient. The amplitude has been found to decrease by about 1 μV
per decade with age. Sural nerve conduction velocity is correlated with age and height,
decreasing by 1.3 m/s per 10 years and 2.0 m/s per 10 cm height. After entering age
and height, the device will automatically determine the status of DPN (normal, mild,
moderate or severe) according to the levels of amplitude and CV with reference to the
calculated normal limit.
8.2.3 Measurements of brachial-ankle pulse wave velocity (baPWV) and
ankle-brachial index (ABI)
The noninvasive measurements of baPWV and ABI will be performed using an
automated recording apparatus (BP-203RPE III, form PWV/ABI or HBP-8000,
Omron Healthcare Co.) in the supine position after resting for at least 5 minutes[17].
Suitable cuffs will be attached to participants around both arms and ankles to take
measurements of both the brachial and tibial arteries by a trained operator. BaPWV
values will be calculated as dividing the transit distance (the distance from the heart to

Protocol Version 2.1 1/3/2022
21 / 35
the ankle minus the distance from the heart to the arm) by the transmission time,
which equals to the time interval from the initial increase in the brachial to that of
tibial artery waveforms[18]. The mean or greater value of the right and left baPWV
will be analyzed. Generally, the upper quartile of baPWV is defined as arterial
stiffness. The systolic blood pressure (SBP) at the ankle is divided by the SBP at the
upper arm to calculate the indicator ABI, which is used to screen peripheral arterial
disease.
8.2.4 Carotid Ultrasonography
Carotid intima-media thickness (IMT) as well as plaques is examined using a Doppler
apparatus. The location to measure IMT of the common carotid artery (C-IMT) is the
distal wall of the common carotid artery, 10 mm proximal to the bifurcation[19]. An
average or larger value of C-IMT on the left and right sides will be recorded for
analysis. Carotid plaque will be determined as “yes” if the plaque is present in either
side of the carotid and its branches.
8.2.5 Electrocardiogram (ECG) and Echocardiogram
The patients will undergo ECG and echocardiographic examinations to detect cardiac
abnormalities. Structured report will be recorded for analysis. In the ECG report, the
cardiac rhythm and diagnosis will be required to record. In the echocardiographic
report, besides the final diagnosis information, the following parameters will also be
obtained: left atrial diameter (LAD), interventricular septal thickness, left ventricular
internal diameter in systole and diastole, posterior wall thickness of left ventricle, left
ventricular ejection fraction (LVEF), and inner diameter of aortic root.

Protocol Version 2.1 1/3/2022
22 / 35
8.3 Clinical Examination at Follow-up Visits
According to the standard protocol, two to four follow-up visits every year are
arranged for enrolled patients, with the same follow-up frequency formulated for
regional, county, or community MMCs. The actual number of visits may be changed
depending on patients’ condition and compliance. The flow chart for clinical
examination at each visit within one-year period are listed in Table 2. The clinical
examination in the follow-up stage beyond one year are also performed with reference
to Table 2.
Urinary albumin-to-creatinine ratio (UACR) will be collected every six months to
define the status of proteinuria. Fundus photography and screening for diabetic
neuropathy will be performed annually. The patients with moderate DR or worse will
be referred to the ophthalmology department for further examination and treatment.
Carotid ultrasonography, baPWV and ABI will be evaluated at least 3 times during the
5-year follow-up period (baseline, year 2 or year 3, and year 5). ECG and
echocardiogram will be arranged at least twice within 5 years (baseline and year 5).
The screening frequency of diabetes related complications may be adjusted if
necessary.
9. Clinical Outcome Measures
9.1 Primary outcome measures: The primary outcomes include incidence of all
diabetes-related clinical endpoints:
1) Mortality
(1) Total mortality;
(2) Cardiovascular mortality: includes fatal myocardial infarction (MI), death due

Protocol Version 2.1 1/3/2022
23 / 35
to stroke, fatal congestive heart failure, unexpected death presumed to be due
to ischemic cardiovascular disease, death due to documented arrhythmia, and
death due to other cardiovascular diseases;
(3) Fatal renal failure
2) The Macrovascular morbidity
(1) Coronary heart disease
a)
non-fatal MI or ischaemic heart disease
b)
Coronary revascularization or coronary artery bypass surgery
c)
Percutaneous transluminal coronary angioplasty (PTCA)
(2) Carotid angioplasty with or without stent; Carotid endarterectomy
(3) Peripheral vascular disease
a)
Peripheral angioplasty with or without stent;
b)
Peripheral vascular surgery (including aortic aneurysm repair);
c)
Peripheral circulatory disorders;
d)
Peripheral vascular disease;
e)
Limb amputation due to vascular disease;
f)
Gangrene.
(4) Stroke
a)
Ischaemic stroke (a nonvascular etiology must be absent);
b)
Intracerebral haemorrhage;
c)
Subarachnoid haemorrhage;
d)
Other and unspecified intracranial haemorrhage;
e)
Stroke of unknown type etiology.
3) Non-fatal congestive heart failure
4) The Microvascular morbidity
(1) Diabetic kidney disease (DKD):
a)
Chronic kidney disease: Estimated glomerular filtration rate (eGFR) <60
ml/min/1.73m2 (as estimated by the EPI equation, eGFR=141 ×
min(Scr/κ, 1)α × max(Scr/κ, 1)-1.209 × 0.993Age × 1.018 [if female] _ 1.159

Protocol Version 2.1 1/3/2022
24 / 35
[if black], where Scr is serum creatinine in mg/dl, κ is 0.7 for females
and 0.9 for males, α is -0.329 for females and -0.411 for males, min
represents the minimum of Scr/κ or 1, and max represents the maximum
of Scr/κ or 1).
b)
End-stage renal disease: Estimated glomerular filtration rate (eGFR) <15
ml/min/1.73m2, or need dialysis, or need renal transplant
c)
Development of microalbuminuria (urinary albumin/creatinine ratio
[UACR] ≥30 and < 300mg albumin per gram creatinine, or UACR ≥
3.39 and < 33.9 mg/mmol in a random sample)
d)
Development of macroalbuminuria (urinary albumin/creatinine ratio
[UACR] ≥300mg albumin per gram creatinine, or UACR ≥33.9
mg/mmol in a random sample)
(2) Diabetic retinopathy (DR):
a)
If both eyes' images were evaluable, the more severe DR grade between
the two was adopted.
b)
If only one eye's image was gradable, the DR grading relied solely on
that eye.
c)
If no gradable image was available for either eye, the patient was
classified as ungradable.
d)
In cases of discrepancy between the on-site and qualified AI result, the
more severe DR grade was selected.
e)
Any occurrence of the following adverse events was classified as an
incidence of DR: undergoing laser treatment or therapy with
anti-vascular endothelial growth factor (VEGF) inhibitors, experiencing
vitreous/preretinal hemorrhage, clinically significant macular edema
(CSME), undergoing vitrectomy, or developing diabetes-related
blindness.
5) Neuropathy
6) Cancer:

Protocol Version 2.1 1/3/2022
25 / 35
The occurrence of any of the cancers include prostate, breast, lung/bronchus,
endometrial, colon, gastric, leukemia, lymphoma, pancreas, kidney/renal pelvis, rectal,
and melanoma;
7) Major infections: include chronic and acute infections, pulmonary and
non-pulmonary;
8) Hospitalization for any of the above reasons.
9.2 Secondary Outcome Measures:
1) Glycated haemoglobin (HbA1c, %)
2) Fasting and postprandial glucose concentrations (mmol/L)
3) fasting and 2-hour postprandialinsulin and C peptide levels, as well as the
variables derived from these measurements (homeostasis model assessment index
for assessing insulin resistance [HOMA-IR and HOMA2-IR]
4) Lipids levels include triglyceride, total cholesterol, high density
lipoprotein-cholesterol (HDL-c) and low density lipoprotein-cholesterol (LDL-c)
5) Blood pressures (mmHg)
6) Body weight, and BMI: Body weight (kg) and height (m) will be combined to
report BMI in kg/m2
7) Visceral fat (cm2) and subcutaneous fat (cm2)
8) Health related quality of life
9) Cognitive function
10) Other anthropometric parameters, include head, neck, waist, and hip
circumferences
11) Carotid plaque and carotid intima-media thickness;
12) Brachial-ankle pulse wave velocity (baPWV) and ankle-brachial pressure index
(ABI)
13) Psychological well being, using physiological parameter, questionnaire
14) The incremental cost per quality adjusted life year (QALY) gained. QALYs will
be measured by the EuroQol-5 Dimensions (EQ-5D) questionnaire.

Protocol Version 2.1 1/3/2022
26 / 35
9.3 Safety measures:
1) Hypoglycemia: any hypoglycemic episode (blood glucose concentration <70
mg/dl [3.9 mmol/l]), and severe hypoglycemic episodes requiring third party
assistance;
2) The alterations of vital signs, 12-lead ECG,
3) Laboratory abnormalities, include blood biochemistry, blood and urine routine
measures;
4) Adverse events (type, frequency, severity, relationship of adverse events to drug
therapies).
9.4 Exploratory measures:
Explore the epidemiology, genetics, new biomarkers, risk factors, and prognostic
methods related to diabetes and its related complications, as well as other metabolic
diseases.
10. Quality assurance and quality control measures for clinical operation
The MMC's four-tiered prevention and control network infrastructure consists of
the MMC leading center (MMC in Ruijin hospital, Shanghai Jiao Tong University
School of Medicine, Shanghai), regional centers, county centers, and community
centers (Figure 4). The MMC leading center establishes a comprehensive set of
written standard operating procedures (SOPs), which are then provided to all MMCs
to ensure quality assurance (QA) throughout every stage, from site construction to
clinical operations. This ensures a uniform and high-quality approach to disease
management across the entire network.

Protocol Version 2.1 1/3/2022
27 / 35
Figure 4. MMC four-level prevention and control network infrastructure

Protocol Version 2.1 1/3/2022
28 / 35
During the initial stage, all staff members in each center, encompassing doctors,
nurses, and technicians, will undergo comprehensive training via the MMC's
specialized internet-based SOPs training platform. Engineers will also be responsible
for conducting on-site training sessions to ensure proficiency in equipment operation.
It is mandatory for the center staff to complete all relevant online courses and pass the
subsequent examination receiving certification of qualification before commencing
patient enrollment (Figure 5).
Figure 5. Certificate of qualification awarded to MMC staff after training
An independent electronic system for data acquisition, tracking, and management
has been developed. This system provides real-time and automatic monitoring of data,
enabling the prompt detection of any abnormal or out-of-range values. In such cases,
the platform automatically sends correction reminders or queries to alert center staff.
This prompts them to review data entries and make timely corrections. Additionally,
to facilitate constant quality improvement across all centers, a free online support
service and a WeChat working group are available to provide prompt assistance and
solutions to any arising issues.

Protocol Version 2.1 1/3/2022
29 / 35
Once the baseline data entries for the initial 20 consecutive patients in each center
have been completed, the quality control (QC) team from the MMC leading center
will promptly conduct a remote data quality evaluation. Feedback and any queries
arising from this evaluation will be promptly communicated to the respective centers
for correction. Following the completion of baseline data entry for 200 consecutive
patients, a second remote manual QC will be carried out to assess the operational
quality and facilitate center certification. Once these steps are completed, each center
will be subject to regular and ongoing data monitoring. Additionally, an automated
monthly online QC report will be generated and made available online to ensure
consistent operational quality across all centers.
An offline QC process has been established to guarantee precise clinical operations.
First, each center is required to have a dedicated local QC staff member who will
conduct a self-assessment based on the established SOPs and monthly QC reports,
making necessary corrections as identified. Second, a clinical research associate from
a third-party organization will conduct regular on-site monitoring. This includes
checking clinical procedures, sample collection methods, verifying the consistency of
source data with original medical records and online entries, as well as monitoring the
follow-up process. Third, well-performing MMCs regularly hold sharing sessions to
disseminate their experiences to other MMCs (Figure 6).
Furthermore, audits conducted by specialists from the MMC Quality Control Group
will be conducted regularly to oversee both the standardization of facilities and
workflow, as well as the operational procedures of staff members in each center.
These audits ensure the maintenance of high-quality standards across all centers.

Protocol Version 2.1 1/3/2022
30 / 35
Figure 6. MMC online and off-line training, experience sharing
To evaluate and enhance the overall quality of the centers, an annual quality
ranking will be performed for all centers nationwide. This ranking will be based on
various metrics, including the center's participant enrollment capacity, the quality of
clinical data, the follow-up rate of participants, and their overall management abilities.

Protocol Version 2.1 1/3/2022
31 / 35
The superior centers will be awarded an honorary certificate (Figure 7). Centers that
fail to pass the quality assessment for two consecutive years will be required to
undergo rectification and improvement measures. Centers that fail to pass the
re-assessment process after rectification will not be recertified, thus will be not
allowed to be involved in subsequent scientific research analysis. This ensures that
only centers meeting the highest standards of quality are certified and continue to
participate in the program.
Figure 7. Certificate awarded to superior MMCs
11. Geographical disparity
All patients are respectively divided into seven regions according to the location of
MMC they MMC they enrolled (Table 3).
Table 3. Provinces/autonomous region/municipality in 7 regions of China
Region
Provinces
East China
Shanghai, Jiangsu, Zhejiang, Anhui, Fujian, Jiangxi, Shangdong,
Taiwan
South China
Guangdong, Guangxi, Hainan, Hong kong, Macao
North China
Beijing, Tianjin, Shanxi, Heibei, Inner Mongolia
Central China
Henan, Hubei, Hunan
Northeast
Heilongjiang, Jilin, Liaoning
Southwest
Sichuan, Guizhou, Yunnan, Chongqing, Tibet
Northwest
Shaanxi, Gansu, Qinghai, Ningxia, Xinjiang

Protocol Version 2.1 1/3/2022
32 / 35
REFERENCES
[1] Xu Y, Wang L, He J, Bi Y, Li M, Wang T, et al. Prevalence and control of diabetes in Chinese adults.
JAMA. 2013;310:948-59.
[2] Collaborators GBDRF. Global, regional, and national comparative risk assessment of 84 behavioural,
environmental and occupational, and metabolic risks or clusters of risks, 1990-2016: a systematic
analysis for the Global Burden of Disease Study 2016. Lancet. 2017;390:1345-422.
[3] Ning G. Decade in review-type 2 diabetes mellitus: At the centre of things. Nat Rev Endocrinol.
2015;11:636-8.
[4] Hu H, Sawhney M, Shi L, Duan S, Yu Y, Wu Z, et al. A systematic review of the direct economic
burden of type 2 diabetes in china. Diabetes Ther. 2015;6:7-16.
[5] Huang Y, Vemer P, Zhu J, Postma MJ, Chen W. Economic Burden in Chinese Patients with Diabetes
Mellitus Using Electronic Insurance Claims Data. PLoS One. 2016;11:e0159297.
[6] Bloomgarden Z, Ning G. Diabetes and aging. J Diabetes. 2013;5:369-71.
[7]. Wang W, Wang G, Wang Y, Ning G, Qu S, Liu P, et al. The construction standards and management
guideline for national metabolic management center. Chin J Endocrinol Metab 2019; 35(11): 907-26
[8] Bi Y, Lu J, Wang W, Mu Y, Zhao J, Liu C, et al. Cohort profile: risk evaluation of cancers in Chinese
diabetic individuals: a longitudinal (REACTION) study. J Diabetes. 2014;6:147-57.
[9] Bi Y, Wang L, Xu Y, Jiang Y, He J, Zhang M, et al. Diabetes-related metabolic risk factors in internal
migrant workers in China: a national surveillance study. Lancet Diabetes Endocrinol. 2016;4:125-35.
[10] Zhang Y, Wang W, Ning G. Metabolic Management Center: An innovation project for the
management of metabolic diseases and complications in China. J Diabetes. 2019;11:11-3.
[11] Gabir MM, Hanson RL, Dabelea D, Imperatore G, Roumain J, Bennett PH, et al. The 1997
American Diabetes Association and 1999 World Health Organization criteria for hyperglycemia in the
diagnosis and prediction of diabetes. Diabetes Care. 2000;23:1108-12.
[12] Zhang Y, Shi J, Peng Y, Zhao Z, Zheng Q, Wang Z, et al. Artificial intelligence-enabled screening for
diabetic retinopathy: a real-world, multicenter and prospective study. BMJ Open Diabetes Res Care.
2020;8.
[13] Lloyd-Jones DM, Hong Y, Labarthe D, Mozaffarian D, Appel LJ, Van Horn L, et al. Defining and
setting national goals for cardiovascular health promotion and disease reduction: the American Heart
Association's strategic Impact Goal through 2020 and beyond. Circulation. 2010;121:586-613.
[14] Bi Y, Jiang Y, He J, Xu Y, Wang L, Xu M, et al. Status of cardiovascular health in Chinese adults. J Am
Coll Cardiol. 2015;65:1013-25.
[15] Craig CL, Marshall AL, Sjostrom M, Bauman AE, Booth ML, Ainsworth BE, et al. International
physical activity questionnaire: 12-country reliability and validity. Med Sci Sports Exerc.
2003;35:1381-95.
[16] MMC Academic Committee MEAC, MMC council, et al. National Metabolic Management Center
Construction Standard and Management Guideline. Chin J Endocrinol Metab. 2019;35:907-26.
[17] Wang S, Shi J, Peng Y, Fang Q, Mu Q, Gu W, et al. Stronger association of triglyceride glucose index
than the HOMA-IR with arterial stiffness in patients with type 2 diabetes: a real-world single-centre
study. Cardiovasc Diabetol. 2021;20:82.
[18] Li M, Zhan A, Huang X, Hu L, Zhou W, Wang T, et al. Positive association between triglyceride
glucose index and arterial stiffness in hypertensive patients: the China H-type Hypertension Registry
Study. Cardiovasc Diabetol. 2020;19:139.

Protocol Version 2.1 1/3/2022
33 / 35
[19] Engelen L, Ferreira I, Stehouwer CD, Boutouyrie P, Laurent S, Reference Values for Arterial
Measurements C. Reference intervals for common carotid intima-media thickness measured with
echotracking: relation with risk factors. Eur Heart J. 2013;34:2368-80.