Research Highlights

The Diabetic Nephropathy (DN) cohort at Khoo Teck Puat Hospital (KTPH) (Alexandra Health Pte Ltd) has been initiated since 2002. It includes ~ 5,499 multi-ethnic patients with type 2 diabetes (age 58.3 ± 11.7 years old, duration of diabetes 12.0 ± 8.7 years, Chinese 67.5%, Malays 19.1%, Asian Indians 13.3% and others 0.2%). Blood and urine samples collected at baseline visit have been cryo-preserved. In collaboration with local and overseas institutions, we aim to study biomarkers (both genetic and non-genetic) associated with the development and progression of DN in multi-ethnic Asians with diabetes.

The cohort is enriched by subjects with renal impairment in accordance with the aim of the study (MDRD eGFR 67.8 ± 37.7 ml/min/1.73m2, CKD stage 1- 28.1%, stage 2-31.3%, stage 3-20.8%, stage 4- 9.0% and stage 5-10.7%). Approximately 30.0% of the subjects are classified as having microalbuminuria (urinary albumin-to-creatinine ratio, .i.e. ACR 30 to 299 mg/g) and 27.7% of them are classified as having macroalbuminuria (ACR >= 300 mg/g). The longitudinal trajectory of eGFR and ACR has also been recorded in a large proportion of the subjects.

The median follow-up duration of this cohort is 5.7 years. Incident diabetes related outcomes can be ascertained by linkage of cohort database with Singapore National Disease registries (Renal Registry, Myocardial Infarct Registry, Death/birth Registry, Stroke Registry and Cancer Registry).

Publications:

1. Genetic markers for urine haptoglobin is associated with decline in renal function in type 2 diabetes in East Asians. Gurung RL, Dorajoo R, Liu S, M Y, Liu JJ, Wang L, Guo L, Yu X, Liu JJ, Lim SC. Sci Rep. 2018 Mar 23;8(1):5109. doi: 10.1038/s41598-018-23407-1
2. Ong YH, Koh WCA, Ng ML, Tam ZY, Lim SC, Boehm BO; Adult-Onset Autoimmune Diabetes Mellitus Consortium (ADAMS). Glutamic acid decarboxylase and islet antigen 2 antibody profiles in people with adult-onset diabetes mellitus: a comparison between mixed ethnic populations in Singapore and Germany. Diabet Med. 2017 Aug;34(8):1145-1153. doi: 10.1111/dme.13358.
3. Liu JJ, Ghosh S, Kovalik JP, Ching J, Choi HW, Tavintharan S, Ong CN, Sum CF, Summers SA, Tai ES, Lim SC. Profiling of Plasma Metabolites Suggests Altered Mitochondrial Fuel Usage and Remodeling of Sphingolipid Metabolism in Individuals With Type 2 Diabetes and Kidney Disease. Kidney International Reports. 2017 May 31;2(3):470-80.
4. Low S, Lim SC, Yeoh LY, Liu YL, Liu JJ, Fun S, Su C, Zhang X, Subramaniam T, SUM CF. The effect of long term glycemic variability on estimated glomerular filtration rate decline among patients with type 2 diabetes mellitus–insights from the Diabetic Nephropathy Cohort in Singapore. Journal of Diabetes. 2016 Dec 1.
5. Low S, Lim SC, Zhang X, Zhou S, Yeoh LY, Liu YL, Tavintharan S, Sum CF. Development and validation of a predictive model for Chronic Kidney Disease progression in Type 2 Diabetes Mellitus based on a 13-year study in Singapore. Diabetes Research & Clinical Practice 2016; 123:49-54
6. Liu JJ*, Liu S*, Wong MDS, Gurung RL and Lim SC. Urinary haptoglobin predicts rapid renal function decline in Asians with type 2 diabetes and early kidney disease. J Clin Endo Metab 2016; 101(10):3794-3802 (* equal contributors)
7. SC Lim*, R Dorajoo*, X Zhang, L Wang, SF Ang, C Tan, Yeoh LY, XW Ng, Na Li, Chang Su, S Liu, M Wong, S Low, AY Ou, Jeevith B, S Fun, SY Zhou, Simon BM Lee, WE Tang, Subramaniam T, CF Sum, JJ Liu. Genetic variants in the receptor for advanced glycation end products (RAGE) gene were associated with circulating soluble RAGE level (sRAGE), but not with renal function among Asians with type 2 diabetes: a genome-wide association study. Neph Dial Transplant 2016; Jul 21. pii: gfw263. [Epub ahead of print]
8. Liu JJ, Lim SC, Yeoh LY, Su C, Tai BC, Low S, Fun S, Tavintharan S, Chia KS, Tai ES and Sum CF. Ethnic disparities in risk of cardiovascular disease, end stage renal disease and all-cause mortality- a prospective study among South East Asians with type 2 diabetes. Diabetic Medicine 2016; 33(3):332-9
9. Low S, Lim SC, Yeoh LY, Su C, Zhang X, Subramaniam T, Sum CF. Long-term diabetes outcomes in multi-ethnic Asians living in Singapore. Diabetes Res Clin Pract 2016; 111: 83-92.
10. Low S, Tai ES, Yeoh LY, Liu YL, Liu JJ, Tan KH, Fun S, Su C, Zhang X, Subramaniam T, Sum CF, Lim SC. Onset and progression of kidney disease in type 2 diabetes among multi-ethnic Asian population. J Diabetes Complications 2016; 30(7): 1248-54.
11. Liu JJ, Liu S, Morgenthaler NG, Wong MDS, Tavintharan S, Sum CF, Lim SC. Association of soluble α-klotho with endothelin-1 in type 2 Diabetes. Atherosclerosis 2014;233(2):415-418
12. Lim SC*, Liu JJ*, Tavintharan S and Sum CF. Elevated circulating alpha-klotho by angiotensin II receptor blocker losartan is associated with reduction of albuminuria in type 2 diabetic patients. Journal of renin-angiotensin-aldosterone system. 2014;15(4):487-90
13. Liu JJ, Liu S, Wong MDS, Tan CS, Tavintharan S, Sum CF and Lim SC. Relationship between circulating irisin, renal function and body composition in type 2 diabetes. J Diabetes Complications 2013;28(2):208-213
14. Liu JJ, Wong MDS, Toy WC, Tan CSH, Liu S, Ng XW, Tavintharan S, Sum CF and Lim SC. Lower circulating irisin is associated with type 2 diabetes mellitus. J Diabetes Complications (with editorial comments) 2013;27(4):365-369
15. JJ Liu, WC Toy, Melvin DS Wong, Clara SH Tan, Subramaniam T; MS Wong, CF Sum and SC Lim. Elevated undercarboxylated and reduced carboxylated osteocalcin are associated with metabolic syndrome in middle age Asian females. Exp Clin Endocrinol Diabetes. 2013;121:329-33. doi: 10.1055/s-0033-1334883.
16. Lim SC, Phua E J, Sharon F Nne, Amizah B Asrap, Wong DS Melvin, Tan SH Clara, Liu J Jun, Toy W Ching, Ng X Wei, Lau PX Dawn, Pek LT Sharon, Woon Kaing, Lin LF Bernice, S Tavintharan, Sum C Fang. Modifiable risk factors associated with arterial stiffness in diabetic nephropathy in an Asian Population Cohort. Journal of ASEAN Federal Endocrine Societies (JAFES) 2011; 26:163-167
17. SC Lim, Dollyn Quek L, WC Toy, Melvin Wong DS, Lee Ying Yeoh, C Tan MF, D Lau, C Tan, T Subramaniam, C F Sum. Adipocytokine zinc alpha-2 glycoprotein (ZAG) as novel urinary biomarker for normo-albuminuric diabetic nephropathy. Diabetic Medicine 2012;29:1-5
18. Toy W C, Liu JJ, Anton Cheng KS, C Tan, D Lau, M Wong, T Subramaniam, Sum C F, Lim SC. Adiponectin Gene Polymorphisms and Type 2 Diabetes among Singaporean Chinese Adults. J Diabetes Metab 2011, 2:8
19. S.C. Lim, J. J. Liu, H. Q. Low, N. G. Morgenthaler, Y. Li, L. Y. Yeoh, Y. S. Wu, S.K. Goh, C. Y. Chionh, S. H. Tan, Y. C. Kon, P. C. Soon, Y. M. Bee, T. Subramaniam, C. F. Sum, K. S. Chia. Microarray analysis of multiple candidate genes and associated plasma proteins for nephropathy secondary to type 2 diabetes among Chinese. Diabetologia 2009 52:1343-51
20. Lim, Su-Chi; Morgenthaler, Nils; Subramaniam, Tavintharan; Wu, Yew-Seng; Goh, Siew-Kheng; Sum, Chee-Fang. The relationship between adrenomedullin, metabolic factors and vascular function in individuals with type 2 diabetes mellitus. Diabetes Care 2007;30:1513-1519
21. SC Lim, H H Tan, SK Goh, T Subramaniam, CF Sum, I K Tan, B L Lee, C N Ong. Oxidative Burden in Pre-diabetic and Diabetic Individuals: Evidence from Plasma Coenzyme Q10. Diabetic Med 2006 23: 1344-1349
22. SC Lim, T Goh, YR Lai, WW Tee, Angela Koh, XH Xu, YS Wu, Eric Yap, T Subramaniam, C F Sum. Relationship between common functional polymorphisms of the p22phox gene (-930A>G & +242 C>T) and nephropathy due to type 2 diabetes among Chinese. Diabetic Medicine 2006 23:1037-1041

DORIS (Diabetic Kidney Disease – Onset and Progression Risk Factors Cohort)

Introduction

In November 2017, we set up a new cohort to better understand the natural history of diabetic kidney disease (DKD) in multi-ethnic Singaporeans with type 2 diabetes (T2DM). We aim (1) to collect and archive DNA, plasma blood and urine samples for study of novel risk factors, biomarkers, and pathophysiological pathways associated with DKD development and progression in the future; (2) to understand the scope of the problem of poor diabetes self-care, poor medication adherence and poor appointment keeping in patients with T2DM; and (3) to examine the relationship between poor diabetes self-care, poor medication adherence and poor appointment keeping, and risk of chronic kidney disease (CKD) outcomes in T2DM. We aim to recruit 1,920 subjects into this study.

Hypothesis

1. Progression of DKD in individuals with T2DM is determined by a network of risk factors interweaving dynamically and temporally on the background of hyperglycemia. Management of DKD should be guided by individualized risk profiles and underlying pathophysiology.
2. Poor self-care behaviour, poor medication adherence and poor appointment keeping are independently associated with CKD progression.

Study Procedures

In this study, we are collecting demographic and anthropometric data, smoking history, social economic status, history of cardiovascular disease, and medication use. We also collect blood and urine for the measurement of a panel of markers that are relevant to DKD. We measure body composition, assess dietary frequency and physical activity, and for those who are classified as cases (i.e. albumin-to-creatitine >300mg/g and/or CKD-epi eGFR <60ml/min/1.73m²), we invite them for 24-hr ambulatory blood pressure monitoring. An overview is provided as follows:

Progress

Output (purely from DORIS)

1. We submitted an abstract to Singapore Health & Biomedical Congress (SHBC) in 2019, which was shortlisted for a poster presentation. The subsequent poster presentation won SHBC Best Poster Award (Allied Health) (Silver). The poster and award can be found in the Appendix 1 (PDF, 692KB).
   
2. Using the data of participants recruited from November 2017 to December 2020, we demonstrated that more frequent self-monitoring of blood glucose (SMBG), as an aspect of self-care, is associated with lower odds of chronic kidney disease (CKD) (Ann Acad Med Singap 2022;52:52-4) Appendix 2 (PDF, 146KB).
3. In a study based on the cohort data and follow-up data from the participants' electronic medical records, we showed that elevated neutrophil/lymphocyte ratio (NLR) is associated with increased prevalence of CKD or albuminuria. Additionally, baseline NLR independently predicted progressive kidney function decline and, to a lesser extent, albuminuria progression. This work was published in Diabetes Research and Clinical Practice in March 2023 (https://doi.org/10.1016/j.diabres.2023.110634).

What is Familial Hypercholesterolemia (FH) ?

Aims to raise awareness of this genetic condition that puts one at risk for early heart disease, its diagnosis and treatment options

Based on global statistics, Familial Hypercholesterolemia (FH) affects approximately 20,000 patients in Singapore but more than 90% are unaware of this condition and remain undiagnosed! Early diagnosis can allow affected individuals and their family members to start treatment early and ultimately reduce the risk of getting early heart attack.

• FH leads to early heart disease, the #1 killer in the world.
• Men with FH have 50% risk of having heart disease by age of 50.
• Women with FH have 30% risk of having heart disease by age of 60.

Diagnosis & Treatment

You may have FH if you have any of the following symptoms/signs

• High blood cholesterol
  Total Cholesterol > 7.5mmol/l or 290mg/dl
  LDL Cholesterol > 4.9mmol/l or 189mg/dl
• Family history of
  • High cholesterol
  • or Early heart attack
  • or Cholesterol deposits around eyes or under skin
• Mutation test (clinical research)
  

Where can I check my cholesterol levels?

You can get your cholesterol levels checked at any public or private clinic. If you suspect you may have one of the above conditions, discuss with your doctor.

Family screening & early treatment

If you have high cholesterol and test positive for mutation, higher dosage of medication may be required. Lifestyle changes such as healthy diet, exercise and medication can help to reduce the risk of heart attack. Early diagnosis and treatment are available. Take action now and seek medical advice.

If you do a mutation test and discover the mutations, your doctor will share the findings with you and advise your immediate family members to come for testing. Patients with FH mutation have a 50% chance of passing it to their children. Early detection will allow you and your affected family members to start medication early and reduce the risk of premature heart attack.

Awareness Activities

In collaboration with Singapore Heart Foundation, the FHCARE team has set up booth on National Heart Week / World Heart Day 2018 and 2019 on 29 September every year to help raise FH awareness to the public. This event is celebrated annually by Singapore Heart Foundation (SHF) provides a platform to motivate fellow Singaporeans to lead a positive and active lifestyle.

The FHCARE team have also participated in various sharing sessions such as at FH Symposium 2019, Singapore Prevention and Cardiac Rehabilitation Symposium 2019 and at Yishun Polyclinic.

Awards, Grants & Publications

NHG Research Award: Outstanding Research Impact Category “Familial Hypercholesterolemia: Case Identification, Assessment and Reduction in Adverse Events (FHCARE)”

Publications

• Sreedharan. A.V, Pek SLT, Tan TH, Tavintharan S, Yap F. Successful pharmacological management of a child with compound heterozygous familial hypercholesterolemia and review of the recent literature. Journal of Clinical Lipidology 2020; In press.
• Vallejo-Vaz AJ, De Marco M, et al. Overview of the current status of familial hypercholesterolaemia care in over 60 countries - The EAS Familial Hypercholesterolaemia Studies Collaboration (FHSC). Atherosclerosis. 2018;277:234-255. doi:10.1016/j.atherosclerosis.2018.08.051
• Pek SLT, Sanjaya Dissanayake, Fong JCW, Lin MX, Chan EZL, Tang JIS, Lee CW, Ong HY, Sum CF, Lim SC,Tavintharan S. Spectrum of mutations in index patients with familial hypercholesterolemia in Singapore: Single Center Study. Atherosclerosis 2018; 269:106-116

Grants

• Singapore Heart Foundation: Improving awareness and identification of Familial Hypercholesterolemia in Singapore among healthcare professionals and patients
• AHPL STAR18202 Prospective observational study of potential genetic and biochemical predictors to response to cholesterol-lowering therapy in patients with Familial Hypercholesterolemia
• Amgen: To support the establishment of a national Familial Hypercholestrolemia (FH) registry in Singapore.
• AHPL STAR16104 Combination of molecular genetic testing and clinical diagnosis for familial hypercholesterolemia (FH) / Autosomal Dominant Hypercholesterolemia (ADH)
• AHPL AHEG1503 Combination of molecular genetic testing and clinical diagnosis for familial hypercholesterolaemia and familial combined hypercholesterolaemia: Pilot study

What is MODY?

• A type of diabetes caused by a single gene abnormality, often misdiagnosed as the common Type 1 or Type 2 diabetes
• Registry set up to identify individuals with MODY and provide a genetic diagnosis so that they can receive the best treatment

MODY stands for Maturity-Onset Diabetes of the Young. It is a type of diabetes that is caused by a single gene abnormality (mutation) and is also known as monogenic diabetes. MODY can often be misdiagnosed as the common Type 1 or Type 2 diabetes as they share similar features. Determining the gene mutation in MODY is important to confirm the diagnosis.

Mutation in more than 20 genes have been shown to cause MODY. The most common ones include HNF4A, GCK and HNF1A (MODY-1,-2 and -3) as well as KCNJ11 and ABCC8 (can cause diabetes as young as 1 year old or less, i.e. neonatal diabetes). These genes directly affect the ability of the insulin-producing cells in the pancreas to sense, produce and release insulin, which is required to control sugar levels in our body.

The KTPH-NHG MODY Registry is set up as part of our research study to identify individuals with MODY and to provide a genetic diagnosis for this group of individuals. A genetic diagnosis of MODY may aid doctors in providing the best treatment for these individuals (e.g. switching from insulin to tablets).

News Feature

Patient with rare diabetes tracked with new registry (The Sunday Times, 15/10/2017)

Related Publication

1. A preliminary study to evaluate the strategy of combining clinical criteria and next generation sequencing (NGS) for the identification of monogenic diabetes among multi-ethnic Asians
2. Cessation of Multiple Daily Insulin Injections in a Person with Twenty-Nine Years of "Type 1 Diabetes"
3. PAX4 R192H is associated with younger onset of Type 2 diabetes in East Asians in Singapore
4. Precision medicine for a man presented with diabetes at 2-month old
5. Response to multiple glucose-lowering agents in a sib-pair with a novel HNF1α (MODY3) variant
6. Clinical experience from a regional monogenic diabetes referral centre in Singapore

MODY Registry

Targeting primarily the population-catchment of NHG-Yishun campus, the KTPH-NHG MODY registry is set up with the following primary aims:

• To identify individuals with MODY and to perform genetic testing for these group of individuals.
• To facilitate optimization of treatment by their care-provider for individuals with confirmed genetic diagnoses (e.g. switching from insulin to oral anti-diabetic medications like sulphonylureas).
• To provide MODY-related counselling to affected individuals and their family members.
• To provide a platform for gathering longitudinal information to better understand and treat monogenic diabetes.

Your participation will help us understand the genetic basis of monogenic diabetes, and also answer questions such as the number of people who are affected in our local population, the typeof treatment that is best for each different genetic type, and other medical problems that might arise due to the presence of such gene mutations. These information will help doctors understand the genetic basis of the disease and offer suitable treatment to the patients.

Do I have MODY?

You may have MODY if you have any of the following features:

• Diabetes diagnosed when you were less than 35 years old. We strongly recommend people with diabetes-onset below 1 year old to receive genetic testing.
• Type 2 Diabetes (T2D) but not overweight
• Longstanding T2D that is well controlled with diet alone
• Strong family history of diabetes (more than 2 generations)

Contact Us

Interested to find out more and participate in our study?

If you think you have MODY and would like to participate in our study, kindly email the following details to ktph.mody.registry@ktph.com.sg.

• Salutation (Mr/Ms/Mdm)
• Full name
• Contact number
• Email address

By sending us the above information, you are deemed to have consented for our study team to contact and invite you to participate in our clinical trials/research. Collection, use and disclosure of your personal data shall be in accordance with our privacy policy.

Are you a physician looking to refer your patient(s)?

More information on our study inclusion & exclusion criteria can be found here. If you would like to refer your patient, please email the following details to ktph.mody.registry@ktph.com.sg.

Patient Details

• Salutation (Mr/Ms/Mdm)
• Full name
• Contact number
• Email Address

Physician Details

• Physician name
• MCR number
• Clinic/Hospital
• Address
• Contact number
• Email Address

Please ensure that patient consent for the collection, use and disclosure of his/her information has been obtained and documented, according to PDPA requirement. Our study team will contact you/patient via the provided contact details. All personal information provided will be kept confidential.

Other enquiries?

Please contact us at ktph.mody.registry@ktph.com.sg.

Participation in the KTPH-NHG Monogenic Diabetes Registry is voluntary and there is no charge to participate. Genetic testing for MODY is performed on a research basis and will be provided at no cost for individuals who are eligible and have given consent for the study.

This study is approved by the NHG Domain Specific Review Board (DSRB 2017/00276) and the research team follows all DSRB guidelines to protect personal health information.

About Monogenic Hypertension (MGH):

Hypertension is common. The vast majority of hypertension have unknown underlying causes, and nearly all treatment for this group is guided by the signs and symptoms of the patients.

In contrast, Monogenic Hypertension is when there is high blood pressure caused by a single abnormal gene.

Characteristics: Severe     Runs in Family   Starts young  Difficult to treat

Purpose of research study:

This study is carried out to find out if there is anything in the blood of patients (genetic code) or, in some patients, anything in the tissues to allow: 

• Accurate diagnosis - you and your doctor will be helped in knowing
• Reduce "diagnostic odyssey" - save time and cost spent on testing
• May help avoid ineffective treatments
• Helps identify at-risk family members for testing
  
• Distinguish between different patterns of inheritance - symptoms varies according to different mode
• Inform family planning

What the study involves:

• Initial Enrolment (~1 hour)
  
  1. One questionnaire
  2. Blood sample taking
• Two Follow-up Visits every 6 months (~ 30 mins)
  
  1. Return of home blood pressure readings

Join us if you have ANY ONE or more of the following:

• High blood pressure before 30 years old
• High blood pressure between 30-40 years old and family history of hypertension
• Uncontrolled high blood pressure despite taking 3 or more blood pressure lowering medications
• Your doctor suspects that you may have Monogenic Hypertension (eg Familial Hyperaldosteronism or Pheochromocytoma for which genetic testing is recommended)

Additional requirements will be discussed with a study representative.

Participants will receive:

• No charge for the tests
  
• Blood pressure monitoring device
• Reimbursement for travel expenses

What else should I know about being enrolled in this study?

• Will be required to take blood pressure (morning and evening for the first week, and subsequently weekly, for 1 year after the enrolment into the study)
• Take note of the number of clinical visits and expenses incurred as standard care for hypertension (only if you have enrolled in this study as proband)

Recruitment expiry date: March 2025
Poster 2 version VI (28/09/2022)
This study is funded by Alexandra Health Pte Ltd (Science Translation Applied Research Grants 20105, 2206)

For more information, contact MGH team:

Ms Diana       8938 2077
Ms Umairah   9646 6874
Email: mgh@ktph.com.sg

Conference Abstract

1. Comprehensive analysis of pathogenic variants in 27 hypertension linked genes in Singapore: Applications to Monogenic Hypertension. Yiamunaa M, Charmaine Koh, Troy Puar Hai Kiat, Lim Su Chi, Resham Lal Gurung, for Monogenic Hypertension study group. Singapore Health & Biomedical Congress, 2022
2. Genetic features of patients suspected of monogenic hypertension: A Pilot Study. Resham L Gurung, Yiamunaa M, Diana Yong, SK Tan, Daphne Lee, Sanjaya Dissanayake, Allen Liu, Su Chi Lim. Singapore Health & Biomedical Congress, 2021

National Medical Research Council Collaborative Grant

(NMRC CG): S$1.5 million

• Collaboration with National University Health System (NUHS)
• Focus on metabolic medicine and a federated data repository using cohorts and clinical epidemiology
• Bio-banking for cohort studies in KTPH, supporting over 200,000 bio-specimens gathered from 17,824 participants
• Goal is to link healthcare and research (including “-omics”) data for each individual in the existing cohorts and configure the data for federated analysis with NUHS

We were awarded NMRC Centre Grant (CG) to comprehensively develop our clinical research capability to meet the growing challenge of Common and Complex Chronic Conditions (4Cs). The quantum of CG awarded is $1.5 millions for 4 years. It consist of 3 main cores i.e. Facility Core, Research Personnel Core and Administrative Core.

Facility Core: The core will provide equipment and consumables necessary for maintaining the biobanking activities. A portion of this core will be used to facilitate federated data repository through collaboration with the National University Health System (NUHS).

Research Personnel Core:The core will provide manpower support for biobanking of human specimens and conducting epidemiological studies. A portion of this core will be supporting manpower in NUHS for data repository.

Administrative Core: The core will provide an oversight of biobanking and research data from ethical, operational and managerial perspectives.

Multi-disciplinary research in fields such as epidemiology, genetics, metabolomics, lifestyle and nutrition to gain insights into functional changes related to obesity among multi-ethnic Asians in Singapore

Obesity is a complex multifaceted disease arising from interactions of biological, behavioural and environmental factors, and contributes to many comorbid conditions e.g. Type 2 diabetes (T2DM). Bariatric Surgery (also known as Gastrointestinal Surgery, or Bariatric and Metabolic Surgery) is highly effective in inducing weight loss among morbidly obese individuals thereby ameliorating adverse metabolic consequences.

The OMICS project is co-initiated by Dr Anton Cheng (Deputy Director of Weight Management Programme at our Health For Life Centre) and Dr Lim Su Chi (Clinical Director, Clinical Research Unit) to provide resources for conducting multidisciplinary research in fields such as epidemiology, genetics, metabolomics, lifestyle and nutrition to elucidate obesity pathophysiology among multi-ethnic Asians in Singapore.

Constituting the core of OMICS is a prospective-cohort founded since 2007. To date, it has ~400 severely obese (mean BMI~40 kg/m2) individuals who underwent bariatric surgery. About one-third of them has T2DM, whom we have performed pre- and post-bariatric surgery multiple time-point OGTT. Additionally, we have established a rich bio-repository of bio-banked blood and urine samples, cryopreserved human primary adipocytes (both subcutaneous and visceral), skeletal myocytes and longitudinal clinical data collected from the research participants.

The goals of the OMICS project are:

1. To understand the best practice for candidate-selection to derive benefit from bariatric surgery
2. To unveil the mechanisms elicited by bariatric surgery so as to facilitate the development of powerful non-invasive interventions for improving obesity and/or T2DM
3. To identify biomarkers to better risk-stratify obesity/T2DM patients i.e. personalized medicine

Publications

1. Pek SL, Sum CF, Lin MX, Cheng AK, Wong MT, Lim SC, Tavintharan S. Circulating and visceral adipose miR-100 is down-regulated in patients with obesity and Type 2 diabetes. Mol Cell Endocrinol. 2016;427:112-23.
2. Toy WC, Liu JJ, Cheng AKS, Tan CSH, Lau DP, Wong MDS, Tavintharan S, Sum CF, Lim SC. Adiponectin gene polymorphisms and type 2 diabetes among Singaporean Chinese adults. J Diabetes Metab. 2011;2(8): 1000152.
3. Kiong KL, Ganesh R, Cheng AKS, Lekshiminarayanan R, Lim SC. Early improvement in type 2 diabetes mellitus post Roux-en-Y gastric bypass in Asian patients. Singapore Med J 2010; 51(12) 937.
4. Ngiam KY, Lee WJ, Lee YC, Cheng A. Efficacy of metabolic surgery on HbA1c decrease in type 2 diabetes mellitus patients with BMI < 35 kg/m2--a review. Obes Surg. 2014 Jan; 24(1):148-58.

Conference Abstracts

1. Moh MC, Lian M, Ang SF, Wong MDS, Zhang X, Lim SC. Whole exome sequencing on a large cohort of severely-obese individuals to investigate pancreatic β-cell function related protein-coding variants potentially protective against type 2 diabetes in the metabolically healthy non-diabetic group. AFES 2017, Yangon, Myanmar.
2. Moh MC, Lim SC, Lim BK, Tavintharan S, Sum CF, Cheng AKS. Evaluation on the early effects of bariatric surgery on the outcome of type 2 diabetes in obese patients. ICO 2014, 12th International Congress on Obesity, Malaysia, Kuala Lumpur.
3. Moh MC, Cheng AKS, Pek SLT, Lim BK, Wong MDS, Lim SC. Alteration of the plasma amino acid profile predicts glucose tolerance after gastro-intestinal metabolic surgery in obese patients with type 2 diabetes. Singapore Health and Biomedical Congress 2015, Singapore.
4. Wong MDS, Moh MC, Cheng AKS, Tan LT, Lim BK, Pek SLT, Sum CF, Tavintharan S, Lim SC. Elevation of plasma long-chain acylcarnitines in obese patients with non-remission of type 2 diabetes after bariatric surgery. Singapore Health and Biomedical Congress 2015, Singapore.
5. Toy WC, Liu JJ, Cheng AKS, Wong MDS, Sylvia, Tan CSH, Sum CF, Lim SC. TNF-α induce fractalkine expression via activation of NF-kB in human adipocytes. Singapore Health and Biomedical Congress 2012, Singapore.
6. Toy WC, Cheng AKS, Tan TJ, Lau DP, Rajmohan L, Tan CSH, Wong MDS, Tavintharan S, Sum CF, Lim SC. The effect of PPARï?§ Rosiglitazone on the gene expression profile of subcutaneous vs visceral adipocytes. Alexandra Health Research Forum 2011, Singapore.
7. Lau DP, Toy WC, Cheng AKS, Tan CSH, Wong MDS, Narayanan R, Sum CF, Tavintharan S, Lim SC. Differential gene expression of inflammatory cytokines and receptors between human visceral and subcutaneous adipose tissue. Alexandra Health Research Forum 2011, Singapore.
8. Toy WC, Tan JJ, Lau DP, Tan CSH, Wong MDS, Tavintharan S, Sum CF, Lim SC, Cheng AKS. The miRNA profiling on the effect of Rosiglitazone on subcutaneous vs visceral adipocytes. Asia-Pacific Metabolic and Bariatric Surgery Society. 21st Oct 2010. Singapore.

Conference Papers

1. Lap adj Gastric Band for morbid Obesity Results at 5 years. Free paper. Aaron Poh, A Cheng. APMBSS Congress Singapore Oct 2010
2. Early improvement in Type 2 DM post RYGB in Asian patients. G Xu, A Cheng. APMBSS Congress Singapore Oct 2010
3. Laparoscopic Adjustable gastric Banding our 5 years experience in AH/KTPH. Ganesh R, A Cheng. ELSA Congress Singapore August 2011
4. Biliopanceatic diversion as a revision bariatric procedure our case series. Ganesh R, A Cheng. ELSA Congress Singapore August 2011
5. Single incision sleeve gastrectomy. Ganesh R, A Cheng. ELSA Congress Singapore August 2011
6. Single incision sleeve gastrectomy video presentation. HS Ho, WD Lau, Desmond Ooi, A Cheng. ELSA Congress Singapore August 2011
7. Laparoscopic Biliopancreatic Diversion, video presentation. Lau WD, Cheng A. ELSA Congress Singapore August 2011
8. Lengthening of BP limb post BPD due to severe malnutrition. Video presentation. Tan CC, Cheng A. ELSA Congress Singapore August 2011
9. Endoscopic stenting of GJ anastomotic leak after RYGB. Desmond Ooi, Ho HS, Lau WD, AKS Cheng. ELSA Congress Singapore August 2011
10. Reasons for loss to follow up in our Bariatric Surgical Center. Lucy Kong, Ganesh R, A Cheng. ELSA Congress Singapore August 2011
11. Laparoscopic Adjustable Gastric Banding 10 years experience, IFSO congress New Delhi, Oct 2012
12. Glycaemic Control after Gastric Bypass Surgery in Morbidly Obese Patients with Diabetes Mellitus: An Asian Experience, IFSO congress New Delhi, Oct 2012

Media Reports

1. Khoo Teck Puat Hospital studying effectiveness of bariatric surgery
2. More opt for drastic weight-loss surgery

Singapore Study of Macro-angiopathy and Microvascular Reactivity in Type 2 Diabetes (SMART2D Cohort Study)

Introduction

The SMART2D cohort was started in 2011, to study the impact of diabetes related metabolic risk factors (RFs) on blood vessel function & common diabetic complications (e.g. diabetic kidney disease, diabetic foot syndrome & cognitive function).

The aims of the study, along with the exposures, biomarkers and outcomes explored in the study.
(DORIS: Diabetic nephropathy – Onset & Risk factors study, is a sister-cohort of SMART2D  https://www.ktph.com.sg/health-professionals/clinical-research/research-highlights#doris)

The SMART2D cohort

• Is a key member of a nationwide, multi-institution consortium to study diabetic kidney disease & retinopathy.
• Receives a total of nearly S$5 million (FY2012 to FY2021) in funding by the National Medical Research Council (NMRC).
  
• Aims to recall all of our past participants to study the RFs (with emphasis on lifestyle factors) & disease progression. In the next phase (year 2024 onwards), we will organize the serial collection of bio-specimens, along with follow-up data on RFs & diabetic complications.
• Has generated over 70 papers in high-impact, international peer-reviewed scientific journals and shared our findings at numerous national and international conferences. 
  

The SMART2D Cohort Study was first launched in 2011 by Drs Lim Su Chi, Tavintharan Subramaniam, Yeoh Lee Ying and Sum Chee Fang, funded by the highly competitive National Medical Research Council's (NMRC) Program Project Grant (PPG). Since then, Dr Lim Su Chi has been awarded two additional NMRC Clinical Scientist Individual Research Grants (CS-IRG) to recall all the participants for re-evaluation to study changes in RF and disease-progression.

By exploiting the synergy between clinical and molecular epidemiology, SMART2D will continue as a longitudinal study that investigates the relationship between risk factors (genetic and non-genetic), vascular function (i.e. intermediate phenotype - endothelial reactivity and arterial stiffness) and final phenotypes (diabetic foot syndrome, nephropathy, retinopathy & cognitive dysfunction).

The SMART2D study collaborates with prestigious institutions such as the Genome Institute of Singapore (GIS), National University of Singapore (NUS), National Healthcare Group Polyclinics (NHGP) and the Wellcome Trust Centre for Human Genetics at Oxford, UK. In addition, the cohort is part of a nation-wide, multi-institution consortium (DYNAMO: Diabetes studY in Nephropathy And other Microvascular cOmplications) devoted to studying diabetic kidney disease and retinopathy.

Recent highlights

We use clinical variables to perform cluster analysis in the SMART2D cohort, allowing us to identify novel subgroups with distinct genetic signatures, lipidomic patterns, and cardio-renal risks in Asian patients with recent-onset type 2 diabetes which may serve as a starting point to stratify the diverse diabetic population into subgroups for precision medicine in our Asian population for better health outcomes. Our work has been covered in the media by the Singapore national newspapers, Berita Harian ("Kajian KTPH buka jalan bagi rawatan penyakit kencing manis lebih tepat", 15 November 2022) and 联合早报 ("糖尿病患者分类型 护理治疗更精准", 28 February 2023).

Diabetologia. 2022 Dec; 65(12):2176. doi: https://doi.org/10.1007/s00125-022-05741-2. 

To enhance the sample-size, we are recruiting new volunteers for our prospective study. Various health assessment tests, including blood and urine tests, foot screening, body composition analysis and questionnaires to investigate diet, physical activity and cognition may be conducted. The results obtained from these tests can be used to inform the volunteers (and their doctors) of any changes in their health status and blood vessel function. If you are interested in learning more about the study or would like to join us as a study volunteer, please contact our lead study coordinator Ms Qi Xiaoge at 8798 3468 or our project manager Dr Keven Ang at 6602 2343. Alternatively, you may also email the study team at ktph.smart2d@ktph.com.sg. Collection, use and disclosure of your personal data shall be in accordance with our institution's privacy policy.

Highlighted Publications

1. Liu, J. J., Liu, S., Wang, J., Pek, S. L. T., Lee, J., Gurung, R. L., Ang, K., Shao, Y. M., Tavintharan, S., Tang, W. E., Sum, C. F., & Lim, S. C. (2023). Urine Leucine-Rich α-2 Glycoprotein 1 (LRG1) Predicts the Risk of Progression to End-Stage Kidney Disease in Patients With Type 2 Diabetes. Diabetes care, 46(2), 408–415. https://doi.org/10.2337/dc22-1611
2. Wang, J., Liu, J. J., Gurung, R. L., Liu, S., Lee, J., M, Y., Ang, K., Shao, Y. M., Tang, J. I., Benke, P. I., Torta, F., Wenk, M. R., Tavintharan, S., Tang, W. E., Sum, C. F., & Lim, S. C. (2022). Clinical variable-based cluster analysis identifies novel subgroups with a distinct genetic signature, lipidomic pattern and cardio-renal risks in Asian patients with recent-onset type 2 diabetes. Diabetologia, 65(12), 2146–2156. https://doi.org/10.1007/s00125-022-05741-2
3. Liu, J. J., Pek, S. L. T., Wang, J., Liu, S., Ang, K., Shao, Y. M., Tang, J. I., Gurung, R. L., Tavintharan, S., Tang, W. E., Sum, C. F., & Lim, S. C. (2021). Association of Plasma Leucine-Rich α-2 Glycoprotein 1, a Modulator of Transforming Growth Factor-β Signaling Pathway, With Incident Heart Failure in Individuals With Type 2 Diabetes. Diabetes care, 44(2), 571–577. https://doi.org/10.2337/dc20-2065
4. Liu, J. J., Pek, S. L. T., Liu, S., Wang, J., Lee, J., Ang, K., Shao, Y. M., Gurung, R. L., Tavintharan, S., Tang, W. E., Sum, C. F., & Lim, S. C. (2021). Association of Plasma Leucine-Rich Alpha-2 Glycoprotein 1 (LRG1) with All-Cause and Cause-Specific Mortality in Individuals with Type 2 Diabetes. Clinical chemistry, 67(12), 1640–1649. https://doi.org/10.1093/clinchem/hvab172
5. Low, S., Goh, K. S., Ng, T. P., Ang, S. F., Moh, A., Wang, J., Ang, K., Subramaniam, T., Sum, C. F., & Lim, S. C. (2020). The prevalence of sarcopenic obesity and its association with cognitive performance in type 2 diabetes in Singapore. Clinical nutrition, 39(7), 2274–2281. https://doi.org/10.1016/j.clnu.2019.10.019
6. Liu, C., Teo, M. H. Y., Pek, S. L. T., Wu, X., Leong, M. L., Tay, H. M., Hou, H. W., Ruedl, C., Moss, S. E., Greenwood, J., Tavintharan, S., Hong, W., & Wang, X. (2020). A Multifunctional Role of Leucine-Rich α-2-Glycoprotein 1 in Cutaneous Wound Healing Under Normal and Diabetic Conditions. Diabetes, 69(11), 2467–2480. https://doi.org/10.2337/db20-0585
7. Liu, J. J., Liu, S., Gurung, R. L., Ang, K., Ee Tang, W., Sum, C. F., Tavintharan, S., Hadjadj, S., & Lim, S. C. (2019). Arterial Stiffness Modulates the Association of Resting Heart Rate With Rapid Renal Function Decline in Individuals With Type 2 Diabetes Mellitus. Arteriosclerosis, thrombosis, and vascular biology, 39(11), 2437–2444. https://doi.org/10.1161/ATVBAHA.119.313163
8. Gurung, R. L., Yiamunaa, M., Liu, S., Liu, J. J., Chan, C., Choo, R. W. M., Ang, K., Sum, C. F., Tavintharan, S., & Lim, S. C. (2019). Association of haptoglobin phenotype with incident acute myocardial infarction in Chinese patients with type 2 diabetes. Cardiovascular diabetology, 18(1), 65. https://doi.org/10.1186/s12933-019-0867-4
9. Dorajoo, R., Chang, X., Gurung, R. L., Li, Z., Wang, L., Wang, R., Beckman, K. B., Adams-Haduch, J., M, Y., Liu, S., Meah, W. Y., Sim, K. S., Lim, S. C., Friedlander, Y., Liu, J., van Dam, R. M., Yuan, J. M., Koh, W. P., Khor, C. C., & Heng, C. K. (2019). Loci for human leukocyte telomere length in the Singaporean Chinese population and trans-ethnic genetic studies. Nature communications 10 (1), 2491. https://doi.org/10.1038/s41467-019-10443-2
   

For other SMART2D Publications, click here.