Ketut Suastika. Faculty of Medicine, Udayana University< Denpasar, Bali, Indonesia

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1 Australia-Indonesia Science Symposium Health Workshop Australia Academic of Science Canberra, 28th-30th November 2016 Ketut Suastika Faculty of Medicine, Udayana University< Denpasar, Bali, Indonesia

2 Prevalence of Adult Obesity (BMI 30 kg/m 2 *) 2000* to date

3 IDF Atlas 2015

4 Prevalence of Obesity and Diabetes in Indonesia: Health Basic Research, 2007, 2013 Men >18 y IFG IGT UD- DM D- DM Total DM Women >18 y Health Basic Research, 2007 and 2013

5 Prevalence of obesity, metabolic syndrome and diabetes in Bali Sangsit 60 1 Component 2 Components 3 Components Pedawa Legian Ubud Pengelipuran Ceningan Tenganan Components 5 Components Male Female Total 35 Prevalence of the components of metabolic syndrome by sex Male Female Total Ceningan Pedawa Tenganan Pengelipuran Ubud Sangsit Legian Total Prevalence of Mets: Male is 16.6% Female is 20% Total is 18.2% The prevalence of metabolic syndrome by sex and village Suastika K et al. J AFES 2011; 26:

6 Prevalence of obesity, metabolic syndrome and diabetes in Bali Pedawa Ubud Sangsit Pengelipuran Tenganan WC BP HDL-C TG FPG Legian 35 Ceningan Male Female Total Prevalence of the components of metabolic syndrome by sex Male Female Total Ceningan Pedawa Tenganan Pengelipuran Ubud Sangsit Legian Total Prevalence of Mets: Male: 16.6% Female: 20% Total: 18.2% The prevalence of metabolic syndrome by sex and village Suastika K et al. J AFES 2011; 26:

7 Prevalence of obesity, metabolic syndrome and diabetes in Bali Central obesity IFG DM MS 61.2 Central obesity IFG DM MetS 35% 13.1% 5.9% 18.2% Ceningan Sangsit Legian Pedawa Ubud Tenganan Pengelipuran Total Suastika K et al. J AFES 2011; 26: Suastika K et al. J Clin Gerontol Geriatrics 2011; 2: Central obesity and diabetes by age ~ >70 Central obesity DM

8 Lifestyle changes: excessive food intake and lack of exercise

9 Abdominal obesity increases the risk of developing type 2 diabetes Relative risk < >96.3 Waist circumference (cm) Carey VJ et al, 1997

10 Abdominal obesity and increased risk of cardiovascular events The HOPE study Adjusted relative risk Waist circumference (cm): 1.29 Tertile 1 Tertile 2 Tertile 3 Men < > Women < > CVD death MI All-cause deaths Adjusted for BMI, age, smoking, sex, CVD disease, DM, HDL-cholesterol, total-c; CVD: cardiovascular disease; MI: myocardial infarction; BMI: body mass index; DM: diabetes mellitus; HDL: high-density lipoprotein cholesterol Dagenais GR et al, 2005

11 Diabetes is associated with significant loss of life years Men Women Years of life lost Non-vascular deaths Vascular deaths Age (year) Age (year) Seshasai et al. N Engl J Med 2011;364:

12 Patophysiology of type 2 diabetes Genetic factors + Insulin resistance Metabolic Syndrome + Beta cells dysfunction Environmental factors

13 Obesity, Metabolic Syndrome, and Insulin Resistance: Environment factors Correlation between waist circumference and components of metabolic syndrome 1 Variables R p Systolic blood pressure Diastolic blood pressure Fasting blood glucose HDL-cholesterol Triglyceride Total-cholesterol LDL-cholesterol <0.001 < <0.001 < HOMA IR Age (y) BMI (kg/m2) WC (cm) Systolic BP (mmhg Diastolic BP (mmhg) T-cholesterol (mg/dl) HDL-C (mg/dl) LDL-C (mg/dl) Triglyceride (mg/dl) R P NS <0.001 < NS < Suastika K et al. 19 th World Diabetes Congress. Cape Town 3-7 December Diabetic Medicine 2006; 23 (Supll.4): Suastika, et al. 1 st International Congress on Prediabetes and Metabolic Syndrome. Berlin 2005

14 Hypomagnesia is a risk factor for metabolic syndrome and type 2 diabetes mellitus in native Balinese Objective: To determine the prevalence of hypomagnesemia and the risk of hypomagnesemia on metabolic syndrome and type 2 diabetes mellitus events in native Balinese. Methods: A cross-sectional population-based study was conducted in 111 subjects among native Balinese. Chi-square test was used to determine the prevalence risk (OR) of hypomagnesemia for metabolic syndrome and diabetes. Results: Prevalence of hypomagnesemia was 17.1%. The prevalence of hypomagnesemia was higher in subjects with metabolic syndrome and type 2 diabetes mellitus than those without (34.7% vs. 12.5%, P = 0.025; and 60.0% vs. 15.1%, P = 0.035). Hypomagnesemia was a risk factor for metabolic syndrome (OR = 3.7; 95% CI, ) and type 2 diabetes mellitus (OR = 8.4; 95% CI, ). Conclusion: The prevalence of hypomagnesemia is very high among native Balinese and hypomagnesemia is an important risk factor for metabolic syndrome and type 2 diabetes mellitus events in the population. Dwipayana P et al. Family Medicine and Community Health. 2013; 1: 14-16

15 Genes were related to obesity, metabolic syndrome and type 2 diabetes in Bali Trp64Arg polymorphism of β3 adrenergic receptor gene was related to obesity in rural female 1 UCP2 gene polymorphisms was related to obesity 2 TCF7L2 gene polymorphisms was related to Mets and T2DM 3 TCF7L2 gene was associated with GLP-1 and insulin levels 4 UCP, uncoupling protein; TCF7L2, Transcription factor 7-like 2 ; GLP-1, glucagon-like peptide-1 1. Malik SG et al. BMC Research Notes 2011, 4:167. Doi: / Oktavianthi S et al. Cardiovascular Diabetology 2012, 11:41 doi: / Oktavianthi S et al. Thesis Saraswati R. Disertation, 2015

16 Correlation between Co-morbidities Factors: Urban vs. Rural Variable Urban Rural P value N Age (years) 43.4 ± ± BMI (kg/m2) 24.1 ± ± 4.0 <0.001 WC (cm) 89.2 ± ± 10.4 <0.001 SBP (mmhg) ± ± DBP (mmhg) 76.4 ± ± FPG (mg/dl) 93.6 ± ± 37.4 <0.001 TG (mg/dl) ± ± 57.9 <0.001 HDL (mg/dl) 52.0 ± ± 12.2 <0.001 LDL (mg/dl) ± ± TC (mg/dl) ± ± Interaction of genetic and enviroment factors might result phenotype Malik SG et al. Unpublished

17 Mechanism of obesity induces insulin resistance In obesity, leptin resistance, reduced adiponectin levels, increased FFA supply, and increased cytokines may all contribute to insulin resistance ( S or V indicates relatively greater contribution from sc or visceral fat, respectively). FFA supply may impact on insulin signaling via DAGs, ceramide, and PKCs via TLRs and NFkB. // indicates reduced secretion (eg, adiponectin) or action (eg, leptin). Hocking S et al. Endocrine Reviews 34: , 2013

18 Underweight is an important risk factor for coronary heart disease in the population of Ceningan Island, Bali A cross-sectional field study was conducted on the popu- lation of Ceningan Island, Bali, Indonesia. From a total population of the island of 888, 305 were recruited by simple random sampling (mean age 43 [14 100] years; male/ female, 148/157). Diagnosis of heart disease was based on electrocardiography (ECG) examination. Classification of nutrition states and obesity were defined by WHO criteria for the Asia Pacific population (2000). Diagnosis of impaired fasting glycaemia and diabetes mellitus was established using the ADA (2009) criteria. Diagnosis of metabolic syndrome was defined by the criteria of A Joint Interim Statement of the IDF TaskForce on Epidemiology and Prevention; NIH; AHA; WHF;IAS; and IASO (2009). Ceningan Island Suastika K et al. Diabetes Vasc Dis Res 2011; 9: 75-77

19 Prevalence risk (odds ratio) of some risk factors for history of myocardial infarction event Male Older age (male 45 year and female 55 year)* No Excercise Alcohol drink Smoking habit No central obesity Underweight (BMI < 18.5 kg/m 2 ) Systolic hypertension (SBP 140 mmhg)* Diastolic hypertension (DBP 90 mmhg)* Diabetes mellitus High total-cholesterol ( 240 mg/dl)* High LDL-cholesterol ( 160 mg/dl)* Low HDL-cholesterol (<40 mg/dl)* High triglyceride ( 200 mg/dl)* Small dense LDL (LDL/Apo B ratio <1.2) Metabolic syndrome Left ventricle hypertrophy Macroalbuminuria Prevalence risk (odds ratio) % Confidence intervals *Cut of point of risk factors are based on ATP-III criteria; not accounted due to any value 0 in one case p < < < Summary A study on the prevalence of coronary heart disease (CHD) and its risk factors in Ceningan Island was conducted. The prevalence of CHD was 11.5%. Older age (odds ratio, OR, 27.0), underweight (OR, 3.6), systolic hypertension (OR, 4.6), high total cholesterol (OR, 5.9), and high low-density lipoprotein cholesterol (OR, 3.1) were risk factors for a history of myocardial infarction (MI). By logistic regression analysis, only age (B=3.937) and underweight (B=1.275) consistently appeared to be risk factors for MI. The prevalence of CHD in the population was comparatively high.

20 Antidiabetic drugs are marketed in Indonesia SUs Glinides TZD AGI SGLT2-I Metformin Insulin Incretin based DPP4-I GLP1-RA

21 T2DM NGT OR (95% CI) P Fasting state Low FGLP-1 (<2.21 pg/l) 12 (60%) 2 (10%) Normal GLP-1 ( 2.21 pg/l) 8 (40%) 18 (90%) Post-glucose loading state Low 1hGLP-1 (<2.57 pg/l) 10 (50%) 3 (15%) Normal 1hGLP-1 ( 2.57 pg/l) 10 (50%) 17 (85%) Difference ( ) 13,5 ( ) ( ) Low GLP-1 (<0.029 pg/l) 2 (10%) 2 (10%) 1.00 ( ) 1.0

22 Algorithm of type 2 diabetes management in Indonesia Healthy Life Style Modification HbA1C <7.5% HbA1C 7.5% HbA1C >9.0% In 3 months, HbA1C > 7% + Monotherapy in 3 months, HbA1C > 7% Clinical features (-) Clinical features (+) Monotherapy* with one of below - Metformin Combination 2 drugs* with different mechanism - GLP1 R-agonist Combination 3 drugs Combination 2 drugs Combination 3 drugs Insulin ± other drugs - GLP1 R-agonist - DPP4-I - AGI - SGLT2-I * - Thiazolidindione - Sulfonylurea - Glinide If HbA1C is not achieved in 3 months, added second drug (combination 2 drugs) Metformin or other first line drug - DPP4-I - Thiazolidindione - SGLT2-I * - Basal Insulin - SU / Glinide - Cholesevelam** - Bromocriptin QR** - AGI If HbA1C is not achieved in 3 months, added third drug (combination 3 drugs) Metformin or other first line drug 2 second line drugs - GLP1 R-agonist - DPP4-I - Thiazolidindione - SGLT2-I * - Basal insulin - SU / Glinide - Cholesevelam** - Bromocriptin QR** - AGI If HbA1C is not achieved in 3 months, started or intensified insulin therapy Notes: Starts or intensification insulin therapy * Registered drugs, it selection and usage is considered based on benefit, adverse, and availability ** Cholesevelam is not yet available in Indonesia, and Bromocriptin QR is generally used in pituitary tumor Indonesian Endocrine Society (Perkeni) Consensus 2015

23 Future direction Indonesia has huge absolute number of people with obesity, metabolic syndrome and type 2 diabetes Promotion and prevention should be conducted intensively. Government, health providers and interested societies have to effort together to propose and implement the program Researches and multi-center/-national clinical trials on new drugs are important to be conducted, since Asian population have difference in genetics, phenotypes, and may be therapy responses compare to Caucasians

24 Acknowledgement Udayana University, Bali, Indonesia: Pande Dwipayana, I Made Ratna Saraswati, Wira Gotera, Anak Agung Gde Budhiarta, I Nengah Dwi Sutanegara, Ketut Suastika Kobe Women s University, Kobe, Japan: Kinuyo Matsumoto, Naemi Kajiwara, Hiroshi Taniguchi Eijkman Institute for Molecular Biology, Jakarta, Indonesia: Safarina G. Malik, Hidayat Trimarsanto, Sukma Oktavianthi, Asri Sulfianti, Wibowo Arindrarto, Herawati Sudoyo, Sangkot Marzuki

25 THANK YOU