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Introduction: Improvements in glycemic outcomes have stalled since 20in some international surveys. We examined the latest trends in drug use and glycemic outcomes following recent introduction of newer classes of glucose lowering drugs (GLDs) in a territory-wide analysis. Methods: Using data from the Hong Kong Diabetes Surveillance Database, we estimated age-specific trends in the proportion of patients reaching different glycemic targets, and rates of severe hypoglycemia (SH) in 963,612 patients between 2002-2019. We assessed patterns of GLDs use by age, sex, presence of atherosclerotic cardiovascular disease (ASCVD) and estimated glomerular filtration rate (eGFR) . Results: HbA1c improved most markedly between 2007-2014 but plateaued since 2014, with 53.1% patients achieving HbA1c Conclusions: Following rapid improvement in 2007-2014, glycemic control and SH rates had plateaued despite the increasing use of SGLT2is and GLP-1RA in Hong Kong. Disclosure A.Yang: None. J.C.Chan: Board Member; Asia Diabetes Foundation, Consultant; Bayer AG, Boehringer Ingelheim International GmbH, Celltrion, Merck Sharp & Dohme Corp., Roche Diabetes Care, Viatris Inc., Research Support; Applied Therapeutics, AstraZeneca, Eli Lilly and Company, Hua Medicine, Servier Laboratories, Stock/Shareholder; GemVCare Ltd. E.Chow: Research Support; Hua Medicine, Medtronic, Powder Pharmaceuticals Inc., Speaker's Bureau; Novartis AG, Sanofi. H.Wu: None. E.S.H.Lau: None. X.Zhang: None. M.Shi: None. B.Fan: None. A.P.Kong: Advisory Panel; Abbott, Kyowa Kirin Co., Ltd., Other Relationship; AstraZeneca, Novo Nordisk, Research Support; Boehringer Ingelheim, Speaker's Bureau; AstraZeneca, Bayer, Eli Lilly and Company, Sanofi, Stock/Shareholder; Aptorum Group Limited. A.Luk: None. R.C.Ma: Other Relationship; Bayer AG, Boehringer Ingelheim International GmbH, Research Support; AstraZeneca, Bayer AG, Novo Nordisk A/S, Pfizer Inc., Tricida, Inc.

Background: Prediabetes is associated with increased risk of cardiovascular disease (CVD) , kidney disease and death but the extent to which the risk associations between prediabetes and clinical events are modified by age is not known. Methods: We conducted a retrospective analysis of a territory-wide diabetes surveillance dataset from the Hong Kong Hospital Authority including 2,692,880 individuals with at least one glycaemic measurement between 2000 and 2019. Prediabetes was defined according to the American Diabetes Association criteria. Proportional Cox regression was used to derive hazard ratios (HR) and 95% CI of prediabetes vs. normoglycaemic for incident CVD, end-stage kidney disease (ESKD) , all-site infection and all-cause death, stratified by baseline age categories (20-39, 40-59, 60-79 and ≥80 years) . Results: Compared with people with normoglycaemia, people with prediabetes had greater hazards for clinical events in all age groups but the effect size attenuated with ascending age. In the youngest and in the oldest age categories, the respective HRs (95% CI) of prediabetes vs. normoglycaemia were 1.93 (1.71-2.17) and 1. (1.01-1.12) for CVD, 1.72 (1.42-2.08) and 1. (1.03-1.17) for ESKD, 1.48 (1.36-1.62) and 1. (1.00-1.08) for all-site infection, and, 1.52 (1.33-1.73) and 1. (1.04-1.10) for all-cause death. The associations remained after excluding people who later developed diabetes and after adjusting for metabolic factors. Conclusion: Prediabetes increases the risk of major clinical events and death independent of subsequent development of diabetes and metabolic factors. The risk relationships between prediabetes and clinical events are stronger in young than older people. Disclosure X.Zhang: None. R.C.Ma: Other Relationship; Bayer AG, Boehringer Ingelheim International GmbH, Research Support; AstraZeneca, Bayer AG, Novo Nordisk A/S, Pfizer Inc., Tricida, Inc. A.Luk: None. H.Wu: None. E.S.H.Lau: None. M.Shi: None. B.Fan: None. A.Yang: None. E.Chow: Research Support; Hua Medicine, Medtronic, Powder Pharmaceuticals Inc., Speaker's Bureau; Novartis AG, Sanofi. A.P.Kong: Advisory Panel; Abbott, Kyowa Kirin Co., Ltd., Other Relationship; AstraZeneca, Novo Nordisk, Research Support; Boehringer Ingelheim, Speaker's Bureau; AstraZeneca, Bayer, Eli Lilly and Company, Sanofi, Stock/Shareholder; Aptorum Group Limited. J.C.Chan: Board Member; Asia Diabetes Foundation, Consultant; Bayer AG, Boehringer Ingelheim International GmbH, Celltrion, Merck Sharp & Dohme Corp., Roche Diabetes Care, Viatris Inc., Research Support; Applied Therapeutics, AstraZeneca, Eli Lilly and Company, Hua Medicine, Servier Laboratories, Stock/Shareholder; GemVCare Ltd.

Introduction: Achieving optimal HbA1c in people with T1D requires good treatment acceptance and self-management. Methods: IDMPS is an international, observational study investigating care practices and clinical profiles of people with diabetes in developing countries. The present analysis of Wave 8 evaluated PROs in people with T1D and their associations with glycemic control using 1) the chronic treatment acceptance questionnaire (ACCEPT) to assess acceptance of long-term medication advantages/disadvantages, and 2) the diabetes self-management questionnaire (DSMQ) to assess health-related behaviors. Results: Of 1103 people with T1D (mean ± SD age 34 ± 12 years, diabetes duration 14 ± 10 years, HbA1c 8.6 ± 2.0 %, 52% were women and 19% had HbA1c Conclusions: Further education for people with T1D could improve self-management and consequently could benefit medication effectiveness. Disclosure J. J. Gagliardino: None. J. C. Chan: Board Member; Asia Diabetes Foundation, Consultant; Bayer AG, Boehringer Ingelheim International GmbH, Celltrion, Merck Sharp & Dohme Corp., Roche Diabetes Care, Viatris Inc., Research Support; Applied Therapeutics, AstraZeneca, Eli Lilly and Company, Hua Medicine, Servier Laboratories, Stock/Shareholder; GemVCare Ltd. P. Aschner: Advisory Panel; Merck & Co., Inc., Sanofi, Speaker's Bureau; AstraZeneca, Boehringer Ingelheim International GmbH, Novo Nordisk. H. M. Ilkova: Advisory Panel; Novo Nordisk. A. Ramachandran: None. J. Mbanya: Advisory Panel; Novo Nordisk, Sanofi, Servier Laboratories. M. V. Shestakova: None. V. Pilorget: None. L. Melas-melt: None. J. Chantelot: Employee; Sanofi, Stock/Shareholder; Sanofi. Funding Sanofi

Background: In patients with type 2 diabetes (T2D) negative for glutamic acid decarboxylase antibodies (GADA-) , the prognostic significance of insulin deficiency (ID) and insulin resistance (IR) remained uncertain. Methods: In 4590 patients with T2D consecutively enrolled to the Hong Kong Diabetes Register in 1995-2012 followed up till 2019, we measured GADA and fasting C peptide (CP) in stored samples at baseline. Using the updated homeostasis model assessment (HOMA2) , we defined below-median HOMA2-%B as ID and above-median HOMA2-IR as IR. We defined incident insulin use as the first insulin prescription of at least 28 days and used ICD-9 codes to define cardiovascular-renal diseases, severe hypoglycemia event (SHE) and all-cause mortality. We used Cox regression model to examine the associations between HOMA2 and clinical outcomes. Results: Amongst 3198 GADA- patients with available HOMA2 data, the median of HOMA2-%B was 52.4 (33.1, 60.9) and that of HOMA2-IR was 1.6 (1.1, 1.8) . The ID group was more likely to initiate insulin treatment [adjusted HR (95%CI) 1.26 (1.11-1.42) ] but less likely to progress to chronic kidney disease (CKD) , end-stage kidney disease (ESKD) and all-cause mortality than the non-ID group. The IR group had increased risks of incident insulin therapy [HR 1.13 (1.00-1.27) ], CKD, ESKD, and all-cause mortality than the non-IR group. Compared with the ID-/IR- group, the ID/IR group had the highest hazard of incident insulin use [HR 1.59 (1.30, 1.94) ], SHE and cardiovascular-renal diseases with HRs ranging from 1.45 to 2.09, although the associations for complications became insignificant after adjusting for metabolic factors and baseline treatments. Conclusions: In GADA- patients with T2D, ID and IR contributed differently to clinical outcomes with the co-existence of ID and IR associated with the highest risk of insulin requirement and adverse clinical outcomes. The assessment of ID and IR using HOMA2 improved risk stratification to identify high risk people for individualized intervention. Disclosure B.Fan: None. A.Luk: None. J.C.Chan: Board Member; Asia Diabetes Foundation, Consultant; Bayer AG, Boehringer Ingelheim International GmbH, Celltrion, Merck Sharp & Dohme Corp., Roche Diabetes Care, Viatris Inc., Research Support; Applied Therapeutics, AstraZeneca, Eli Lilly and Company, Hua Medicine, Servier Laboratories, Stock/Shareholder; GemVCare Ltd. E.S.H.Lau: None. H.Wu: None. M.Shi: None. A.Yang: None. C.K.Lim: None. A.P.Kong: Advisory Panel; Abbott, Kyowa Kirin Co., Ltd., Other Relationship; AstraZeneca, Novo Nordisk, Research Support; Boehringer Ingelheim, Speaker's Bureau; AstraZeneca, Bayer, Eli Lilly and Company, Sanofi, Stock/Shareholder; Aptorum Group Limited. E.Chow: Research Support; Hua Medicine, Medtronic, Powder Pharmaceuticals Inc., Speaker's Bureau; Novartis AG, Sanofi. R.C.Ma: Other Relationship; Bayer AG, Boehringer Ingelheim International GmbH, Research Support; AstraZeneca, Bayer AG, Novo Nordisk A/S, Pfizer Inc., Tricida, Inc. Funding The HKG Health Medical and Research Fund and RGC Research Impact Fund

Introduction: IDMPS is an international, observational study to assess care practices and clinical profiles of people with diabetes in developing countries. Treatment non-adherence is a major barrier to treatment effectiveness. Open-ended self-reported reasons for omitting or adhering to glucose-lowering drugs in people with T2D were analyzed. Methods: NLP and clustering methods were used to analyze responses on omitting medications (Q1) , not taking medications as prescribed (Q2) , and methods to improve adherence (Q3) , with Q1+2 responses merged as reasons for ‘omission’. Results: Of 2475 participants from 13 countries (mean ± SD age 58 ± 12 years, 49% male, diabetes duration ± 8 years, 43% on insulin) , 85%, 79%, and 37% had responses for Q1-3 respectively. Of these, 36% had responses indicative of non-adherence, 62% of adherence, and 2% uncertain responses (Q1+2) . Non-adherent patients were younger (55 ± 12 vs. 60 ± 12 years) , had shorter diabetes duration (± 8 vs. 12 ± 9 years) , and higher HbA1c (8.3 ± 1.9 vs. 7.9 ± 1.8 %) vs. adherent patients (all p Conclusions: Conflicts with daily routine are the main barrier to therapy adherence, while planning and habit formation can improve adherence. Disclosure J.C.Chan: Board Member; Asia Diabetes Foundation, Consultant; Bayer AG, Boehringer Ingelheim International GmbH, Celltrion, Merck Sharp & Dohme Corp., Roche Diabetes Care, Viatris Inc., Research Support; Applied Therapeutics, AstraZeneca, Eli Lilly and Company, Hua Medicine, Servier Laboratories, Stock/Shareholder; GemVCare Ltd. J.Chantelot: Employee; Sanofi, Stock/Shareholder; Sanofi. P.Aschner: Advisory Panel; Merck & Co., Inc., Sanofi, Speaker's Bureau; AstraZeneca, Boehringer Ingelheim International GmbH, Novo Nordisk. J.J.Gagliardino: None. H.M.Ilkova: Advisory Panel; Novo Nordisk. A.Ramachandran: None. J.Mbanya: Advisory Panel; Novo Nordisk, Sanofi, Servier Laboratories. M.V.Shestakova: None. M.Rollot: Other Relationship; Sanofi. M.Blanchon: Other Relationship; Sanofi. P.Hayat: Other Relationship; Sanofi. Funding Sanofi

Glucokinase maturity onset diabetes of the young (GCK-MODY) is caused by heterozygous inactivating mutations in GCK that is not responsive to conventional glucose lowering drugs. We investigated the effects of dorzagliatin, a novel allosteric activator of hepatic and beta-cell GCK on insulin secretion rates (ISR) and glucose sensitivity (GS) in GCK-MODY and recent onset type 2 diabetes (T2D) . In a double-blind, randomized cross-over study, 8 GCK-MODY (mean±SD age 36.1­±6.4years) and T2D subjects (mean age 50.2±6.9 years, median T2D duration 0.90 [0.60-1.42] years) underwent 2-hour 12 mmol/L hyperglycemic clamps following a single oral dose of dorzagliatin 75mg or matched placebo. Insulin and C-peptide were measured. GCK-MODY group showed significantly higher absolute (mean±SD 432±85 versus 272±91 pmol/min/m2, p=0.002) and incremental (342­±91 vs. 241±74 pmol/min/m2, p=0.004) second-phase ISR following dorzagliatin versus placebo. Dorzagliatin significantly improved GS in GCK-MODY (51±21 vs. 33­±13 pmol/min/m2 per mmol/L p=0.028) with an upward and leftward shift in ISR-glucose response. In T2D, basal ISR was significantly improved following dorzagliatin (102±57 vs. 60±42, p=0.018) with smaller increases in second phase ISR and GS. Dorzagliatin improves second phase ISR and GS, with larger effects in GCK-MODY than T2D. Disclosure E.Chow: Research Support; Hua Medicine, Medtronic, Powder Pharmaceuticals Inc., Speaker's Bureau; Novartis AG, Sanofi. L.Chen: Employee; Hua Medicine. J.C.Chan: Board Member; Asia Diabetes Foundation, Consultant; Bayer AG, Boehringer Ingelheim International GmbH, Celltrion, Merck Sharp & Dohme Corp., Roche Diabetes Care, Viatris Inc., Research Support; Applied Therapeutics, AstraZeneca, Eli Lilly and Company, Hua Medicine, Servier Laboratories, Stock/Shareholder; GemVCare Ltd. K.Wang: None. C.K.P.Lim: None. S.Tsoi: None. B.Fan: None. A.Luk: None. R.C.Ma: Other Relationship; Bayer AG, Boehringer Ingelheim International GmbH, Research Support; AstraZeneca, Bayer AG, Novo Nordisk A/S, Pfizer Inc., Tricida, Inc. E.Ferrannini: Advisory Panel; Boehringer Ingelheim International GmbH, Novo Nordisk, Oramed Pharmaceuticals, Consultant; Elgia Therapeutics, Research Support; Janssen Research & Development, LLC, Oramed Pharmaceuticals, Sanofi-Aventis U.S., Speaker's Bureau; Boehringer Ingelheim International GmbH. A.Mari: Consultant; Lilly, Research Support; Lilly. Funding Hua Medicine Investigator Initiated Clinical Research

Background: In patients with type 2 diabetes (T2D) and non-ketotic presentation, low C-peptide (CP) and positivity for glutamic acid decarboxylase antibodies (GADA+) indicate early insulin requirement. In GADA- patients, the associations of CP with insulin use, glycemic response and severe hypoglycemia event (SHE) are unknown. Methods: We measured fasting CP and GADA in 4590 Chinese patients with T2D enrolled in the Hong Kong Diabetes Register in 1995-2012 followed up till 2019. The updated homeostasis model assessment (HOMA2) was derived from fasting CP and plasma glucose. We defined incident insulin use as the first insulin prescription of at least 28 days, glycemic response as HbA1c reduction at one year after insulin initiation, and SHE using ICD-9 codes. Linear and Cox regression models were applied for association analyses. Results: At enrolment, 32% had low CP ( Conclusions: In patients with T2D, CP interacted with GADA to influence disease progressions including early insulin therapy and SHE. C-peptide might be correlated with IR in patients with GADA-. These subphenotypes allowed more precise classification of beta cell function to guide personalized treatment. Disclosure B.Fan: None. A.Luk: None. J.C.Chan: Board Member; Asia Diabetes Foundation, Consultant; Bayer AG, Boehringer Ingelheim International GmbH, Celltrion, Merck Sharp & Dohme Corp., Roche Diabetes Care, Viatris Inc., Research Support; Applied Therapeutics, AstraZeneca, Eli Lilly and Company, Hua Medicine, Servier Laboratories, Stock/Shareholder; GemVCare Ltd. E.S.H.Lau: None. H.Wu: None. M.Shi: None. A.Yang: None. C.K.P.Lim: None. A.P.Kong: Advisory Panel; Abbott, Kyowa Kirin Co., Ltd., Other Relationship; AstraZeneca, Novo Nordisk, Research Support; Boehringer Ingelheim, Speaker's Bureau; AstraZeneca, Bayer, Eli Lilly and Company, Sanofi, Stock/Shareholder; Aptorum Group Limited. E.Chow: Research Support; Hua Medicine, Medtronic, Powder Pharmaceuticals Inc., Speaker's Bureau; Novartis AG, Sanofi. R.C.Ma: Other Relationship; Bayer AG, Boehringer Ingelheim International GmbH, Research Support; AstraZeneca, Bayer AG, Novo Nordisk A/S, Pfizer Inc., Tricida, Inc. Funding The HKG Health Medical and Research Fund and RGC Research Impact Fund

Background: Few studies reported incidence rates of late-stage complications in people with youth-onset type 2 diabetes. We compared the clinical characteristics and incidence of cardiovascular disease (CVD) , end-stage kidney disease (ESKD) and death in a cohort of Chinese youth with type 2 and type 1 diabetes. Method: We performed a retrospective analysis of 1221 people with type 2 diabetes and 641 with type 1 diabetes diagnosed at age Result: At baseline, people with youth-onset type 2 diabetes were older at diagnosis (16 [14-18] vs. [8-15] years, p Conclusion: People with youth-onset type 2 diabetes had 2-fold increased risk of CVD and ESKD, in part driven by greater burden of obesity and other metabolic risk factors in this group. Disclosure Y.Fan: None. E.S.H.Lau: None. H.Wu: None. A.Yang: None. E.Chow: Research Support; Hua Medicine, Medtronic, Powder Pharmaceuticals Inc., Speaker's Bureau; Novartis AG, Sanofi. A.P.Kong: Advisory Panel; Abbott, Kyowa Kirin Co., Ltd., Other Relationship; AstraZeneca, Novo Nordisk, Research Support; Boehringer Ingelheim, Speaker's Bureau; AstraZeneca, Bayer, Eli Lilly and Company, Sanofi, Stock/Shareholder; Aptorum Group Limited. R.C.Ma: Other Relationship; Bayer AG, Boehringer Ingelheim International GmbH, Research Support; AstraZeneca, Bayer AG, Novo Nordisk A/S, Pfizer Inc., Tricida, Inc. J.C.Chan: Board Member; Asia Diabetes Foundation, Consultant; Bayer AG, Boehringer Ingelheim International GmbH, Celltrion, Merck Sharp & Dohme Corp., Roche Diabetes Care, Viatris Inc., Research Support; Applied Therapeutics, AstraZeneca, Eli Lilly and Company, Hua Medicine, Servier Laboratories, Stock/Shareholder; GemVCare Ltd. A.Luk: None.

Objective: The rare risk association of bullous pemphigoid (BP) with use of dipeptidyl peptidase-4 inhibitors (DPP-4i) had been reported including genetic association with HLA variants. We assessed genetic susceptibility of BP associated with DPP-4i use in patients with type 2 diabetes (T2D) . Methods: In a prospective cohort of 30,129 Chinese patients with T2D enrolled in the Hong Kong Diabetes Register between 1995 to 2018, we curated multiple case-control cohorts with available genotype data to explore the genetic associations of major histocompatibility complex (MHC) region with DDP-4i-associated BP. Results: During a median follow period of 9 years, 60 patients developed BP (incidence of 2.cases per 10,000 patient-years) . 20 patient developed BP after DPP-4i use, with median exposure to DPP-4i of 1.7 years (incidence of 4.76 cases per 10,000 patient-years) and an adjusted odds ratio of 1.1 (95% CI 0.5-1.6) . 32 patients developed BP and were not exposed to DPP-4i (incidence of 2.87 cases per 10,000 patient-years) . In 1:2 matched case:control cohort of patients who tolerated DPP-4i and did not develop of BP, multiple variants in the second intron of HLA-DQB1 exhibited strong association with DPP4i-associated BP, including the well-reported HLA-DQB1*03: (OR 12.00; 95% CI 1.99-72.35; P-value 6.71e-03) and a novel single nucleotide polymorphism rs281863580 (OR 11.96; 95% CI 4.14-34.54; P-value 4.53e-06) . We additionally identified variants located in other HLA regions that were associated with BP in non-DPP4i users. Conclusion: Multiple genetic polymorphisms in the second intron of HLA-DQB1 were associated with increased susceptibility to incident BP in DPP-4i users. Further exploration of the extended MHC region beyond HLA alleles might identify a combination panel for assessing the genetic risk of BP rather than a single HLA allele. Disclosure M.Shi: None. A.Yang: None. E.Chow: Research Support; Hua Medicine, Medtronic, Powder Pharmaceuticals Inc., Speaker's Bureau; Novartis AG, Sanofi. E.S.Lau: None. C.H.Tam: None. R.C.Ma: Other Relationship; Bayer AG, Boehringer Ingelheim International GmbH, Research Support; AstraZeneca, Bayer AG, Novo Nordisk A/S, Pfizer Inc., Tricida, Inc. M.Cheung: None. J.C.Chan: Board Member; Asia Diabetes Foundation, Consultant; Bayer AG, Boehringer Ingelheim International GmbH, Celltrion, Merck Sharp & Dohme Corp., Roche Diabetes Care, Viatris Inc., Research Support; Applied Therapeutics, AstraZeneca, Eli Lilly and Company, Hua Medicine, Servier Laboratories, Stock/Shareholder; GemVCare Ltd. W.Chan: None. Funding The Hong Kong Government Research Grants Committee Theme-based Research Scheme (T12-402/13N) .2) Impact Research Impact Fund (R4012-18) .

Introduction: Whether angiotensin converting enzyme inhibitors (ACEi) and angiotensin receptor blockers (ARBs) should be discontinued in advanced diabetic kidney disease (DKD) remains controversial. We examined the association of discontinuation of ACEi/ARBs when estimated glomerular filtration rate (eGFR) reached Methods: We performed a prospective analysis of a register including 11,323 patients stratified by continuation of ACEi/ARBs within 6 months of reaching eGFR Results: Of 11,323 ACEi/ARBs users with new-onset eGFR Conclusions: Discontinuation of ACEi/ARBs was associated with increased risk of cardiovascular-renal events in support of their continued use in patients with advanced DKD. Disclosure M.Shi: None. J.C.Chan: Board Member; Asia Diabetes Foundation, Consultant; Bayer AG, Boehringer Ingelheim International GmbH, Celltrion, Merck Sharp & Dohme Corp., Roche Diabetes Care, Viatris Inc., Research Support; Applied Therapeutics, AstraZeneca, Eli Lilly and Company, Hua Medicine, Servier Laboratories, Stock/Shareholder; GemVCare Ltd. E.Chow: Research Support; Hua Medicine, Medtronic, Powder Pharmaceuticals Inc., Speaker's Bureau; Novartis AG, Sanofi. A.Yang: None. E.S.H.Lau: None. H.Wu: None. X.Zhang: None. B.Fan: None. A.P.Kong: Advisory Panel; Abbott, Kyowa Kirin Co., Ltd., Other Relationship; AstraZeneca, Novo Nordisk, Research Support; Boehringer Ingelheim, Speaker's Bureau; AstraZeneca, Bayer, Eli Lilly and Company, Sanofi, Stock/Shareholder; Aptorum Group Limited. A.Luk: None. R.C.Ma: Other Relationship; Bayer AG, Boehringer Ingelheim International GmbH, Research Support; AstraZeneca, Bayer AG, Novo Nordisk A/S, Pfizer Inc., Tricida, Inc.

Introduction: Treatment acceptance and self-management are essential for achieving better HbA1c in people with diabetes. Methods: IDMPS is an international, observational study investigating care practices and clinical profiles of people with diabetes in developing countries. This analysis of Wave 8 evaluated PROs in people with T2D and their associations with glycemic control using 1) the chronic treatment acceptance questionnaire (ACCEPT) to assess acceptance of long-term medication advantages/disadvantages, and 2) the diabetes self-management questionnaire (DSMQ) to assess health-related behaviors. Results: Of 2475 people with T2D (mean ± SD age 58 ± 12 years, 51% women, diabetes duration ± 8 years, BMI 31 ± 6 kg/m2, HbA1c 8.0 ± 1.8 %, 43% on insulin, HbA1c Conclusions: Despite high medication acceptance in developing countries, low self-management calls for further education to improve medication effectiveness. Disclosure P.Aschner: Advisory Panel; Merck & Co., Inc., Sanofi, Speaker's Bureau; AstraZeneca, Boehringer Ingelheim International GmbH, Novo Nordisk. J.C.Chan: Board Member; Asia Diabetes Foundation, Consultant; Bayer AG, Boehringer Ingelheim International GmbH, Celltrion, Merck Sharp & Dohme Corp., Roche Diabetes Care, Viatris Inc., Research Support; Applied Therapeutics, AstraZeneca, Eli Lilly and Company, Hua Medicine, Servier Laboratories, Stock/Shareholder; GemVCare Ltd. J.J.Gagliardino: None. H.M.Ilkova: Advisory Panel; Novo Nordisk. A.Ramachandran: None. J.Mbanya: Advisory Panel; Novo Nordisk, Sanofi, Servier Laboratories. M.V.Shestakova: None. V.Pilorget: None. L.Melas-melt: None. J.Chantelot: Employee; Sanofi, Stock/Shareholder; Sanofi. Funding Sanofi

Fermentable oligo-, di-, monosaccharides, and polyols (FODMAPs) are fermentable short-chain carbohydrates that include fructans, galactooligosaccharides (GOS) , lactose, excess fructose, mannitol and sorbitol. Low FODMAP diets in irritable bowel syndrome were associated with reductions in metabolically beneficial, short-chain fatty acids (SCFA) - producing bacteria. We examined the interactions between FODMAP, gut microbiota and glucose tolerance in this exploratory analysis. Twenty subjects underwent oral glucose tolerance tests (OGTT) with C peptide measurements. Ten were classified as normal glucose tolerant (mean ±SD 55±years, body mass index (BMI) 22.7­±2.5 kg/m2, 2-hour plasma glucose 5.7±1.0 mmol/L) and with impaired glucose tolerance (58±­5 years, BMI 23.5±2.9 kg/m2, 2-hour glucose 9.0±0.9 mmol/L) . FODMAPs and macronutrients were assessed from 3-day food diaries. Fecal samples were collected for microbiome analysis. Total FODMAPs were positively correlated to presence of Dorea (r=0.49, p=0.027) . For individual FODMAP items, lactose was positively correlated with Akkermansia (r=0.54, p=0.013) , Bifidobacterium (r=0.42, p=0.037) and negatively correlated with Shigella (r=0.35, p=0.031) in both groups. GOS were positively correlated with Lactobacillus (r= 0.21, p=0.006) and negatively with Shigella (r=0.28, p=0.043) . In the whole group, lower insulin resistance as shown by homeostasis model assessment HOMA2-IR was associated with higher abundance of Bifidobacterium logum (r=0.48, p=0.01) . HOMA2-beta showed correlation with Dorea (r=0.43, p=0.056) . FODMAPs increased the health-promoting microbiota (e.g. Dorea, Lactobacillus, Akkermansia, and Bifidobacterium) . These SCFA promoting microbiota were associated with lower insulin resistance and improved beta-cell function while suppressing the growth of opportunistic pathogens, such as Escherichia spp. Disclosure N. Chu: None. J. He: None. R.C. Ma: Research Support; AstraZeneca, Bayer AG, Novo Nordisk A/S, Pfizer Inc., Tricida, Inc. Other Relationship; Bayer AG, Boehringer Ingelheim International GmbH. A.P. Kong: Advisory Panel; Abbott, Kyowa Kirin Co., Ltd. Research Support; Boehringer Ingelheim. Speaker's Bureau; AstraZeneca, Bayer, Eli Lilly and Company, Sanofi. Stock/Shareholder; Aptorum Group Limited. Other Relationship; AstraZeneca, Novo Nordisk. J.C. Chan: Board Member; Asia Diabetes Foundation. Consultant; Bayer AG, Boehringer Ingelheim International GmbH, Celltrion, Merck Sharp & Dohme Corp., Roche Diabetes Care, Viatris Inc. Research Support; Applied Therapeutics, AstraZeneca, Eli Lilly and Company, Hua Medicine, Servier Laboratories. Stock/Shareholder; GemVCare Ltd. E. Chow: Research Support; Hua Medicine, Medtronic, Powder Pharmaceuticals Inc. Speaker's Bureau; Novartis AG, Sanofi. Funding Health Medical Research Fund (17180431) Hong Kong College of Physicians Young Investigator's Research Grant

Background: The diabetes-cancer link may be mediated by inflammation due to infection such as Human Papilloma Virus (HPV). Exendin 4, a Glucagon-like-peptide 1 agonist, has anti-hyperglycemic and anti- inflammatory effect and can attenuate certain cancer growth. Methods: We used RNA microarray analysis to detect the gene expression after Exendin 4 treatment in the db/db mouse tumor, which was established by inoculation of mouse PV cancer cells (CUP-1). The latter originates from the kidney of baby C57BL/6J mice expressing HPV-16 E7 oncogene. We examined the effect of Exendin 4 on cell proliferation, apoptosis and gene expression along the inflammatory pathway in CUP-1 under different glucose environment. We developed CUP-1 cells with or without target gene overexpression (OE) or downregulation (DR) for inoculation into the db/db mouse. We compared RNA expression of the target gene in cervical cancer specimen from patients with or without diabetes. Results: RNA expression of proteasome 20s (psma) was decreased after Exendin 4 treatment in the db/db mouse tumor. High glucose environment increased cell proliferation in CUP-1 cells, which was enhanced after OE of psma but attenuated after DR of psma. Exendin 4 suppressed NFκB P65 and IκB activation in CUP-1 cells under high glucose medium. After inoculation of CUP-1 cells with DR and OE of psma, the tumor size was decreased and increased in db/db mice respectively. Exendin 4 decreased the tumor volume in the db/db mice of psma OE group. In human cervical cancer specimen, RNA expression of psma was increased in patients with diabetes versus those without diabetes. Conclusion: High glucose increased expression of psma, which activated NFκB inflammation pathway and promoted carcinogenesis. Exendin 4 suppressed the NFκB pathway activation and decreased tumor volume with corroborative evidence from human samples, suggesting that the anti-cancer effect of Exendin 4 might be mediated by the psma-NFκB pathway. Disclosure D. Mao: None. J.C. Chan: None.

Mutations in the LMNA gene (encoding lamin A/C) underlie familial partial lipodystrophy, a syndrome of monogenic insulin resistance and diabetes. LMNA maps to the well-replicated diabetes-linkage region on chromosome 1q, and there are reported associations between LMNA single nucleotide polymorphisms (SNPs) (particularly rs4641; H566H) and metabolic syndrome components. We examined the relationship between LMNA variation and type 2 diabetes (using six tag SNPs capturing >90% of common variation) in several large datasets. Analysis of 2,490 U.K. diabetic case and 2,556 control subjects revealed no significant associations at either genotype or haplotype level: the minor allele at rs4641 was no more frequent in case subjects (allelic odds ratio [OR] 1.07 [95% CI 0.98-1.17], P = 0.15). In 390 U.K. trios, family-based association analyses revealed nominally significant overtransmission of the major allele at rs12063564 (P = 0.01), which was not corroborated in other samples. Finally, genotypes for 2,817 additional subjects from the International 1q Consortium revealed no consistent case-control or family-based associations with LMNA variants. Across all our data, the OR for the rs4641 minor allele approached but did not attain significance (1.07 [0.99-1.15], P = 0.08). Our data do not therefore support a major effect of LMNA variation on diabetes risk. However, in a meta-analysis including other available data, there is evidence that rs4641 has a modest effect on diabetes susceptibility (1.10 [1.04-1.16], P = 0.001).