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Inspiration from the historical evolution of large-scale clinical studies in diabetes – the cardiovascular safety of hypoglycemic therapy
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Speech Abstracts / Diabetes Research and Clinical Practice 120S1 (2016) S1–S39
Metabolic dysregulation plays a critical role during the development of diabetic cardiomyopathy and diabetes aggravates heart failure. Mitochondria are the major source of ATP production in the heart, via glycolysis and β-oxidation. Glycolytic Oxidative phosphorylation is significantly reduced in the diabetic myocardium, thereby creating a metabolic switch to selectively relying on β-oxidation, which is associated with lipotoxicity and inefficient energy conversion. We have shown that insulin stimulated Akt1 translocation to mitochondria and modulated mitochondria function in cardiac muscle, and translocation of Akt1 to mitochondria was significantly reduced in diabetic myocardium. Activation of Akt1 signaling in mitochondria increased glucose uptake, enhanced respiration efficiency, reduced superoxide generation, and increased ATP production. To elucidate the causal relationship between impaired Akt1 translocation to mitochondria in diabetic myocardium and the development of diabetic cardiomyopathy, we have generated a transgenic mouse line by knocking in a tamoxifen-inducible mitochondria-targeting dominant negative Akt (mdnAkt) into the Rosa26 locus (CAMDAKT mice). Cardiac specificity was achieved with the Cre-Lox strategy. After Tamoxifen induction, CAMDAKT mice developed heart failure within 7 days. Analysis showed altered mitochondria ultrastructure and loss of mitochondria cristae. These findings were followed by reduction of muscle mass, inflammation, cardiac fibrosis, and biventricular heart failure. Proteomic analysis indicated pyruvate dehydrogenase complex (PDC) as a signaling target of Akt1 in mitochondria. Akt1 interacted with the E3 subunit of PDC, activation of mitochondrial Akt1 increased pyruvate dehydrogenase (PDH) activity. We have computationally analyzed protein−protein domains interfacing Akt1/E3 interaction. Screening compounds library yielded two small molecules that structurally disrupted Akt1-E3 interaction. Further analysis with recombinant proteins confirmed interaction of Akt1-E3 and the small molecule compound suppressed Akt1 activation of PDC activity in cardiac mitochondria. These findings suggest that impaired Akt1 translocation to mitochondria played a critical role in the development of diabetic cardiomyopathy. S08-2 Inspiration from the historical evolution of large-scale clinical studies in diabetes – the cardiovascular safety of hypoglycemic therapy W. YANG1. 1Department of Endocrinology, China-Japan Friendship Hospital, Beijing, China The prevalence of diabetes increases with increasing age. Several diabetic guidelines indicate that T2DM patients have cardiovascular risk. Studies exploring the hypoglycemic strategies and the risk of CVD never stop. Cardiovascular safety has become one of the important factors to evaluate antidiabetic agents. A meta-analysis in 2007 showed that rosiglitazone increased cardiovascular death, causing the attention on the cardiovascular safety of hypoglycemic agents. FDA requires that cardiovascular safety must be evaluated in premarketing and postmarketing clinical trials for hypoglycemic agents. Many large-scale clinical studies for hypoglycemic agents, such as SAVOR, TECOS, EMPA-REG OUTCOME studies, all set cardiovascular death, nonfatal myocardial infarction and nonfatal stroke as the primary endpoints, and were all designed as multi-center, randomized, double-blind, placebo-controlled trials. The non-inferiority or superiority of the hypoglycemic agents compared to placebo was assessed independently. These large-scale clinical studies provide guiding benefits for appropriate selection and personal application of hypoglycemic agents in clinical practices.
DM Nephropathy: Risk, Mechanism, Management and Outcome S15-2 Individualized blood pressure targets in Asian diabetic patients with or without nephropathy Juliana C.N. CHAN1. 1Department of Medicine and Therapeutics, Hong Kong Institute of Diabetes and Obesity, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong Diabetes is a leading cause of end stage renal disease which can be prevented by optimal control of cardiometabolic risk factors including blood pressure (BP), blood lipids, blood glucose as well as appropriate use of renin-angiotensin system inhibitors. Although there is broad consensus on the benefits of multi-factorial management on organ protection, the target values of BP control remains controversial. Several large scale studies including the ACCORD Trial failed to demonstrate reduction of BP to less than 120/80 mmHg conferred cardiovascular benefits and might increase adverse effects in high risk patients. Some of the controversies on intensity of BP management relate to the heterogeneous nature of risk factors and complications which interact with interventions to give rise to different consequences. Here, BP control remains a major modifying factor which can interact with blood glucose to reduce microvascular complications such as albuminuria and renal function as well as with lipids to reduce macrovascular diseases such as coronary heart disease and stroke. However, in high risk patients such as elderly or patients with generalised atherosclerosis or poor autoregulation, excessive reduction in BP may compromise blood flow to cause impaired organ functions such as kidney and heart. On the other hand, since young patients face long disease duration, early control of all risk factors including blood pressure, blood glucose and blood lipid is important to reduce lifetime risk for complications, such as diabetic kidney disease. In the ORIENT study which included Chinese and Japanese patients with type 2 diabetes, chronic kidney disease and macroalbuminuria, a post-hoc analysis showed linear association between follow up systolic BP and renal outcomes, where BP level of 120 mmHg was associated with the slowest rate of decline of renal function. In a recent meta-analysis, intensive BP control reduced albuminuria but not cardiovascular disease. Taken together, given the heterogeneous nature of diabetes with different combinations of age, sex, disease duration, risk factors, complications and co-morbidities, individualization of BP goal is as important as that for glycemic control. References 1. Imai E, Haneda M, Yamasaki T, Kobayashi F, Harada A, Ito S, Chan JC, Makino H. Effects of dual blockade of the reninangiotensin system on renal and cardiovascular outcomes in type 2 diabetes with overt nephropathy and hypertension in the orient: A post-hoc analysis (Orient-Hypertension). Hypertension Research 2013;36:1051–1059. 2. Imai E, Ito S, Haneda M, Harada A, Kobayashi F, Yamasaki T, Makino H, Chan JC. Effects of blood pressure on renal and cardiovascular outcomes in Asian patients with type 2 diabetes and overt nephropathy: A post hoc analysis (Orient-blood pressure). Nephrology, Dialysis, Transplantation: Official Publication of the European Dialysis and Transplant Association – European Renal Association. 2016;31:447–454 S15-3 Choice of antidiabetic agents and glycemic goals in patients with diabetic kidney disease Shyi-Jang SHIN1,2. 1Department of Internal Medicine, College of Medicine, Kaohsiung Medical University, 2Division of Endocrinology and Metabolism, KMU Hospital, Kaohsiung, Taiwan
Speech Abstracts / Diabetes Research and Clinical Practice 120S1 (2016) S1–S39
Metabolic dysregulation plays a critical role during the development of diabetic cardiomyopathy and diabetes aggravates heart failure. Mitochondria are the major source of ATP production in the heart, via glycolysis and β-oxidation. Glycolytic Oxidative phosphorylation is significantly reduced in the diabetic myocardium, thereby creating a metabolic switch to selectively relying on β-oxidation, which is associated with lipotoxicity and inefficient energy conversion. We have shown that insulin stimulated Akt1 translocation to mitochondria and modulated mitochondria function in cardiac muscle, and translocation of Akt1 to mitochondria was significantly reduced in diabetic myocardium. Activation of Akt1 signaling in mitochondria increased glucose uptake, enhanced respiration efficiency, reduced superoxide generation, and increased ATP production. To elucidate the causal relationship between impaired Akt1 translocation to mitochondria in diabetic myocardium and the development of diabetic cardiomyopathy, we have generated a transgenic mouse line by knocking in a tamoxifen-inducible mitochondria-targeting dominant negative Akt (mdnAkt) into the Rosa26 locus (CAMDAKT mice). Cardiac specificity was achieved with the Cre-Lox strategy. After Tamoxifen induction, CAMDAKT mice developed heart failure within 7 days. Analysis showed altered mitochondria ultrastructure and loss of mitochondria cristae. These findings were followed by reduction of muscle mass, inflammation, cardiac fibrosis, and biventricular heart failure. Proteomic analysis indicated pyruvate dehydrogenase complex (PDC) as a signaling target of Akt1 in mitochondria. Akt1 interacted with the E3 subunit of PDC, activation of mitochondrial Akt1 increased pyruvate dehydrogenase (PDH) activity. We have computationally analyzed protein−protein domains interfacing Akt1/E3 interaction. Screening compounds library yielded two small molecules that structurally disrupted Akt1-E3 interaction. Further analysis with recombinant proteins confirmed interaction of Akt1-E3 and the small molecule compound suppressed Akt1 activation of PDC activity in cardiac mitochondria. These findings suggest that impaired Akt1 translocation to mitochondria played a critical role in the development of diabetic cardiomyopathy. S08-2 Inspiration from the historical evolution of large-scale clinical studies in diabetes – the cardiovascular safety of hypoglycemic therapy W. YANG1. 1Department of Endocrinology, China-Japan Friendship Hospital, Beijing, China The prevalence of diabetes increases with increasing age. Several diabetic guidelines indicate that T2DM patients have cardiovascular risk. Studies exploring the hypoglycemic strategies and the risk of CVD never stop. Cardiovascular safety has become one of the important factors to evaluate antidiabetic agents. A meta-analysis in 2007 showed that rosiglitazone increased cardiovascular death, causing the attention on the cardiovascular safety of hypoglycemic agents. FDA requires that cardiovascular safety must be evaluated in premarketing and postmarketing clinical trials for hypoglycemic agents. Many large-scale clinical studies for hypoglycemic agents, such as SAVOR, TECOS, EMPA-REG OUTCOME studies, all set cardiovascular death, nonfatal myocardial infarction and nonfatal stroke as the primary endpoints, and were all designed as multi-center, randomized, double-blind, placebo-controlled trials. The non-inferiority or superiority of the hypoglycemic agents compared to placebo was assessed independently. These large-scale clinical studies provide guiding benefits for appropriate selection and personal application of hypoglycemic agents in clinical practices.
DM Nephropathy: Risk, Mechanism, Management and Outcome S15-2 Individualized blood pressure targets in Asian diabetic patients with or without nephropathy Juliana C.N. CHAN1. 1Department of Medicine and Therapeutics, Hong Kong Institute of Diabetes and Obesity, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong Diabetes is a leading cause of end stage renal disease which can be prevented by optimal control of cardiometabolic risk factors including blood pressure (BP), blood lipids, blood glucose as well as appropriate use of renin-angiotensin system inhibitors. Although there is broad consensus on the benefits of multi-factorial management on organ protection, the target values of BP control remains controversial. Several large scale studies including the ACCORD Trial failed to demonstrate reduction of BP to less than 120/80 mmHg conferred cardiovascular benefits and might increase adverse effects in high risk patients. Some of the controversies on intensity of BP management relate to the heterogeneous nature of risk factors and complications which interact with interventions to give rise to different consequences. Here, BP control remains a major modifying factor which can interact with blood glucose to reduce microvascular complications such as albuminuria and renal function as well as with lipids to reduce macrovascular diseases such as coronary heart disease and stroke. However, in high risk patients such as elderly or patients with generalised atherosclerosis or poor autoregulation, excessive reduction in BP may compromise blood flow to cause impaired organ functions such as kidney and heart. On the other hand, since young patients face long disease duration, early control of all risk factors including blood pressure, blood glucose and blood lipid is important to reduce lifetime risk for complications, such as diabetic kidney disease. In the ORIENT study which included Chinese and Japanese patients with type 2 diabetes, chronic kidney disease and macroalbuminuria, a post-hoc analysis showed linear association between follow up systolic BP and renal outcomes, where BP level of 120 mmHg was associated with the slowest rate of decline of renal function. In a recent meta-analysis, intensive BP control reduced albuminuria but not cardiovascular disease. Taken together, given the heterogeneous nature of diabetes with different combinations of age, sex, disease duration, risk factors, complications and co-morbidities, individualization of BP goal is as important as that for glycemic control. References 1. Imai E, Haneda M, Yamasaki T, Kobayashi F, Harada A, Ito S, Chan JC, Makino H. Effects of dual blockade of the reninangiotensin system on renal and cardiovascular outcomes in type 2 diabetes with overt nephropathy and hypertension in the orient: A post-hoc analysis (Orient-Hypertension). Hypertension Research 2013;36:1051–1059. 2. Imai E, Ito S, Haneda M, Harada A, Kobayashi F, Yamasaki T, Makino H, Chan JC. Effects of blood pressure on renal and cardiovascular outcomes in Asian patients with type 2 diabetes and overt nephropathy: A post hoc analysis (Orient-blood pressure). Nephrology, Dialysis, Transplantation: Official Publication of the European Dialysis and Transplant Association – European Renal Association. 2016;31:447–454 S15-3 Choice of antidiabetic agents and glycemic goals in patients with diabetic kidney disease Shyi-Jang SHIN1,2. 1Department of Internal Medicine, College of Medicine, Kaohsiung Medical University, 2Division of Endocrinology and Metabolism, KMU Hospital, Kaohsiung, Taiwan