Diabetes Research and Clinical Practice - Volume 120 - Supplement 1 - October 2016

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Metabolic dysregulation plays a critical role during the devel-
opment 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 asso-
ciated 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 gener-
ation, and increased ATP production. To elucidate the causal
relationship between impaired Akt1 translocation to mito-
chondria in diabetic myocardium and the development of
diabetic cardiomyopathy, we have generated a transgenic
mouse line by knocking in a tamoxifen-inducible mito-
chondria-targeting dominant negative Akt (mdnAkt) into the
Rosa26 locus (CAMDAKT mice). Cardiac specificity was
achieved with the Cre-Lox strategy. After Tamoxifen induc-
tion, 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 mito-
chondria. These findings suggest that impaired Akt1 trans-
location 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. 1 Department 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 strat-
egies and the risk of CVD never stop. Cardiovascular safety
has become one of the important factors to evaluate anti-
diabetic agents. A meta-analysis in 2007 showed that rosigli-
tazone 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 hypogly-
cemic agents. Many large-scale clinical studies for hypogly-
cemic 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 appli-
cation 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
withbloodglucose to reducemicrovascularcomplications 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 autoregula-
tion, 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 associ-
ation 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 reducedalbuminuria 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 renin-
angiotensin 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 S12