Objectives: Asians are at high risk for diabetes mellitus (DM), yet there is little population-based information about DM prevalence among subgroups of immigrants and US-born Asians in the US over time. The purpose of this study is to compare the prevalence and odds ratios (ORs) of DM between Asian and Asian subgroup immigrants and White in California using data from 2003, 2005, 2007, 2009, 2011, 2013 California Health Interview Survey (CHIS).

Methods: Six CHIS datasets were analyzed and compared to determine the prevalence of DM among Asian Immigrants and White from 2003 to 2013. Subjects who reported a physician-diagnosis of diabetes (type 1 and type 2) were considered to have DM (borderline/prediabetes and gestational diabetes were not included). Multivariable logistic regression models were built to calculate adjusted ORs of DM and to find the potential explanations for the differences in the prevalence results.

Results: There was a trend towards higher rate of diabetes for both Asian Immigrants and White in California over the last decade. Asian Immigrants had a continuously higher prevalence of DM compared to White, and the difference was greater especially in 2013. Prevalence of DM varied greatly among Asian subgroups with Filipinos and Koreans being two highest groups. After adjusting for confounding variables (age, sex, obesity, education attainment, insurance status, English proficiency, smoking status, taking medication to control high blood pressure), the ORs of DM between Asian Immigrants and White were 1.71(0.96-3.05), 1.31(0.81-2.13), 1.22(0.79-1.89), 2.19*(1.13-4.22), 1.81*(1.15-2.87), 2.09*(1.05-4.18) for 2003, 2005, 2007, 2009, 2011 and 2013 CHIS dataset respectively.

Conclusions: Overall, Asian Immigrants were more likely to develop DM compared to White in California during the last decade, even after controlling for confounding variables. Great variability exists in DM prevalence among Asian subgroups and this should be considered in future studies.

Diabetic cardiomyopathy, the changes to myocardial structure and function directly attributed to diabetes, is increasing in prevalence, correlating with this rise of the diabetes and obesity epidemics. Despite this, the exact mechanisms are unclear and no specific treatments for diabetic cardiomyopathy (DCM) yet exists, thus the need for further research. Mitochondrial dysfunction is characteristic of DCM and we have demonstrated that impaired translocation of AKT1 to mitochondria due to insulin resistance in animal models of diet-induced diabetes, accompanied by changes of mitochondrial structure and function. Here we showed that maintaining mito-Akt1 signaling in the context of diet-induced diabetes protected against the development of DCM. I investigated the underlying mechanisms, using a novel cardiomyocyte-specific transgenic mice harboring an inducible mitochondria-targeting constitutively active AKT (CAMCAKT) with a Cre-lox strategy. Under a high fat, high fructose diet, diabetic CAMCAKT mice exhibited improved heart function, whereby ejection fraction was 17 % higher than in diabetic controls (p < 0.05) and fractional shortening was 22% greater (p < 0.05). Left ventricular hypertrophy and perivascular fibrosis was also significantly reduced (p < 0.05). Gene expression analysis suggested that fatty acid. metabolism was upregulated by mito-Akt1 while simultaneously, extracellular flux assays measured improved respiratory efficiency coupled with increased myocardial ATP concentration (p < 0.05). Interestingly, improvements in heart function was associated with improvements in whole body metabolism, in vivo studies indicated increased energy expenditure (p < 0.05) and improved whole body leanness (p < 0.05). Liver steatosis was reduced (p < 0.05) in the CAMCAKT mice, furthermore, inter organ endocrine peptide analysis predicted remote modulation of liver metabolism by the heart. In summary, we showed a substantial role of cardiac mitochondrial AKT signaling during the development of DCM and demonstrated its metabolic and regulatory benefits in both the myocardium and also in whole body metabolism.

The ability of self-renewal and the unlimited potential to differentiate into three germ layers make pluripotent stem cells a key player in regenerative medicine and disease modeling. Recent studies have shown that several signaling pathways and the bioenergetic function of mitochondria play critical roles in the regulation of stem cell differentiation and somatic cell reprogramming. Phosphatidylinositol-3 kinase/Akt signaling (PI3K/Akt) has been previously reported to be critical for maintaining the pluripotency of embryonic stem cells (ESC) via interaction with other signaling pathways, such as LIF/JAK/STAT. It has been shown that Akt translocates into mitochondria after growth factor or cytokine stimulation in differentiated cells. Herein, we demonstrated the translocation of Akt into mitochondria also occurs in human embryonic stem cells (hESCs) after serum stimulation. Intriguingly, our previous data showed that activation of mitochondrial Akt signaling enhanced somatic cell reprogramming. However, the effect of mitochondrial Akt signaling on stem cell differentiation has not yet been investigated.

Testing the effect of temporarily inhibiting mitochondrial Akt1 signaling in hESCs, I transduced cells with the His-tagged mitochondrial-targeting dominant negative Akt1/GFP adenoviral vector (Ad-mdnAkt1/GFP) or the GFP adenoviral vector (Ad-GFP) and differentiated spontaneously in vitro in differentiation medium. Evaluating transduction rate by fluorescence microscopy and flow cytometry and was determined to be over 60% in both groups. Immunoblotting was used to verify mutant Akt1 expression, and respiratory function of cells was evaluated by an extracellular flux analyzer. Spontaneous differentiation in vitro was characterized with H&E staining and showed that Ad-mdnAkt1/GFP treated cells formed more organized colonies than Ad-GFP treated cells. In line with this, bulk RNA analyzed by human cell lineage identification qPCR array showed that marker genes of mesoderm and endoderm were up-regulated and marker genes of ectoderm were down-regulated in Ad-mdnAkt1/GFP treated cells. Further Identification of unique development by single-cell RNA sequencing revealed inhibition of hematological and immune cells differentiation and promotion of lung and kidney development, middle ear morphogenesis and smooth muscle cell differentiation in Ad-mdnAkt1/GFP treated cells.

Acute kidney injury (AKI) is a significant public health issue with high morbidity and mortality. Recent evidences suggest that renal tubular dysfunction may modulate glomerular function; however, its mechanism remains unknown. We hypothesized that mitochondrial AKT1 signaling could play a protective role in the pathogenesis of AKI and subsequent kidney failure. We have generated novel renal tubular cell-specific transgenic mice harboring an inducible mitochondria-targeting dominant negative AKT1 (KMDAKT) or constitutively active AKT1 (KMCAKT) with Cre-lox strategy. AKI was induced by ischemia-reperfusion injury (IRI). IRI induced greater renal injury with increased Jablonski score (p=0.018), an index of overall renal tubular injuries, in the tamoxifen (TAM)-injected KMDAKT mice. Renal fibrosis areas (%) by Masson’s trichrome stain was significantly larger in the KMDAKT mice as compared to the control mice (p<0.001). Marker for renal tubule injury (kidney injury molecule-1, KIM-1) was significantly increased in the KMDAKT mice (p=0.002). Grades of Periodic acid Schiff (PAS) stain of glomerulosclerosis were significantly higher on day 45 post AKI in the TAM-KMDAKT (p<0.001). Creatinine (Cr.) was significantly higher in the TAM-KMDAKT group 45 days post AKI (p<0.001). Survival rate was significantly lower in the TAM-MDAKT mice 7 days post ischemia (46.67%) as compared to the controls (85.71%) (p=0.0013). To study whether enhancing tubule mitochondrial AKT1 signaling can further protect kidney injury, we used KMCAKT mice as our experimental model. Histology analysis confirmed lesser renal injury with decreased Jablonski score after AKI (p=0.038). Renal fibrosis areas (%) was significantly smaller when compared to the control mice (p=0.002). KIM-1 were decreased in the KMCAKT mice (p<0.001). PAS stain of glomerulosclerosis were significantly lower in the TAM injected KMCAKT mice45 days post AKI (p<0.001). Survival rate in the TAM-KMCAKT mice after AKI was improved (p<0.001). Mitochondria respiration was investigated and the results showed increased basal respiration (p<0.001), spare respiration (p<0.001), adenosine triphosphate (ATP) dependent respiration (p<0.001), and proton leak in the KMDAKT tubule cells. Activation of mitochondrial AKT1 signaling protected kidney injury from glomerulosclerosis after IRI through attenuating renal tubular damage, therefore, mitochondrial AKT1 is a novel target for therapeutic intervention to prevent AKI and subsequent development of CKD.

Embryonic stem cells (ESC) are distinguished by their capacity for self-renewal and differentiation, abilities that are foundational to emerging research on cell-based therapies and regenerative medicine. The mechanisms underlying stem cell pluripotency and differentiation however, remain poorly understood. The discovery of induced pluripotent stem cells (iPSCs) advanced our understanding of pluripotency and broadened the applications of stem cell; it also bypassed the ethical issue of using embryonic stem cells. Although the technique has been broadly applied and modified in the last decade, the mechanistic details remain elusive. It has been demonstrated that activation of phosphatidylinositol-3 kinase/Akt signaling enhanced stem cell pluripotency and iPSC reprogramming. Activation of Akt1 has been reported translocating from cytoplasm to mitochondria. However, the roles of mitochondrial Akt1 plays in the regulation of stem cell pluripotency and iPSC reprogramming have not yet been determined. Using Yamanaka factor reprogramming, we demonstrated that activation of mitochondrial Akt1 signaling enhanced reprogramming efficiency. In addition, we also observed that the DNA methylation status at the OCT4 and NANOG promoters of the resulting Yamanaka factors- mitochondrial Akt1-reprogrammed cell displayed a more profound de-methylation profile. We also demonstrated that the resulting Yamanaka-mitochondrial Akt1-reprogrammed cells displayed a respiration profile more similar to that in ESCs. Increasing evidence has implicated the importance of mitochondria and cellular metabolism in iPSC reprogramming. Interestingly, we observed that activation of mitochondrial Akt1 signaling reduced cellular oxygen consumption, NADH levels and maintained ATP levels, leading to lower reactive oxygen species production and lower apoptosis levels under stress conditions. We further identified the interaction of Akt1 with pyruvate dehydrogenase (PDH) complex (PDC) in mitochondria, that the dihydrolipoamide dehydrogenase (E3) subunit of the PDC preferentially bound to Akt1. The activation of mitochondrial Akt1 signaling enhanced PDH activity. Using computational method, we identified a protein-protein interaction site on Akt1 and further screened and obtained two potential small molecule compounds, NSC 34766 and NSC 628725, that may bind to Akt1 via this site. Follow up studies indicated that the compounds disrupted the Akt1-E3 interaction and reduced the effects of mitochondrial Akt1 and insulin on PDH activity.