Background. Mitochondrial dynamics (mtDYN) has been proposed as a bridge between mitochondrial dysfunction and insulin resistance (IR), which is involved in the pathogenesis of type 2 diabetes (T2D). Our previous study has identified that mitochondrial DNA (mtDNA) haplogroup B4 is a T2D‐susceptible genotype. Using transmitochondrial cybrid model, we have confirmed that haplogroup B4 contributes to cellular IR as well as a profission mtDYN, which can be reversed by antioxidant treatment. However, the causal relationship between mtDYN and cellular IR pertaining to T2D‐susceptible haplogroup B4 remains unanswered. Methods. To dissect the mechanisms between mtDYN and IR, knockdown or overexpression of MFN1, MFN2, DRP1, and FIS1 was performed using cybrid B4. We then examined the mitochondrial network and mitochondrial oxidative stress (mtROS) as well as insulin signaling IRS‐AKT pathway and glucose transporters (GLUT) translocation to plasma membrane stimulated by insulin. We employed Drp1 inhibitor, mdivi‐1, to interfere with endogenous expression of fission to validate the pharmacological effects on IR. Results. Overexpression of MFN1 or MFN2 increased mitochondrial network and reduced mtROS, while knockdown had an opposing effect. In contrast, overexpression of DRP1 or FIS1 decreased mitochondrial network and increased mtROS, while knockdown had an opposing effect. Concomitant with the enhanced mitochondrial network, activation of the IRS1‐AKT pathway and GLUT translocation stimulated by insulin were improved. On the contrary, suppression of mitochondrial network caused a reduction of the IRS1‐AKT pathway and GLUT translocation stimulated by insulin. Pharmacologically inhibiting mitochondrial fission by the Drp1 inhibitor, mdivi‐1, also rescued mitochondrial network, reduced mtROS, and improved insulin signaling of diabetes‐susceptible cybrid cells. Conclusion. Our results discovered the causal role of mtDYN proteins in regulating IR resulted from diabetes‐susceptible mitochondrial haplogroup. The existence of a bidirectional interaction between mtDYN and mtROS plays an important role. Direct intervention to reverse profission in mtDYN provides a novel therapeutic strategy for IR and T2D.

Type 2 diabetes mellitus (T2DM) is significantly associated with osteoarthritis (OA). This study investigated the effects of two resistance exercise approaches on glycated hemoglobin (HbA1c) level and function performance. Enrolled were 70 older patients with both T2DM and knee OA. The dynamic group performed resistance exercises with an elastic resistance band. The isometric group underwent isometric contraction exercises. After the 12-week intervention, a significant within-group improvement (all p < 0.001) was observed for the chair stand test (CST; 10.8%, vs. 7.1%), timed up and go (TUG) test (12.6% vs. 7.6%), Western Ontario and McMaster Universities Osteoarthritis (WOMAC) physical function subscale (62.3% vs. 36.1%), and overall WOMAC (54.5% vs. 34.5%) in the dynamic and isometric group, respectively. In addition, in terms of between-group differences, the dynamic group had significant improvements in CST (p = 0.011), TUG (p < 0.001), WOMAC physical function subscale (p = 0.033), and overall WOMAC (p = 0.036) scores compared with the isometric group. However, no significant change in HbA1c was observed in either group. In conclusion, the dynamic resistance exercise significantly improved muscle strength, dynamic balance, and physical function in this comorbid population; however, there was no notable difference in change in HbA1c among different resistance exercises.

Aims: Obesity-induced excessive visceral fat (VF) accumulation is associated with insulin resistance (IR), systemic oxidative stress, and chronic inflammation. As toll-like receptor 4 (TLR4) plays an important role in innate immunity, we herein investigate the effect of TLR4 knockout (T4KO) in a high-fat high-sucrose diet (HFD)-induced obesity mouse model. Results: C57BL6 wild-type (WT) and T4KO mice were fed with either control diet (CD) or HFD for 12 months, rendering four experimental groups: WT+CD, WT+HFD, T4KO+CD, and T4KO+HFD. Compared with WT+CD, WT+HFD demonstrated significant increase in VF accumulation, oxidative damage, M1/M2 macrophage ratio, chronic inflammation, and development of IR. Compared with WT+HFD, T4KO+HFD presented increased BW and body fat with higher subcutaneous fat (SF)/VF ratio, but lower body temperature, as well as decreased oxidative damage, M1/M2 macrophage ratio, chronic inflammation, and IR. Unlike WT+HFD, T4KO+HFD exhibited an increase in mitochondrial electron transport chain activity but a decrease of uncoupling protein 2 (UCP2) level. While T4KO hindered HFD-induced increasing mitochondrial oxygen consumption rate, a shift toward a higher extracellular acidification rate in VF was observed. Notably, T4KO inhibits HFD-induced mitochondrial translocation of nuclear factor of activated T cells 2 (NFATC2), which contributed to mitochondrial metabolic reprogramming. Both fat distribution shifting from VF to SF and mitochondrial metabolic reprogramming may alleviate systemic oxidative stress and chronic inflammation. Innovation and Conclusion: Abrogation of TLR4 contributes to reduction of oxidative stress through metabolic reprogramming of mitochondria in VF, mitigating obesity-induced IR. The study provides critical insight into associating innate immunity–mitochondria interplay with prevention of diabetes.

Background: This study was conducted to compare the staging systems for the prediction of long-term disease status in patients with well-differentiated thyroid carcinoma (WDTC), and to find out the earliest postoperative period predictor of long-term persistence/recurrence of disease. Methods: Patients with WDTC (n = 356; M_age = 41.5 ± 12.7 years) followed for at least five years (12.3 ± 5.0 years) after thyroidectomy and ¹³¹I remnant ablation at a tertiary regional hospital in Taiwan were retrospectively studied. Each patient was risk stratified using the American Joint Cancer Committee (stage I–IV) and American Thyroid Association (low, intermediate, and high risk) staging systems after operation and first ¹³¹I remnant ablation and using response to initial therapy reclassification (RTR; excellent, indeterminate, biochemical incomplete, and structural incomplete response) system, which is determined 6–24 months after the first ¹³¹I ablation. The clinical outcome was defined as no evidence of disease (NED; suppressed thyroglobulin [Tg] <0.5 ng/mL, stimulated Tg <1 ng/mL, and no structural detectable disease), biochemical persistent disease (BPD; suppressed Tg ≥0.5 ng/mL or stimulated Tg ≥1 ng/mL in the absence of structural disease), structural persistent disease (SPD; locoregional or distant metastases with any Tg level), or recurrent disease (RD; biochemical or structural disease identified after a period of NED). Results: At the time of final follow-up, 78.4% (n = 279) of the patients had NED, 9.3% (n = 33) had BPD, 10.1% (n = 36) had SPD, and 2.2% (n = 8) developed RD. All three systems could predict the increasing trend of SPD and the decreasing trend of NED with advancing stage of disease. However, the ATA risk estimates could be significantly refined by the RTR system, especially for the ATA high-risk group, in which 29.2% developed SPD/RD during follow-up. The RTR system reduced the likelihood of finding SPD/RD to 3.7% in those demonstrating an excellent response to therapy, and increased the likelihood to 78.6% in those demonstrating a structural incomplete response. Among the earliest postoperative factors, only the Tg level at the first ¹³¹I ablation could predict long-term persistence/recurrence. Conclusions: The results highly support incorporating the RTR system to modify the initial risk estimate during follow-up among Chinese patients with WDTC.