Glucagon-like peptide 1 (GLP-1), a kind of gut hormone, is used in the treatment of type 2 diabetes (T2D). Emerging evidence indicates that GLP-1 has anti-inflammatory activity. Chronic inflammation in the adipose tissue of obese individuals is a cause of insulin resistance and T2D. We hypothesized that GLP-1 analogue therapy in patients with T2D could suppress the inflammatory response of macrophages, and therefore inhibit insulin resistance. Our results showed that GLP-1 agonist (exendin-4) not only attenuated macrophage infiltration, but also inhibited the macrophage secretion of inflammatory cytokines including TNF-β, IL-6, and IL-1β. Furthermore, we observed that lipopolysaccharide (LPS)-induced macrophage conditioned media could impair insulin-stimulated glucose uptake. This effect was compensated by treatment with the conditioned media from macrophages treated with the combination of LPS and exendin-4. It was also observed that exendin-4 directly inhibited the activation of NF-κB in macrophages. In conclusion, our results indicated that GLP-1 improved inflammatory macrophage-derived insulin resistance by inhibiting NF-κB pathway and secretion of inflammatory cytokines in macrophages. Furthermore, our observations suggested that the anti-inflammatory effect of GLP-1 on macrophages can contribute to GLP-1 analogue therapy of T2D.

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.