Therapeutic Potential of Multitasking Factors for Beta-cells in Type 2 Diabetes Mellitus
Type 2 diabetes mellitus (T2DM) is clinically diagnosed by elevated plasma glucose levels. However, loss of pancreatic beta-cell function occurs before diabetes is diagnosed clinically. It was reported that patients with impaired glucose tolerance have <50% of normal beta-cell function, whereas it is <15% for patients with T2DM, demonstrating the progressive nature of beta-cell dysfunction in the course of T2DM1. As a vast majority of patients with T2DM exhibit a failure of beta-cells, methods for preserving or restoring beta-cell function have long been in the spotlight of research for diabetes. Traditional pharmacological strategies focused on enhancing insulin secretion capacity of beta-cells2. However, recent opinions challenged on the efficacy of increasing the workload of beta-cells while interventions targeting beta-cell dysfunction is of interest in particular2.
Alternative approach to Beta-cell exhaustion
Certain type 2 diabetes mellitus (T2DM) therapies such as sulfonylureas function mainly by stimulating insulin secretion from the beta-cells, increases the workload of dysfunctional beta-cells2. Although effective glycaemic control can be achieved initially, the therapies would increase the risk of beta-cell exhaustion and death2. In contrast, reducing the workload of dysfunctional beta-cells would produce durable glycaemic control as compared to traditional therapies. This approach is supported by clinical data of the ADOPT (A Diabetes Outcome Progression Trial) study, which demonstrated that promoting insulin sensitisation is a viable approach in reducing beta-cell workload and improving glycaemic control3.
Improving insulin secretion and signaling by multitasking factors
In light of the concept that reducing beta-cell workload could yield durable glycaemic control, preclinical studies and ex vivo human islet studies targeting single endogenous factors, which facilitate the multitask of beta-cells and peripheral insulin-sensitive cells are emerging. These multitasking factors enhance the efficiency of glucose-stimulated insulin secretion and glucose uptake, respectively, in a coordinated manner2. The syntaxin 4 (STX4) is one of the potential multitasking factors essential for the insulin secretion process in beta-cells4. Soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) proteins control the efficiency of insulin secretion from beta-cells that mature insulin granules at the cell surface. They undergo SNARE-mediated docking and fusion steps in order to be released, whereas STX4 is needed for the process4. Additionally, STX4 also functions at the distal end of the insulin signaling cascade to promote clearance of excess glucose from the blood5. Therefore, changes in STX4 levels affect two of the most important processes for regulating blood glucose levels and maintaining glucose homeostasis5. Previous report demonstrated that type 2 diabetic human islets are deficient in STX4, while replenishing the exocytosis factor restores pancreatic islets function4.
On the other hand, the p21-activated kinase 1 (PAK1), is a key mediator of stimulus-induced actin remodeling and is found to be deficient in T2DM human islets, whereas enhancement of PAK1 protects beta-cell function and supports skeletal muscle glucose uptake6. Recent studies have indicated that PAK1 is an essential element in glucose transporter type 4 (GLUT4) recruitment in mouse skeletal muscle in vivo7, whereas, in pancreatic beta-cells, PAK1 participates in insulin granule localisation and vesicle release8. In addition, PAK1 has been reported to play a role in controlling the production of the incretin hormone glucagon-like peptide-1 (GLP-1) in the gut endocrine L cells. While the Cdc42/Rac1 signalling pathway is evidently involved in the glucose-stimulated insulin secretion in beta-cells, Cdc42-dependent PAK1 Thr423 phosphorylation was observed. Of note, the phosphorylation of PAK1 was Rac1 independent. Essentially, knockdown of PAK1 expression in mouse beta-cell line abolished Cdc42-mediated Rac1 activation9. These observations thus implicate the existence of the Cdc42-PAK1-Rac1 axis in insulin secretion in pancreas.
Besides, members of TGF-β superfamily, including bone morphogenetic proteins (BMPs), have been shown to be involved in islet morphogenesis, establishment of beta-cell mass and adipose cell fate determination. In particular, bone morphogenetic factor 7 (BMP7) has been demonstrated to play a direct role in regulation of glucose homeostasis and insulin resistance. It has been reported that BMP7, in coupled with BMP4, regulates insulin signaling and hence glucose homeostasis. BMP7 augmented glucose uptake in the insulin sensitive tissues, such as the adipose and muscle, by increasing GLUT4 translocation to the plasma membrane through phosphorylation and activation of phosphoinositide-dependent kinase-1 (PDK1) and protein kinase B (Akt), and phosphorylation and translocation of Forkhead box protein O1 (FoxO1) to the cytoplasm in liver/HepG2 cells. Importantly, former animal study showed that restoration of serum level of BMP7 resulted in decreased blood glucose levels. Therefore, the results demonstrated the therapeutic potentials of BMP7 in T2DM, through reducing body fat and strengthening insulin signaling10.
The above examples highlight the fact that better understanding on the mechanisms of action of potential multitasking factors would open up a promising therapeutic avenue for T2DM.
Therapeutic potential of multitasking factors
Currently, enormous effort has been put on developing treatments and medications for T2DM, in particular, preclinical findings on the efficacy of multitasking factors for pancreatic beta-cells on glucose homeostasis are emerging. For instance, Oh et al (2014) demonstrated in a mice model that STX4 up-regulation in human islets enhanced beta-cell function by approximately 2-fold in each phase of insulin secretion. Essentially, the streptozotocin-induced diabetic mice transplanted with STX4-enriched human islets had their streptozotocin-induced diabetes effectively attenuated. The results suggested that addition of STX4 would improve insulin secretory function to diabetic human islets4.
Besides, in a recent work by Veluthakal et al (2018), human islets from donors with T2DM was found to have profound defects in glucose-stimulated Cdc42-PAK1 activation and insulin secretion, whereas these defects were rescued by cAMP-regulated guanine nucleotide exchange factor (Epac) activator11.
Final remarks
The health burden of diabetes mellitus and prediabetes, i.e. impaired fasting glucose and/or impaired glucose tolerance, is substantial with an increasing trend. Therefore, in addition to traditional therapies, developing new approaches to reduce diabetic progression is desirable. Based on the emerging research findings, multitasking factors, which improve both beta-cell dysfunction and peripheral insulin sensitivity, would be candidates for promising therapies.
References
1. Page et al. Curr Diab Rep. 2013;13(2):252-260. 2. Salunkhe et al. Diabetologia. 2018;61(9):1895-1901. 3. Kahn et al. Diabetes. 2011;60(5):1552-1560. 4. Oh et al. J Clin Endocrinol Metab. 2014;99(5):866-870. 5. Glowicz. Physiol Behav. 2017;176(5):139-148. 6. Ahn et al. Diabetologia. 2016;59(10):2145-2155. 7. Tunduguru. Physiol Behav. 2017;176(3):139-148. 8. Chiang et al. Am J Physiol Metab. 2014;306(7):E707-E722. 9. Wang et al. J Biol Chem. 2007;282(13):9536-9546. 10. Chattopadhyay et al. BioFactors. 2017;43(2):195-209. 11. Veluthakal et al. Diabetes. Vol 67. 2018:199-2011.
