From stem cells to pancreatic ß-cells: strategies, applications, and potential treatments for diabetes.

Loss and functional failure of pancreatic ß-cells results in disruption of glucose homeostasis and progression of diabetes. Although whole pancreas or pancreatic islet transplantation serves as a promising approach for ß-cell replenishment and diabetes therapy, the severe scarcity of donor islets makes it unattainable for most diabetic patients. Stem cells, particularly induced pluripotent stem cells (iPSCs), are promising for the treatment of diabetes owing to their self-renewal capacity and ability to differentiate into functional ß-cells. In this review, we first introduce the development of functional ß-cells and their heterogeneity and then turn to highlight recent advances in the generation of ß-cells from stem cells and their potential applications in disease modeling, drug discovery and clinical therapy. Finally, we have discussed the current challenges in developing stem cell-based therapeutic strategies for improving the treatment of diabetes. Although some significant technical hurdles remain, stem cells offer great hope for patients with diabetes and will certainly transform future clinical practice.

Liraglutide ameliorates hepatic steatosis via retinoic acid receptor-related orphan receptor α-mediated autophagy pathway.

Liraglutide, an analog of human glucagon-like peptide-1 (GLP-1), has been found to improve hepatic steatosis in clinical practice. However, the underlying mechanism remains to be fully defined. Increasing evidence suggests that retinoic acid receptor-related orphan receptor α (RORα) is involved in hepatic lipid accumulation. In the current study, we investigated whether the ameliorating impact of liraglutide on lipid-induced hepatic steatosis is dependent on RORα activity and examined the underlying mechanisms. Cre-loxP-mediated, liver-specific Rorα knockout (Rora LKO) mice, and littermate controls with a Roraloxp/loxp genotype were established. The effects of liraglutide on lipid accumulation were evaluated in mice challenged with a high-fat diet (HFD) for 12 weeks. Moreover, mouse AML12 hepatocytes expressing small interfering RNA (siRNA) of Rora were exposed to palmitic acid to explore the pharmacological mechanism of liraglutide. The results showed that liraglutide treatment significantly alleviated HFD-induced liver steatosis, marked by reduced liver weight and triglyceride accumulation, improved glucose tolerance and serum levels of lipid profiles and aminotransferase. Consistently, liraglutide also ameliorated lipid deposits in a steatotic hepatocyte model in vitro. In addition, liraglutide treatment reversed the HFD-induced downregulation of Rora expression and autophagic activity in mouse liver tissues. However, the beneficial effect of liraglutide on hepatic steatosis was not observed in Rora LKO mice. Mechanistically, the ablation of Rorα in hepatocytes diminished liraglutide-induced autophagosome formation and the fusion of autophagosomes and lysosomes, resulting in weakened autophagic flux activation. Thus, our findings suggest that RORα is essential for the beneficial impact of liraglutide on lipid deposition in hepatocytes and regulates autophagic activity in the underlying mechanism.

Pancreatic ß-cell failure, clinical implications, and therapeutic strategies in type 2 diabetes.

ABSTRACT: Pancreatic ß-cell failure due to a reduction in function and mass has been defined as a primary contributor to the progression of type 2 diabetes (T2D). Reserving insulin-producing ß-cells and hence restoring insulin production are gaining attention in translational diabetes research, and ß-cell replenishment has been the main focus for diabetes treatment. Significant findings in ß-cell proliferation, transdifferentiation, pluripotent stem cell differentiation, and associated small molecules have served as promising strategies to regenerate ß-cells. In this review, we summarize current knowledge on the mechanisms implicated in ß-cell dynamic processes under physiological and diabetic conditions, in which genetic factors, age-related alterations, metabolic stresses, and compromised identity are critical factors contributing to ß-cell failure in T2D. The article also focuses on recent advances in therapeutic strategies for diabetes treatment by promoting ß-cell proliferation, inducing non-ß-cell transdifferentiation, and reprograming stem cell differentiation. Although a significant challenge remains for each of these strategies, the recognition of the mechanisms responsible for ß-cell development and mature endocrine cell plasticity and remarkable advances in the generation of exogenous ß-cells from stem cells and single-cell studies pave the way for developing potential approaches to cure diabetes.

Aging-induced short-chain acyl-CoA dehydrogenase promotes age-related hepatic steatosis by suppressing lipophagy.

Hepatic steatosis, the first step in the development of nonalcoholic fatty liver disease (NAFLD), is frequently observed in the aging population. However, the underlying molecular mechanism remains largely unknown. In this study, we first employed GSEA enrichment analysis to identify short-chain acyl-CoA dehydrogenase (SCAD), which participates in the mitochondrial ß-oxidation of fatty acids and may be associated with hepatic steatosis in elderly individuals. Subsequently, we examined SCAD expression and hepatic triglyceride content in various aged humans and mice and found that triglycerides were markedly increased and that SCAD was upregulated in aged livers. Our further evidence in SCAD-ablated mice suggested that SCAD deletion was able to slow liver aging and ameliorate aging-associated fatty liver. Examination of the molecular pathways by which the deletion of SCAD attenuates steatosis revealed that the autophagic degradation of lipid droplets, which was not detected in elderly wild-type mice, was maintained in SCAD-deficient old mice. This was due to the decrease in the production of acetyl-coenzyme A (acetyl-CoA), which is abundant in the livers of old wild-type mice. In conclusion, our findings demonstrate that the suppression of SCAD may prevent age-associated hepatic steatosis by promoting lipophagy and that SCAD could be a promising therapeutic target for liver aging and associated steatosis.

Novel association of SNP rs2297828 in PRDM16 gene with predisposition to type 2 diabetes.

OBJECTIVES: Transcriptional regulator PRD1-BF-1-RIZ1 homology (PR) domain containing protein-16 (PRDM16) has a fundamental function in maintaining energy homeostasis and regulating glucose and lipid metabolism, which are responsible for the development of type 2 diabetes (T2D). However, the impact of genetic variation of PRDM16 gene on T2D risk remains to be investigated. Thus, we evaluated the possible association between genetic variants within PRDM16 region and T2D development in Chinese individuals. METHODS: A total of 427 T2D patients and 408 healthy controls were enrolled. Ten single-nucleotide variants across PRDM16 gene were screened with the SNaPshot assay. The effect of genotypes and alleles of different variant on the T2D risk was examined under diverse genetic models. The impact of genetic variant on promoter activity was determined using an in vitro luciferase reporter gene assay. RESULTS: Genotypic frequency of rs2297828 in the PRDM16 promoter region was significantly different between patients with T2D and controls (P = 0.004). The minor allele A of rs2297828 was potentially associated with a higher T2D susceptibility in a dominant model (AG + AA vs GG: OR = 1.54, 95 % CI: 1.12-1.12; P = 0.007), and the subjects with either an AA homozygote or an AG heterozygote displayed increased fasting blood levels of glucose and lipids. Reporter gene assays demonstrated that rs2297828 can influence the activity of the PRDM16 promoter. CONCLUSIONS: We firstly observed that PRDM16 variation might influence T2D occurrence, and rs2297828 might be a functional variant that can influence the expression of PRDM16.

Nuclear factor-Y mediates pancreatic ß-cell compensation by repressing reactive oxygen species-induced apoptosis under metabolic stress.

BACKGROUND: Pancreatic ß-cells elevate insulin production and secretion through a compensatory mechanism to override insulin resistance under metabolic stress conditions. Deficits in ß-cell compensatory capacity result in hyperglycemia and type 2 diabetes (T2D). However, the mechanism in the regulation of ß-cell compensative capacity remains elusive. Nuclear factor-Y (NF-Y) is critical for pancreatic islets' homeostasis under physiological conditions, but its role in ß-cell compensatory response to insulin resistance in obesity is unclear. METHODS: In this study, using obese ( ob/ob ) mice with an absence of NF-Y subunit A (NF-YA) in ß-cells ( ob , Nf-ya ßKO) as well as rat insulinoma cell line (INS1)-based models, we determined whether NF-Y-mediated apoptosis makes an essential contribution to ß-cell compensation upon metabolic stress. RESULTS: Obese animals had markedly augmented NF-Y expression in pancreatic islets. Deletion of ß-cell Nf-ya in obese mice worsened glucose intolerance and resulted in ß-cell dysfunction, which was attributable to augmented ß-cell apoptosis and reactive oxygen species (ROS). Furthermore, primary pancreatic islets from Nf-ya ßKO mice were sensitive to palmitate-induced ß-cell apoptosis due to mitochondrial impairment and the attenuated antioxidant response, which resulted in the aggravation of phosphorylated c-Jun N-terminal kinase (JNK) and cleaved caspase-3. These detrimental effects were completely relieved by ROS scavenger. Ultimately, forced overexpression of NF-Y in INS1 ß-cell line could rescue palmitate-induced ß-cell apoptosis, dysfunction, and mitochondrial impairment. CONCLUSION: Pancreatic NF-Y might be an essential regulator of ß-cell compensation under metabolic stress.

Cholesterol Sulfate Exerts Protective Effect on Pancreatic ß-Cells by Regulating ß-Cell Mass and Insulin Secretion.

Rational: Cholesterol sulfate (CS) is the most abundant known sterol sulfate in human plasma, and it plays a significant role in the control of metabolism and inflammatory response, which contribute to the pathogenesis of insulin resistance, ß-cell dysfunction and the resultant development of diabetes. However, the role of CS in ß-cells and its effect on the development of diabetes remain unknown. Here, we determined the physiological function of CS in pancreatic ß-cell homeostasis. Materials and Methods: Blood CS levels in streptozotocin (STZ)- or high-fat diet-induced diabetic mice and patients with type 1 or 2 diabetes were determined by LC-MS/MS. The impact of CS on ß-cell mass and insulin secretion was investigated in vitro in isolated mouse islets and the ß-cell line INS-1 and in vivo in STZ-induced diabetic mice. The molecular mechanism of CS was explored by viability assay, EdU incorporation analysis, flow cytometry, intracellular Ca2+ influx analysis, mitochondrial membrane potential and cellular ROS assays, and metabolism assay kits. Results: Plasma CS levels in mice and humans were significantly elevated under diabetic conditions. CS attenuated diabetes in a low-dose STZ-induced mouse model. Mechanistically, CS promoted ß-cell proliferation and protected ß-cells against apoptosis under stressful conditions, which in turn preserved ß-cell mass. In addition, CS supported glucose transporter-2 (GLUT2) expression and mitochondrial integrity, which then resulted in a less reactive oxygen species (ROS) generation and an increase in ATP production, thereby enabling insulin secretion machinery in the islets to function adequately. Conclusion: This study revealed a novel dual role of CS in integrating ß-cell survival and cell function, suggesting that CS might offer a physiologic approach to preserve ß-cells and protect against the development of diabetes mellitus.