Type 2 diabetes is a metabolic, chronic disorder characterized by insulin resistance and elevated blood glucose levels. Although a large drug portfolio exists to keep the blood glucose levels under control, these medications are not without side effects. More importantly, once diagnosed diabetes is rarely reversible. Dysfunctions in the kidney, retina, cardiovascular system, neurons, and liver represent the common complications of diabetes, which again lack effective therapies that can reverse organ injury. Overall, the molecular mechanisms of how type 2 diabetes develops and leads to irreparable organ damage remain elusive. This review particularly focuses on novel targets that may play role in pathogenesis of type 2 diabetes. Further research on these targets may eventually pave the way to novel therapies for the treatment-or even the prevention-of type 2 diabetes along with its complications.

Emerging Targets in Type 2 Diabetes and Diabetic Complications.

Lipid metabolism in sickness and in health: Emerging regulators of lipotoxicity.

Abstract Vascular complications of diabetes pose a severe threat to human health. Prevention and treatment protocols based on a single vascular complication are no longer suitable for the long-term management of patients with diabetes. Diabetic panvascular disease (DPD) is a clinical syndrome in which vessels of various sizes, including macrovessels and microvessels in the cardiac, cerebral, renal, ophthalmic, and peripheral systems of patients with diabetes, develop atherosclerosis as a common pathology. Pathological manifestations of DPDs usually manifest macrovascular atherosclerosis, as well as microvascular endothelial function impairment, basement membrane thickening, and microthrombosis. Cardiac, cerebral, and peripheral microangiopathy coexist with microangiopathy, while renal and retinal are predominantly microangiopathic. The following associations exist between DPDs: numerous similar molecular mechanisms, and risk-predictive relationships between diseases. Aggressive glycemic control combined with early comprehensive vascular intervention is the key to prevention and treatment. In addition to the widely recommended metformin, glucagon-like peptide-1 agonist, and sodium-glucose cotransporter-2 inhibitors, for the latest molecular mechanisms, aldose reductase inhibitors, peroxisome proliferator-activated receptor-γ agonizts, glucokinases agonizts, mitochondrial energy modulators, etc. are under active development. DPDs are proposed for patients to obtain more systematic clinical care requires a comprehensive diabetes care center focusing on panvascular diseases. This would leverage the advantages of a cross-disciplinary approach to achieve better integration of the pathogenesis and therapeutic evidence. Such a strategy would confer more clinical benefits to patients and promote the comprehensive development of DPD as a discipline. 

/pdf/diabetic-vascular-diseases-molecular-mechanisms-and-1zl82fwd.pdf

Diabetic vascular diseases: molecular mechanisms and therapeutic strategies

Abstract Chronic kidney disease (CKD) is a chronic renal dysfunction syndrome that is characterized by nephron loss, inflammation, myofibroblasts activation, and extracellular matrix (ECM) deposition. Lipotoxicity and oxidative stress are the driving force for the loss of nephron including tubules, glomerulus, and endothelium. NLRP3 inflammasome signaling, MAPK signaling, PI3K/Akt signaling, and RAAS signaling involves in lipotoxicity. The upregulated Nox expression and the decreased Nrf2 expression result in oxidative stress directly. The injured renal resident cells release proinflammatory cytokines and chemokines to recruit immune cells such as macrophages from bone marrow. NF-κB signaling, NLRP3 inflammasome signaling, JAK-STAT signaling, Toll-like receptor signaling, and cGAS-STING signaling are major signaling pathways that mediate inflammation in inflammatory cells including immune cells and injured renal resident cells. The inflammatory cells produce and secret a great number of profibrotic cytokines such as TGF-β1, Wnt ligands, and angiotensin II. TGF-β signaling, Wnt signaling, RAAS signaling, and Notch signaling evoke the activation of myofibroblasts and promote the generation of ECM. The potential therapies targeted to these signaling pathways are also introduced here. In this review, we update the key signaling pathways of lipotoxicity, oxidative stress, inflammation, and myofibroblasts activation in kidneys with chronic injury, and the targeted drugs based on the latest studies. Unifying these pathways and the targeted therapies will be instrumental to advance further basic and clinical investigation in CKD. 

https://www.nature.com/articles/s41392-022-01036-5.pdf

Signaling pathways of chronic kidney diseases, implications for therapeutics

Kidney lipid dysmetabolism and lipid droplet accumulation in chronic kidney disease

Elevation of JAML Promotes Diabetic Kidney Disease by Modulating Podocyte Lipid Metabolism

Background & objective The carcinogenesis of gastric carcinoma is related to many factors. Helicobacter pylori (HP) infection is one of the factors causing gastric carcinoma, but the exact molecular mechanism is not clear. Mismatch repair genes are important in keeping the accuracy of DNA replication. They are associated with carcinogenesis of alimentary canal. In order to investigate the role of hMSH2 and hMLH1 in stomach cancer and the possible mechanism of carcinogenesis caused by HP infection, we tested cancer tissue, surrounding mucosa and chronic superficial gastritic mucosa with and without HP infection. Methods HP infection was determined with quick-ureolytase method. Immunohistochemistry staining was used to exam the expression of hMSH2 and hMLH1 in tumor tissue and their surrounding mucosa and gastric mucosa. Chi-square was used for statistic analysis. Results The positive rate (67.1%) of hMSH2 expression in cancer tissue was significantly higher than those of surrounding mucosa (35.5%) and gastritic mucosa (42.1%) (P 0.05). The positive rate (47.1%) of hMLH1 expression in mucoid carcinoma group was significantly higher than those in well middle differentiation group (81.8%) and poor differentiation group (97.3%) (P 0.05). In cancer tissue, the positive rate (56.8%) of hMSH2 expression in HP infection group was significantly lower than that without HP infection group (81.3%) (P 0.05). In surrounding mucosa, the positive rate of hMSH2 expression was 29.5% in HP infection group and 43.8% in without HP infection group, as well as those of hMLH1 were 86.4% and 96.9%, there were no significant differences between the groups. In gastritic mucosa, the positive rate of hMSH2 expression was 38.5% in HP infection group and 50.5% in HP-negative group, as well as those of hMLH1 were 88.5% and 91.7%; there was no significant difference between the groups. Conclusion The expression of hMSH2 is associated with carcinogenesis of stomach cancer, and its high expression may be a potential marker of stomach cancer; HP infection inducing low expression of hMSH2 and hMLH1 may be one of molecular mechanisms by which HP infection leads to stomach cancer.

Expression of hMSH2 and hMLH1 in stomach cancer and their correlation with Helicobacter pylori infection

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Elevation of JAML Promotes Diabetic Kidney Disease by Modulating Podocyte Lipid Metabolism

Expression of hMSH2 and hMLH1 in stomach cancer and their correlation with Helicobacter pylori infection