The circular RNA circGlis3 protects against islet β-cell dysfunction and apoptosis during obesity

The molecular link between obesity and β-cell decompensation that causes diabetes remains incompletely understood. Here we found that circGlis3, a circular RNA derived from Glis3, plays a critical role in islet β-cell compensation. circGlis3 was increased in islets of obese mouse models and moderately diabetic individuals with compensated β-cell function by Quaking (QKI)-mediated splicing. Overexpression of circGlis3 functions to restrain islet β-cell dysfunction and maintain β-cell mass in high-fat diet (HFD) fed mice and Leprdb/db mice. The cellular levels of circGlis3 modulate both insulin synthesis and secretion and lipotoxicity-induced apoptosis, resulting in profound changes in β-cell compensation. In an obesity model, circGlis3 promotes the synthesis and secretion of insulin by upregulating NeuroD1 and Creb1 through sponging miR-124-3p. In addition, we identified SCOTIN and fused in sarcoma (FUS) as interacting proteins using quantitative mass spectrometry. We demonstrated that the binding of SCOTIN to circGlis3 regulated the apoptosis of β-cell. And more, FUS binding to circGlis3 could decrease free circGlis3 in cytoplasm and block mechanism of circGlis3 via abnormal stable formation of stress granules (SGs) in hyperactive response to chronic stresses in obesity that is thought to contribute to the β-cell decompensation. These findings highlight a physiological role for circRNAs in compensation and indicate that modulation of circGlis3 expression may represent a potential strategy to protect against islet β-cell dysfunction and apoptosis during obesity.

VITAMIN B1 BIOLOGICAL FUNCTION IMPLEMENTATION IN THE BLOOD OF PATIENTS WITH STOMACH CANCER UNDER SURGICAL INTERVENTION

Background. The probability of undergoing surgery always predetermines the state of stress in a person; therefore, it is advisable to search for ways to optimize and (or) reduce this unfavourable effect. Objective. To find out the mechanism of vitamin B1 antistress activity during surgery. Material and methods. Metabolism intensity was investigated on donors’ blood lysates (n = 19) and those of patients with stage III stomach cancer (n = 64), referred to an elective surgery, aged 51-70. The blood was taken from the cubital vein three days before the operation, after premedication, during the most traumatic moment of the operation, after extubation, as well as on the first and third days of the postoperative period. The surgery was performed under combined multicomponent anesthesia using nitric oxide, sodium hydroxybutyrate, and epidural block. Thiamine and thiamine diphosphate kinase activities were assessed by the concentration of the formed thiamine di- and triphosphates of the vitamin. The activities of thiamine mono-, di- and triphosphatases were determined by the release of inorganic phosphate. The concentration of inorganic phosphate was recorded colorimetrically. The content of B1 and its derivatives in the blood was determined by the method of ion-pair reversed-phase HPLC. Results. There has been observed an increased content of thiamine monophosphate and that of free thiamine in the blood of donors and patients with stomach cancer. The registered rate of the hydrolytic thiamine monophosphatase reaction is not high. At the stages of premedication and maximum trauma of surgical exposure, the concentration of monophosphoric ester rapidly decreases alongside with monophosphatase activation. Therefore, the thiamine monophosphate hydrolysis is the rate-limiting link of vitamin B1 metabolism. The level of free thiamine remains persistently increased at all stages of surgical treatment. Thiamine monophosphatase activity is manifested at two pH optima – of 6.0 and 9.0. Thiamine monophosphate hydrolysis at pH of 9.0 is catalyzed by alkaline phosphatase. At pH of 6.0, in addition to thiamine monophosphoric ester, the enzyme hydrolyzes only p-nitrophenyl phosphate, flavin mononucleotide and phosphotyrosine, that allows it to be classified as hepatic acid phosphatase. The noted changes in B1 metabolism under stress concern mainly non-coenzyme forms - thiamine mono-, triphosphate, and free thiamine, which are used at the stages of thiol reduction as important components of insulin synthesis. Conclusions. The use of vitamin B1 allows to optimize the development of the stress response at all stages of surgical treatment. Its protective effect is achieved through the activation of the insulin-synthetic function of the pancreas, which increases the level of immunoreactive insulin in the blood. The formation of the most favorable physiological conditions for insulin synthesis provides an increased background of free thiamine, which is created due to the hydrolysis of noncoenzyme forms of the vitamin. The relationship between thiamine metabolism and B2 exchange and regulation of intracellular signaling pathways has been traced.

Study of TNF-α, IL-6 and Insulin Resistance in Type 2 Diabetes Mellitus at Vidharbha Region

Background: DM is a metabolic condition caused by deficiencies in insulin synthesis, insulin action, or both. It is characterised by chronic hyperglycemia and glycosuria, as well as abnormalities in carbohydrate, fat, and protein metabolism. Diabetes and its complications are believed to be caused by a variety of causes. Genetics, diet, sedentary lifestyle, perinatal causes, age, and obesity are among them. The relationship and interaction of various risk factors with disease severity is still unknown, so the aim of the proposed study was to determine the possible relationship between biochemical markers glycosylated haemoglobin, lipid profile, insulin resistance, and immunological markers TNF- and IL-6, in order to suggest appropriate measures to reduce the country's diabetes burden. Materials and Methods: A total of 300 people were chosen for the study after visiting Shalinitai Meghe hospital in Nagpur for a health check-up. The three groups were contained in this area. Results: Both biochemical and immunological parameters rose in managed diabetic patients and significantly increased in uncontrolled diabetic patients, according to the report, but values did not differ between groups 1. Conclusion: Low-grade inflammation and inflammatory mediator upregulation have been suggested to play a role in T2DM etiology. TNF- and IL-6 have a positive connection with T2DM and insulin sensitivity, according to our data. These can be used as T2DM biomarkers in the early stages of the disease. To help doctors monitor and treat T2DM successfully, more research on a larger spectrum of pro and anti-inflammatory cytokines (mediators) in conjunction with other biochemical, immunoassay, and hematological markers is needed.

An insight of association of insulin resistance with polycystic ovary syndrome

Polycystic ovary syndrome (PCOS), a multifaceted condition, often has salient features like insulin resistance (IR). Abnormal alternation in insulin synthesis and function usually alters PCOS expressivity by deviating molecular and biochemical activity underlying this pathophysiology.This review intends to unveil the molecular basis of the genetic polymorphism of IR and its correlation with PCOS. It also highlights the existing methods of IR estimation. Searching of different articles using keywords including PCOS, IR, and polymorphism in various databases was performed to illustrate the review article.POCS, and IR are complex and multifactorial conditions in terms of the contributing factors, their interactions, and expressivity. Further studies on diversified genotype responses to environmental and ethnic variances are required for precise understanding.Insulin resistance (IR) and polycystic ovary syndrome (PCOS) are intricately interacted conditions that abnormally alter functions from genetic to organ system level. Complex gene-environment interactions make it difficult to understand the etiology and manifestation, and so diagnosis and management approaches of the heterogeneous pathophysiology are not foolproof. Further studies on genetic susceptibility related to ethnic distribution are essential for the implementation of personalized treatment of IR and PCOS.

Kudzu Resistant Starch: An Effective Regulator of Type 2 Diabetes Mellitus

Kudzu is a traditional medicinal dietary supplement, and recent research has shown its significant benefits in the prevention/treatment of type 2 diabetes mellitus (T2DM). Starch is one of the main substances in Kudzu that contribute decisively to the treatment of T2DM. However, the underlying mechanism of the hypoglycemic activity is not clear. In this study, the effect of Kudzu resistant starch supplementation on the insulin resistance, gut physical barrier, and gut microbiota was investigated in T2DM mice. The result showed that Kudzu resistant starch could significantly decrease the value of fasting blood glucose and the levels of total cholesterol, total triglyceride, and high-density lipoprotein, as well as low-density lipoprotein, in the blood of T2DM mice. The insulin signaling sensitivity in liver tissue was analyzed; the result indicated that intake of different doses of Kudzu resistant starch can help restore the expression of IRS-1, p-PI3K, p-Akt, and Glut4 and thus enhance the efficiency of insulin synthesis. Furthermore, the intestinal microorganism changes before and after ingestion of Kudzu resistant starch were also analyzed; the result revealed that supplementation of KRS helps to alleviate and improve the dysbiosis of the gut microbiota caused by T2DM. These results validated that Kudzu resistant starch could improve the glucose sensitivity of T2DM mice by modulating IRS-1/PI3K/AKT/Glut4 signaling transduction. Kudzu resistant starch can be used as a promising prebiotic, and it also has beneficial effects on the gut microbiota structure of T2DM mice.

Exendin-4 Improves Cognitive Function of Diabetic Mice via Increasing Brain Insulin Synthesis

Background and Objective: Type 2 diabetes(T2D) patients are more prone to develop Alzheimer’s disease (AD). We have previously shown that Glucagon-like peptide-1 receptor agon- ist exendin-4 (Ex-4) reduces tau hyperphosphorylation in T2D animals through upregulating in- sulin signaling, and peripheral injected Ex-4 increases insulin levels in the T2D brain. This study aims to further clarify whether the elevated insulin in the brain is produced by nerve cells under the action of Ex-4. Methods: The neuronal cell line-HT22 was treated with Ex-4 under high glucose or normal cultiva- tion, and the number of insulin-positive cells as well as the expression levels of insulin synthesis-re- lated genes were examined. The db/db mice were treated with a peripheral injection of Ex-4 and/or intracerebroventricular (ICV) injection of siRNA to inhibit the expression of insulin synthesis-relat- ed genes and the behavior tests were carried on. Finally, plasma glucose, cerebrospinal fluid (CSF) glucose, CSF insulin, phosphorylation of tau, phosphorylation of AKT and GSK-3β of db/db mice were detected. Results : We found that Ex-4 promoted the expression of insulin synthesis-related genes and in- duced an obvious increase of insulin-positive HT-22 neuronal cells in a high glucose environment. Peripheral injection of Ex-4 improved the cognitive function of db/db mice and increased brain in- sulin levels which activated brain insulin signaling and subsequently alleviated tau hyperphosphory- lation. However, when siRNA-neurod1 was injected to block insulin synthesis, the cognitive func- tion of db/db mice was not improved under the action of Ex-4 anymore. Moreover, the brain in- sulin levels dropped to an extremely low level, and the phosphorylation level of tau increased signi- ficantly. Conclusion: This study demonstrated that Ex-4 improved cognition function by promoting brain in- sulin synthesis followed by the activation of brain insulin signaling and alleviation of tau hyper- phosphorylation.

MARKET OF ORAL ANTIDIABETIC DRUGS IN THE REPUBLIC OF CRIMEA

Diabetes mellitus is one of the most significant social problems of public health. The main pathogenetic factors in the development of type 2 diabetes mellitus are a decrease in insulin synthesis by β­cells of Langerhans islets or impaired insulin receptor sensitivity to insulin, which leads to a high risk of insulin resistance and β­cell dysfunction.

Collagen type I enhance cell growth and insulin biosynthesis in rat pancreatic cells

Type I collagen (collagen I) is the most abundant component of ECM in pancreas. We previously reported that collagen I-coated culture dishes enhanced proliferation of rat pancreatic β cell line, INS-1 cells, via up-regulation of β-catenin nuclear translocation. In this study, we further investigated the effects of collagen I on insulin production of INS-1 cells. The results indicate that insulin synthesis as well as cell proliferation is increased in the INS-1 cells cultured on the dishes coated with collagen I. Up regulation of insulin-like growth factor 1 receptor (IGF-1R) on the INS-1 cells cultured on the collagen-coated dishes is involved in up-regulation of cell proliferation and increase of insulin biosynthesis; however, up-regulation of insulin secretion in the INS-1 cells on collagen I-coated dishes was further enhanced by inhibition of IGF-1R. Autophagy of INS-1 cells on collagen I-coated dishes was repressed via IGF-1R upregulation, and inhibition of autophagy with 3MA further enhanced cell proliferation and insulin biosynthesis, but did not affect insulin secretion. E-cadherin/β-catenin adherent junction complexes are stabilized by autophagy. That is, autophagy negatively regulates nuclear translocation of β-catenin that leads to insulin biosynthesis and cell proliferation. In conclusion, IGF-1R/down regulation of autophagy/nuclear translocation of β-catenin is involved in collagen I-induced INS-1 cell proliferation and insulin synthesis.

Bee Pollen Polysaccharide From Rosa rugosa Thunb. (Rosaceae) Promotes Pancreatic β-Cell Proliferation and Insulin Secretion

Insufficient pancreatic β-cell or insulin-producing β-cell are implicated in all types of diabetes mellitus. Our previous studies showed bee pollen polysaccharide RBPP-P improves insulin resistance in type 2 diabetic mice by inhibiting liver fat deposition. However, its potential of regulating β-cell function and integrity is not fully known. Herein, we observed that β-cell proliferation (n = 10), insulin synthesis (n = 5, p = 0.01684) and insulin incretion (n = 5, p = 0.02115) were intensely activated in MIN6 cells when treatment with RBPP-P. In alloxan-induced diabetic mice, oral administration of RBPP-P (n = 10) effectively decreased the blood glucose (p = 0.0326), drink intake (p < 0.001) and urine (p < 0.001). It directly stimulated phosphorylation of p38 (p = 0.00439), ERK (p = 0.02951) and AKT (p = 0.0072) to maintain the islet function and mass. Thus, our data suggest that RBPP-P is a natural compound to regulate β-cell proliferation and function, indicating it might have therapeutic potential against type 1 diabetes.

Autophagy, immunological response, and inflammation all rely on the TRIM family proteins. TRIM-based therapeutics for inflammatory illnesses including diabetes and diabetic comorbidities are promising

Autophagy is a system that recycles for cellular repair and stability. TRIM regulates the autophagy and pyroptotic pathways. Autophagy, immunological response, and inflammation all rely on the TRIM family proteins. Changes in TRIM function or expression are prevalent in people with diabetes. Yoshinori Ohsumi discovered ATG in yeast genetic screening. Many yeast autophagy pathways are shared across yeast and humans. The TRIMFamily impacts autophagosome and Pyroptosis, controlling both of these processes. This will examine the TrIM family's function in diabetes and diabetic complications. The treatment of acute myeloid leukemia (AML) with chemotherapy reduces the chance of malignancy. The way TRIM proteins regulate autophagy is unclear. TRIM proteins have been found to participate in pyroptotic cell death via inflammasomes. This study might lead to greater understanding of TRIM-based therapeutics for inflammatory illnesses including diabetes and diabetic comorbidities. NLRP3 is triggered by both infection-related plasma membrane damage and ROS-induced activation of the inflammasome. Human caspases 1 and 4/5 and mouse caspase 11 are activated by inflammasomes. Caspases cleave GSDMD, the most well-studied member of the gasdermin family.Pyroptosis and the generation of inflammatory cytokines are both catalyzed by Gasdermin D. Circular perforations in membranes release mature cytokines and cell lysis. Each step of Pyroptotic cell death is influenced by several circumstances. Several TRIM proteins have been shown to mediate pyroptotic cell death via inflammasomes. TRIM30, for example, inhibits NLRP3-mediated inflammation by regulating ROS levels. NLRP1 and NLRP2 require NFB to activate and assemble. TRIM family proteins (such as TRIM59, TRIM9, and TRIM39) have been associated with inflammation in various studies. Additional study on TRIM protein's impact on pyroposis is required. Inflammatory responses triggered by inflammasomes are commonly connected to diabetes, gout, and neurological diseases, including Alzheimer's disease. Functional cell mass loss is a key pathophysiology of DM. The role of TRIM proteins in pyroptotic cell death will provide new insights for TRIM-based therapies for specific inflammatory diseases in the clinic.Auto-Phagy and Pyraptosis mediate IL1 activation in T1DM and T2DM. Hyperglycemia boosts NLRP3-induced inflammation, which yields IL1 Higher levels of IL-1 in the islet microenvironment increase pro-apoptotic signaling. Activation of the innate immune system reduces insulin synthesis, which is the foundation of diabetes. Diabetes and diabetic complications are correlated with the TRIM family proteins. Liver and skeletal muscle tissues are shown to have TRIM32-dependent insulin resistance. Recent studies concluded that TRIM72 was not a cause of DM. We need more research to determine the importance of TRim72 in diabetes, and perhaps a novel therapeutic target may be discovered.