Pathogenesis Of Type 1 Diabetes Research Articles

Possible heterogeneity of initial pancreatic islet beta-cell autoimmunity heralding type 1 diabetes.

The etiology of type 1 diabetes (T1D) foreshadows the pancreatic islet beta-cell autoimmune pathogenesis that heralds the clinical onset of T1D. Standardized and harmonized tests of autoantibodies against insulin (IAA), glutamic acid decarboxylase (GADA), islet antigen-2 (IA-2A), and ZnT8 transporter (ZnT8A) allowed children to be followed from birth until the appearance of a first islet autoantibody. In the Environmental Determinants of Diabetes in the Young (TEDDY) study, a multicenter (Finland, Germany, Sweden, and the United States) observational study, children were identified at birth for the T1D high-risk HLA haploid genotypes DQ2/DQ8, DQ2/DQ2, DQ8/DQ8, and DQ4/DQ8. The TEDDY study was preceded by smaller studies in Finland, Germany, Colorado, Washington, and Sweden. The aims were to follow children at increased genetic risk to identify environmental factors that trigger the first-appearing autoantibody (etiology) and progress to T1D (pathogenesis). The larger TEDDY study found that the incidence rate of the first-appearing autoantibody was split into two patterns. IAA first peaked already during the first year of life and tapered off by 3-4 years of age. GADA first appeared by 2-3 years of age to reach a plateau by about 4 years. Prior to the first-appearing autoantibody, genetic variants were either common or unique to either pattern. A split was also observed in whole blood transcriptomics, metabolomics, dietary factors, and exposures such as gestational life events and early infections associated with prolonged shedding of virus. An innate immune reaction prior to the adaptive response cannot be excluded. Clarifying the mechanisms by which autoimmunity is triggered to either insulin or GAD65 is key to uncovering the etiology of autoimmune T1D.

Beta Cell Dysfunction in Youth- and Adult-Onset Type 2 Diabetes: An Extensive Narrative Review with a Special Focus on the Role of Nutrients.

Traditionally a disease of adults, type 2 diabetes (T2D) has been increasingly diagnosed in youth, particularly among adolescents and young adults of minority ethnic groups. Especially, during the recent COVID-19 pandemic, obesity and prediabetes have surged not only in minority ethnic groups but also in the general population, further raising T2D risk. Regarding its pathogenesis, a gradually increasing insulin resistance due to central adiposity combined with a progressively defective β-cell function are the main culprits. Especially in youth-onset T2D, a rapid β-cell activity decline has been observed, leading to higher treatment failure rates, and early complications. In addition, it is well established that both the quantity and quality of food ingested by individuals play a key role in T2D pathogenesis. A chronic imbalance between caloric intake and expenditure together with impaired micronutrient intake can lead to obesity and insulin resistance on one hand, and β-cell failure and defective insulin production on the other. This review summarizes our evolving understanding of the pathophysiological mechanisms involved in defective insulin secretion by the pancreatic islets in youth- and adult-onset T2D and, further, of the role various micronutrients play in these pathomechanisms. This knowledge is essential if we are to curtail the serious long-term complications of T2D both in pediatric and adult populations.

Is TNF alpha a mediator in the co-existence of malaria and type 2 diabetes in a malaria endemic population?

Malaria remains a disease of public health importance globally, especially in sub-Saharan Africa. Malaria deaths reduced globally steadily between 2000-2019, however there was a 10% increase in 2020 due to disruptions in medical service during the COVID-19 pandemic. Globally, about 96% of malaria deaths occurred in 29 countries; out of which, four countries (Nigeria, the Democratic Republic of the Congo, the Niger, and the United Republic of Tanzania) accounted for just over half of the malaria deaths. Nigeria leads the four countries with the highest malaria deaths (accounting for 31% globally). Parallelly, sub-Saharan Africa is faced with a rise in the incidence of Type 2 diabetes (T2D). Until recently, T2D was a disease of adulthood and old age. However, this is changing as T2D in children and adolescents is becoming an increasingly important public health problem. Nigeria has been reported to have the highest burden of diabetes in Africa with a prevalence of 5.77% in the country. Several studies conducted in the last decade investigating the interaction between malaria and T2D in developing countries have led to the emergence of the intra-uterine hypothesis. The hypothesis has arisen as a possible explanation for the rise of T2D in malaria endemic areas; malaria in pregnancy could lead to intra-uterine stress which could contribute to low birth weight and may be a potential cause of T2D later in life. Hence, previous, and continuous exposure to malaria infection leads to a higher risk of T2D. Current and emerging evidence suggests that an inflammation-mediated link exists between malaria and eventual T2D emergence. The inflammatory process thus, is an important link for the co-existence of malaria and T2D because these two diseases are inflammatory-related. A key feature of T2D is systemic inflammation, characterized by the upregulation of inflammatory cytokines such as tumor necrosis factor alpha (TNF-α) which leads to impaired insulin signaling. Malaria infection is an inflammatory disease in which TNF-α also plays a major role. TNF-α plays an important role in the pathogenesis and development of malaria and T2D. We therefore hypothesize that TNF-α is an important link in the increasing co-existence of T2D.

Lnk/Sh2b3 modulates bioenergetic metabolism of activated CD8 T cells and control the development of Type 1 Diabetes

Abstract Recent genome-wide association studies (GWAS) have shown a strong correlation between a genetic polymorphism in the SH2B3gene and the development of autoimmune diseases, including type 1 diabetes (T1D). Lnk/Sh2b3 is an adaptor protein interacting with various intracellular proteins involved in JAK/STAT cytokine signaling of different cell types, including CD8 T cells. Additionally, Sh2b3-deficient CD8 T cells are hypersensitive to IL-15 stimulation. However, how reduced Sh2b3 function affects the molecular mechanisms that activate and sustain CD8 T cells promoting T1D development remains elusive. We hypothesized that genetic deletion of Sh2b3 in the non-obese diabetic (NOD) mouse would impact T1D incidence by altering T cell activation. NOD. Sh2b3−/− mice developed diabetes faster than wild-type controls. Additionally, Sh2b3-deficient CD8 T cells were hyperresponsive to IL-15 stimulation, promoting the generation of the activated CD44 high CD8 T cell population. Intriguingly, IL-15-stimulated Sh2b3−/− splenocytes possessed significantly higher mitochondrial respiratory capacity (SRC) and ATP synthesis than the wild-type counterparts. Furthermore, CD8 T cells of NOD. Sh2b3−/− mice showed increased expression of genes associated with mitochondrial biogenesis and oxidative metabolisms in response to in vitroIL-15 stimulation. Overall, our study supports a role of Sh2b3 in T1D development by regulating mitochondrial biogenesis and metabolism of IL-15-stimulated CD8 T cell. Our study provides new insight into the role of Sh2b3 in activating and sustaining the CD8 T cell response in the pathogenesis of T1D. Funded by NIH DK097605 Funded by NIH DK097605

Leveraging IgG N-glycosylation to infer the causality between T2D and hypertension

BackgroundObservational studies demonstrated a bidirectional association between type 2 diabetes (T2D) and hypertension, whereas Mendelian randomization (MR) analyses supported the causality from T2D to hypertension but not causal from hypertension to T2D. We previously found that IgG N-glycosylation is associated with both T2D and hypertension, and thus IgG N-glycosylation might link the causality between them.MethodsWe carried out a genome-wide association study (GWAS) to identify IgG N-glycosylation-quantitative-trait loci (QTLs) integrating GWAS for T2D and hypertension and then performed bidirectional univariable and multivariable MR analyses to infer the causal association among them. The inverse-variance-weighted (IVW) analysis was performed as the primary analysis, followed by some sensitivity analyses to explore the stability of the results.ResultsSix putatively causal IgG N-glycans for T2D and four for hypertension were identified in the IVW method. Genetically predicted T2D increased the risk of hypertension (odds ratio [OR] = 1.177, 95% confidence interval (95% CI) = 1.037–1.338, P = 0.012) and vice versa (OR = 1.391, 95% CI = 1.081–1.790, P = 0.010). Multivariable MR showed that T2D remained at risk effect with hypertension ([OR] = 1.229, 95% CI = 1.140–1.325, P = 7.817 × 10–8) after conditioning on T2D-related IgG-glycans. Conversely, hypertension was associated with higher T2D risk (OR = 1.287, 95% CI = 1.107–1.497, P = 0.001) after adjusting for related IgG-glycans. No evidence of horizontal pleiotropy was observed, as MR‒Egger regression provided P values for intercept > 0.05.ConclusionOur study validated the mutual causality between T2D and hypertension from the perspective of IgG N-glycosylation, further validating the “common soil” hypothesis underlying the pathogenesis of T2D and hypertension.

Development of Type 1 Diabetes in Mice Is Associated with a Decrease in IL-2-Producing ILC3 and FoxP3+ Treg in the Small Intestine.

Recent data indicate the link between the number and function of T regulatory cells (Treg) in the gut immune tissue and initiation and development of autoimmunity associated with type 1 diabetes (T1D). Since type 3 innate lymphoid cells (ILC3) in the small intestine are essential for maintaining FoxP3+ Treg and there are no data about the possible role of ILC3 in T1D pathogenesis, the aim of this study was to explore ILC3-Treg link during the development of T1D. Mature diabetic NOD mice had lower frequencies of IL-2-producing ILC3 and Treg in small intestine lamina propria (SILP) compared to prediabetic NOD mice. Similarly, in multiple low doses of streptozotocin (MLDS)-induced T1D in C57BL/6 mice, hyperglycemic mice exhibited lower numbers of ILC3, IL-2+ ILC3 and Treg in SILP compared to healthy controls. To boost T1D severity, mice were treated with broad-spectrum antibiotics (ABX) for 14 days prior to T1D induction by MLDS. The higher incidence of T1D in ABX-treated mice was associated with significantly lower frequencies of IL-2+ ILC3 and FoxP3+ Treg in SILP compared with mice without ABX treatment. The obtained findings show that the lower proportions of IL-2-expressing ILC3 and FoxP3+ Treg in SILP coincided with diabetes progression and severity.

Altered expression of synaptic proteins and adhesion molecules in the hippocampus and cortex following the onset of diabetes in nonobese diabetic mice

Mounting evidence links Type 1 diabetes (T1D) with cognitive dysfunction, psychiatric disorders, and synaptic alterations; however, the underlying mechanism remains unclear. Numerous synaptic proteins and synaptic adhesion molecules (SAMs) that orchestrate synaptic formation, restructuring, and elimination are essential for proper brain function. Currently, it is unclear whether the pathogenesis of T1D is related to the expression of synaptic proteins and SAMs. Here, we investigated whether T1D mice exhibited altered synaptic protein and SAM expression in the hippocampus and cortex. We discovered that T1D mice exhibited partially decreased levels of excitatory and inhibitory synapse proteins and SAMs, such as neurexins, neuroligins, and synaptic cell adhesion molecules. We also found that compared to control mice, T1D mice showed a marginal decrease in body weight and a significant increase in plasma glycoalbumin levels (a hyperglycemia marker). These results provide novel molecular-level insights into synaptic dysfunction in mice with T1D.

Recent advances of long non-coding RNAs in control of hepatic gluconeogenesis.

Gluconeogenesis is the main process for endogenous glucose production during prolonged fasting, or certain pathological conditions, which occurs primarily in the liver. Hepatic gluconeogenesis is a biochemical process that is finely controlled by hormones such as insulin and glucagon, and it is of great importance for maintaining normal physiological blood glucose levels. Dysregulated gluconeogenesis induced by obesity is often associated with hyperglycemia, hyperinsulinemia, and type 2 diabetes (T2D). Long noncoding RNAs (lncRNAs) are involved in various cellular events, from gene transcription to protein translation, stability, and function. In recent years, a growing number of evidences has shown that lncRNAs play a key role in hepatic gluconeogenesis and thereby, affect the pathogenesis of T2D. Here we summarized the recent progress in lncRNAs and hepatic gluconeogenesis.

Circulating Metabolomic and Lipidomic Signatures Identify a Type 2 Diabetes Risk Profile in Low-Birth-Weight Men with Non-Alcoholic Fatty Liver Disease

The extent to which increased liver fat content influences differences in circulating metabolites and/or lipids between low-birth-weight (LBW) individuals, at increased risk of type 2 diabetes (T2D), and normal-birth-weight (NBW) controls is unknown. The objective of the study was to perform untargeted serum metabolomics and lipidomics analyses in 26 healthy, non-obese early-middle-aged LBW men, including five men with screen-detected and previously unrecognized non-alcoholic fatty liver disease (NAFLD), compared with 22 age- and BMI-matched NBW men (controls). While four metabolites (out of 65) and fifteen lipids (out of 279) differentiated the 26 LBW men from the 22 NBW controls (p ≤ 0.05), subgroup analyses of the LBW men with and without NAFLD revealed more pronounced differences, with 11 metabolites and 56 lipids differentiating (p ≤ 0.05) the groups. The differences in the LBW men with NAFLD included increased levels of ornithine and tyrosine (PFDR ≤ 0.1), as well as of triglycerides and phosphatidylcholines with shorter carbon-chain lengths and fewer double bonds. Pathway and network analyses demonstrated downregulation of transfer RNA (tRNA) charging, altered urea cycling, insulin resistance, and an increased risk of T2D in the LBW men with NAFLD. Our findings highlight the importance of increased liver fat in the pathogenesis of T2D in LBW individuals.

Investigating the Role of Immune System in Type 1 Diabetes

Type 1 diabetes (T1D) refers to the immune system's eradication of the cells that produce insulin in the patients’ islets. Dendritic cells (DCs), macrophages, and lymphocytes are some of the immune cells attended in the relevant immune responses and have been connected to the pathogenesis of T1D. In addition, it is also highlighted that cytokines also activate regulatory processes, like tumor necrosis factor α (TNF-α), interleukin 6 (IL-6) and interleukin 7 (IL-7). It is possible to develop clinical trials for T1D that combine selective cytokine blocking as a component of preventive or interventional immunotherapy. In this project, the current knowledge on the relationship between inflammation and T1D is summarized. Non-specific immune system and specific immune system are highly involved in the complex mechanism and have specific responsibilities respectively. In addition, the roles of different types of cytokines in T1D and cytokine-related potential treatment options are also be discussed in this article.

Selected Serum Markers Associated with Pathogenesis and Clinical Course of Type 1 Diabetes in Pediatric Patients—The Effect of Disease Duration

Biochemical abnormalities in the course of type 1 diabetes (T1D) may cause the production/activation of various proteins and peptides influencing treatment and causing a risk of complications. The aim of this study was to assess concentrations of selected serum substances involved in the pathogenesis and course of T1D and to correlate their concentrations with the duration of T1D. The study included patients with T1D (n = 156) at the age of 3-17, who were divided according to the duration of the disease into those newly diagnosed (n = 30), diagnosed after 3-5 (n = 77), 6-7 (n = 25), and over 7 (n = 24) years from the onset of T1D, and age-matched healthy controls (n = 30). Concentrations of amylin (IAPP), proamylin (proIAPP), catestatin (CST), chromogranin A (ChgA), nerve growth factor (NFG), platelet-activating factor (PAF), uromodulin (UMOD), and intestinal fatty acid binding protein (I-FABP) were measured in sera using immunoenzymatic tests. There were significant differences in concentrations of all the substances except UMOD and NGF between T1D patients and healthy children. The duration of the disease affected concentrations of CST, ChgA, PAF, and NGF, i.e., proteins/peptides which could have an impact on the course of T1D and the development of complications. In long-term patients, a decrease in concentrations of CST and ChgA, and an increase in PAF concentrations were found. In the case of NGF, a decrease was observed after the initial high values, followed by an increase over 7 years after T1D diagnosis. Concluding, the results show that concentrations of selected serum indicators may change in the course of T1D. Further studies are needed to establish whether these indicators could be used in the context of predicting long-term complications.

Lipid domain boundary triggers membrane damage and protein folding of human islet amyloid polypeptide in the early pathogenesis of amyloid diseases

The misfolding and self-aggregation of human Islet Amyloid Polypeptide (hIAPP) are linked to the onset of type 2 diabetes (T2D). However, the mechanism of how the disordered hIAPP aggregates trigger membrane damage leading to the loss of Islet cells in T2D is unknown. Using coarse-grained (CG) and all-atom (AA) molecular dynamics simulations, we have investigated the membrane-disruption behaviors of hIAPP oligomers on the phase-separated lipid nanodomains that mimic the highly heterogeneous lipid raft structures of cell membranes. Our results revealed that hIAPP oligomers preferentially bind to the liquid-ordered and liquid-disordered domain boundary around two hydrophobic residues at L16 and I26, and lipid acyl chain order disruption and beta-sheet formation occur upon hIAPP binding to the membrane surface. We propose that the lipid order disruption and surface-induced beta-sheet formation on the lipid domain boundary represent the early molecular events of membrane damage associated with the early pathogenesis of T2D.

Probiotics and Prebiotics as Dietary Supplements for the Adjunctive Treatment of Type 2 Diabetes

In modern lifestyles, high-fat diets and prolonged inactivity lead to more people developing type 2 diabetes (T2D). Based on the modern pathogenesis of T2D, food, and its components have become one of the top concerns for patients. Recent studies have found that dysbiosis and gut-related inflammation are more common in T2D patients. Probiotics and prebiotics play complementary roles in the gut as dietary supplements. Together, they may help improve dysbiosis and intestinal inflammation in people with T2D, increase the production of blood glucose-lowering hormones such as incretin, and help reduce insulin resistance and lower blood glucose. Therefore, changing the dietary structure and increasing the intake of probiotics and prebiotics is expected to become a new strategy for the adjuvant treatment of T2D.

Vitamin A regulates tissue-specific organ remodeling in diet-induced obesity independent of mitochondrial function.

Perturbed mitochondrial energetics and vitamin A (VitA) metabolism are associated with the pathogenesis of diet-induced obesity (DIO) and type 2 diabetes (T2D). To test the hypothesis that VitA regulates tissue-specific mitochondrial energetics and adverse organ remodeling in DIO, we utilized a murine model of impaired VitA availability and high fat diet (HFD) feeding. Mitochondrial respiratory capacity and organ remodeling were assessed in liver, skeletal muscle, and kidney tissue, which are organs affected by T2D-associated complications and are critical for the pathogenesis of T2D. In liver, VitA had no impact on maximal ADP-stimulated mitochondrial respiratory capacity (VADP) following HFD feeding with palmitoyl-carnitine and pyruvate each combined with malate as substrates. Interestingly, histopathological and gene expression analyses revealed that VitA mediates steatosis and adverse remodeling in DIO. In skeletal muscle, VitA did not affect VADP following HFD feeding. No morphological differences were detected between groups. In kidney, VADP was not different between groups with both combinations of substrates and VitA transduced the pro-fibrotic transcriptional response following HFD feeding. The present study identifies an unexpected and tissue-specific role for VitA in DIO that regulates the pro-fibrotic transcriptional response and that results in organ damage independent of changes in mitochondrial energetics.

Heterogeneity of Islet-Infiltrating IL-21+ CD4 T Cells in a Mouse Model of Type 1 Diabetes.

IL-21 is essential for type 1 diabetes (T1D) development in the NOD mouse model. IL-21-expressing CD4 T cells are present in pancreatic islets where they contribute to T1D progression. However, little is known about their phenotype and differentiation states. To fill this gap, we generated, to our knowledge, a novel IL-21 reporter NOD strain to further characterize IL-21+ CD4 T cells in T1D. IL-21+ CD4 T cells accumulate in pancreatic islets and recognize β cell Ags. Single-cell RNA sequencing revealed that CD4 T effector cells in islets actively express IL-21 and they are highly diabetogenic despite expressing multiple inhibitory molecules, including PD-1 and LAG3. Islet IL-21+ CD4 T cells segregate into four phenotypically and transcriptionally distinct differentiation states, that is, less differentiated early effectors, T follicular helper (Tfh)-like cells, and two Th1 subsets. Trajectory analysis predicts that early effectors differentiate into both Tfh-like and terminal Th1 cells. We further demonstrated that intrinsic IL-27 signaling controls the differentiation of islet IL-21+ CD4 T cells, contributing to their helper function. Collectively, our study reveals the heterogeneity of islet-infiltrating IL-21+ CD4 T cells and indicates that both Tfh-like and Th1 subsets produce IL-21 throughout their differentiation process, highlighting the important sources of IL-21 in T1D pathogenesis.

Somatostatin Containing δ-Cell Number Is Reduced in Type-2 Diabetes.

Recent developments suggest that increased glucagon and decreased somatostatin secretion from the pancreas contribute to hyperglycaemia in type-2 diabetes (T2D) patients. There is a huge need to understand changes in glucagon and somatostatin secretion to develop potential anti-diabetic drugs. To further describe the role of somatostatin in the pathogenesis of T2D, reliable means to detect islet δ-cells and somatostatin secretion are necessary. In this study, we first tested currently available anti-somatostatin antibodies against a mouse model that fluorescently labels δ-cells. We found that these antibodies only label 10-15% of the fluorescently labelled δ-cells in pancreatic islets. We further tested six antibodies (newly developed) that can label both somatostatin 14 (SST14) and 28 (SST28) and found that four of them were able to detect above 70% of the fluorescent cells in the transgenic islets. This is quite efficient compared to the commercially available antibodies. Using one of these antibodies (SST10G5), we compared the cytoarchitecture of mouse and human pancreatic islets and found fewer δ-cells in the periphery of human islets. Interestingly, the δ-cell number was also reduced in islets from T2D donors compared to non-diabetic donors. Finally, with the aim to measure SST secretion from pancreatic islets, one of the candidate antibodies was used to develop a direct-ELISA-based SST assay. Using this novel assay, we could detect SST secretion under low and high glucose conditions from the pancreatic islets, both in mice and humans. Overall, using antibody-based tools provided by Mercodia AB, our study indicates reduced δ-cell numbers and SST secretion in diabetic islets.

Single molecule spatial transcriptomics demonstrates spatial heterogeneity of pre-miRNA and classifies β-cells in type 1 diabetes.

Recently developed spatial transcriptomics approaches combine RNA sequencing (RNA-Seq) with cell localization to reveal the spatial heterogeneity of transcriptomes in tissue samples. However, the interrogation of transcriptomic profiles in subcellular locations has not been reported. Here we propose a quantitative approach to measure the spatial distribution of single-cell transcriptomes, and we use this technique to study pre-miRNA expression in single β-cells obtained from human pancreatic tissues. A multi-dimensional quantitative model was established to describe the spatial distribution of RNAs as “features”, including RNA expression, location, and degree of clustering/dispersion. These features were analyzed using statistical distribution modeling and supervised machine learning to enable the classification of β-cells from the pancreas of non-diabetic control organ donors, autoantibody-positive (AAb+) organ donors, and organ donors with type 1 diabetes (T1D). This approach provided a quantitative evaluation of the distinctive features contributing to the classification and phenotyping and showed that expression levels of pre-miR-155 in β cells differ significantly among the groups, with more pre-miR-155 in the nucleus than cytoplasm of β-cells in the T1D and AAb+ samples compared to β-cells from control donors (p<0.0001). Interestingly, pre-miRNA distribution directly correlated with β-cell phenotype and T1D disease status. Results show higher degree of clustering for nuclear pre-miR-155 at short distances and greater amount of aggregation at the nuclear boundary for T1D samples (p<0.0001). These findings suggest that the spatial heterogeneity of the transcriptome of β-cells can classify these cells into different pathological conditions. Taken together, data from this study reveal fundamental mechanisms associated with RNA distribution and the β-cell phenotype during the pathogenesis of T1D. This approach could lead to the discovery of important subcellular spatial transcriptomic features that may have clinical relevance in stratifying T1D phenotypes.

Glucagon in type 2 diabetes: Friend or foe?

Hyperglucagonemia is one of the 'ominous' eight factors underlying the pathogenesis of type 2 diabetes (T2D). Glucagon is a peptide hormone involved in maintaining glucose homoeostasis by increasing hepatic glucose output to counterbalance insulin action. Long neglected, the introduction of dual and triple agonists exploiting glucagon signalling pathways has rekindled the interest in this hormone beyond its classic effect on glycaemia. Glucagon can promote weight loss by regulating food intake, energy expenditure, and brown and white adipose tissue functions through mechanisms still to be fully elucidated, thus its role in T2D pathogenesis should be further investigated. Moreover, the role of glucagon in the development of T2D micro- and macro-vascular complications is elusive. Mounting evidence suggests its beneficial effect in non-alcoholic fatty liver disease, while few studies postulated its favourable role in peripheral neuropathy and retinopathy. Contrarily, glucagon receptor agonism might induce renal changes resembling diabetic nephropathy, and data concerning glucagon actions on the cardiovascular system are conflicting. This review aims to summarise the available findings on the role of glucagon in the pathogenesis of T2D and its complications. Further experimental and clinical data are warranted to better understand the implications of glucagon signalling modulation with new antidiabetic drugs.

Type 2 Diabetes and Alzheimer's Disease: The Emerging Role of Cellular Lipotoxicity.

Type 2 diabetes (T2D) and Alzheimer's diseases (AD) represent major health issues that have reached alarming levels in the last decades. Although growing evidence demonstrates that AD is a significant comorbidity of T2D, and there is a ~1.4-2-fold increase in the risk of developing AD among T2D patients, the involvement of possible common triggers in the pathogenesis of these two diseases remains largely unknown. Of note, recent mechanistic insights suggest that lipotoxicity could represent the missing ring in the pathogenetic mechanisms linking T2D to AD. Indeed, obesity, which represents the main cause of lipotoxicity, has been recognized as a major risk factor for both pathological conditions. Lipotoxicity can lead to inflammation, insulin resistance, oxidative stress, ceramide and amyloid accumulation, endoplasmic reticulum stress, ferroptosis, and autophagy, which are shared biological events in the pathogenesis of T2D and AD. In the current review, we try to provide a critical and comprehensive view of the common molecular pathways activated by lipotoxicity in T2D and AD, attempting to summarize how these mechanisms can drive future research and open the way to new therapeutic perspectives.

Triterpenoid CDDO-EA inhibits lipopolysaccharide-induced inflammatory responses in skeletal muscle cells through suppression of NF-κB.

Chronic inflammation is a major contributor to the development of obesity-induced insulin resistance, which then can lead to the development of type 2 diabetes (T2D). Skeletal muscle plays a pivotal role in insulin-stimulated whole-body glucose disposal. Therefore, dysregulation of glucose metabolism by inflammation in skeletal muscle can adversely affect skeletal muscle insulin sensitivity and contribute to the pathogenesis of T2D. The mechanism underlying insulin resistance is not well known; however, macrophages are important initiators in the development of the chronic inflammatory state leading to insulin resistance. Skeletal muscle consists of resident macrophages which can be activated by lipopolysaccharide (LPS). These activated macrophages affect myocytes via a paracrine action of pro-inflammatory mediators resulting in secretion of myokines that contribute to inflammation and ultimately skeletal muscle insulin resistance. Therefore, knowing that synthetic triterpenoid 2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oic acids (CDDOs) can attenuate macrophage pro-inflammatory responses in chronic disorders, such as cancer and obesity, and that macrophage pro-inflammatory responses can modulate skeletal muscle inflammation, we first examined whether CDDO-ethyl amide (CDDO-EA) inhibited chemokine and cytokine production in macrophages since this had not been reported for CDDO-EA. CDDO-EA blocked LPS-induced tumor necrosis factor-alpha (TNF-α), monocyte chemotactic protein-1 (MCP-1), interleukine-1beta (IL-1β), and interleukine-6 (IL-6) production in RAW 264.7 mouse and THP-1 human macrophages. Although many studies show that CDDOs have anti-inflammatory properties in several tissues and cells, little is known about the anti-inflammatory effects of CDDOs on skeletal muscle. We hypothesized that CDDO-EA protects skeletal muscle from LPS-induced inflammation by blocking nuclear factor kappa B (NF-κB) signaling. Our studies demonstrate that CDDO-EA prevented LPS-induced TNF-α and MCP-1 gene expression by inhibiting the NF-κB signaling pathway in L6-GLUT4myc rat myotubes. Our findings suggest that CDDO-EA suppresses LPS-induced inflammation in macrophages and myocytes and that CDDO-EA is a promising compound as a therapeutic agent for protecting skeletal muscle from inflammation.