Human Type 1 Diabetes Research Articles

Association Between Circulating Vitamin K Levels, Gut Microbiome, and Type 1 Diabetes: A Mendelian Randomization Study

Background/Objectives: Nutritional deficiencies have been proposed as possible etiological causes for autoimmune diseases, among which type 1 diabetes (T1D). Vitamin K (VK) has potentially positive effects on type 2 diabetes, but its role on T1D in humans remains largely unknown. We aimed to examine the presence of a causal association between VK and T1D using a Mendelian randomization (MR) approach. Methods: Genetic variants from a genome-wide association study (GWAS) for VK (N= 2138 Europeans) were used as instruments in our two-sample MR study to investigate whether circulating VK levels are causally associated with the risk of T1D in a large European T1D GWAS cohort (18,942 cases/520,580 controls). Through a multivariable MR (MVMR), the effects of both VK and specific gut microbiota on T1D were investigated given that the gut microbiome synthesizes VK. Results: We found that changes in levels of circulating VK did not affect T1D risk in our univariate two-sample MR, but this study had limited power to detect small effects of VK (OR for T1D of less than 0.8). However, our MVMR indicated a suggestive association of VK with the risk of T1D adjusting for two different gut microbiome populations. Conclusions In conclusion, VK levels are unlikely to significantly affect the risk of T1D, but small effects cannot be excluded, and the role of gut microbiome in this association should be further investigated.

Type 1 diabetes and parasite infection: An exploratory study in NOD mice.

Microorganisms have long been suspected to influence the outcome of immune-related syndromes, particularly autoimmune diseases. Type 1 diabetes (T1D) results from the autoimmune destruction of the insulin-producing beta cells of pancreatic islets, causing high glycemia levels. Genetics is part of its aetiology, but environmental factors, particularly infectious microorganisms, also play a role. Bacteria, viruses, and parasites influence the outcome of T1D in mice and humans. We used nonobese diabetic (NOD) mice, which spontaneously develop T1D, to investigate the influence of a parasitic infection, leishmaniasis. Leishmania amazonensis is an intracellular eukaryotic parasite that replicates predominantly in macrophages and is responsible for cutaneous leishmaniasis. The implication of Th1 immune responses in T1D and leishmaniasis led us to study this parasite in the NOD mouse model. We previously constructed osteopontin knockout mice with a NOD genetic background and demonstrated that this protein plays a role in the T1D phenotype. In addition, osteopontin (OPN) has been found to play a role in the immune response to various infectious microorganisms and to be implicated in other autoimmune conditions, such as multiple sclerosis in humans and experimental autoimmune encephalomyelitis (EAE) in mice. We present herein data demonstrating the role of OPN in the response to Leishmania in NOD mice and the influence of this parasitic infection on T1D. This exploratory study aimed to investigate the environmental infectious component of the autoimmune response, including Th1 immunity, which is common to both T1D and leishmaniasis.

Periodontitis and Diabetes Differentially Affect Inflammation in Obesity

Periodontitis (PD) potentiates systemic inflammatory diseases and fuels a feed-forward loop of pathogenic inflammation in obesity and type 2 diabetes (T2D). Published work in this area often conflates obesity with obesity-associated T2D; thus, it remains unclear whether PD similarly affects the inflammatory profiles of these 2 distinct systemic diseases. We collected peripheral blood mononuclear cells (PBMCs) from cross-sectionally recruited subjects to estimate the ability of PD to affect cytokine production in human obesity and/or T2D. We analyzed 2 major sources of systemic inflammation: T cells and myeloid cells. Bioplex quantitated cytokines secreted by PBMCs stimulated with T cell– or myeloid-targeting activators, and we combinatorially analyzed outcomes using partial least squares discriminant analysis. Our data show that PD significantly shifts peripheral T cell– and myeloid-generated inflammation in obesity. PD also changed myeloid- but not T cell–generated inflammation in T2D. T2D changed inflammation in samples from subjects with PD, and PD changed inflammation in samples from subjects with T2D, consistent with the bidirectional relationship of inflammation between these 2 conditions. PBMCs from T2D subjects with stage IV PD produced lower amounts of T cell and myeloid cytokines compared with PBMCs from T2D subjects with stage II to III PD. We conclude that PD and T2D affect systemic inflammation through overlapping but nonidentical mechanisms in obesity, indicating that characterizing both oral and metabolic status (beyond obesity) is critical for identifying mechanisms linking PD to systemic diseases such as obesity and T2D. The finding that stage IV PD cells generate fewer cytokines in T2D provides an explanation for the paradoxical findings that the immune system can appear activated or suppressed in PD, given that many studies do not report PD stage. Finally, our data indicate that a focus on multiple cellular sources of cytokines will be imperative to clinically address the systemic effects of PD in people with obesity.

2-Hydroxylation is a chemical switch linking fatty acids to glucose-stimulated insulin secretion

Glucose-stimulated insulin secretion (GSIS) in pancreatic β-cells is metabolically regulated and progressively diminished during the development of type 2 diabetes (T2D). This dynamic process is tightly coupled with fatty acid metabolism, but the underlying mechanisms remain poorly understood. Fatty acid 2-hydroxylase (FA2H) catalyzes the conversion of fatty acids to chiral specific (R)-2-hydroxy fatty acids ((R)-2-OHFAs), which influences cell metabolism. However, little is known about its potential coupling with GSIS in pancreatic β cells. Here, we showed that Fa2h knockout decreases plasma membrane localization and protein level of glucose transporter 2 (GLUT2), which is essential for GSIS, thereby controlling blood glucose homeostasis. Conversely, FA2H overexpression increases GLUT2 on the plasma membrane and enhances GSIS. Mechanistically, FA2H suppresses the internalization and trafficking of GLUT2 to the lysosomes for degradation. Overexpression of wild-type FA2H, but not its mutant with impaired hydroxylase activity in the pancreatic β-cells, improves glucose tolerance by promoting insulin secretion. Levels of 2-OHFAs and Fa2h gene expression are lower in high-fat diet-induced obese mouse islets with impaired GSIS. Moreover, lower gene expression of FA2H is observed in a set of human T2D islets when the insulin secretion index is significantly suppressed, indicating the potential involvement of FA2H in regulating mouse and human GSIS. Collectively, our results identified an FA chemical switch to maintain the proper response of GSIS in pancreatic β cells and provided a new perspective on the β-cell failure that triggers T2D.

Immune perturbations in human pancreas lymphatic tissues prior to and after type 1 diabetes onset.

Autoimmune destruction of pancreatic β cells results in type 1 diabetes (T1D), with pancreatic immune infiltrate representing a key feature in this process. Studies of human T1D immunobiology have predominantly focused on circulating immune cells in the blood, while mouse models suggest diabetogenic lymphocytes primarily reside in pancreas-draining lymph nodes (pLN). A comprehensive study of immune cells in human T1D was conducted using pancreas draining lymphatic tissues, including pLN and mesenteric lymph nodes, and the spleen from non-diabetic control, β cell autoantibody positive non-diabetic (AAb+), and T1D organ donors using complementary approaches of high parameter flow cytometry and CITEseq. Immune perturbations suggestive of a proinflammatory environment were specific for T1D pLN and AAb+ pLN. In addition, certain immune populations correlated with high T1D genetic risk independent of disease state. These datasets form an extensive resource for profiling human lymphatic tissue immune cells in the context of autoimmunity and T1D.

Disruption of insulin receptor substrate 2 (IRS2) causes non-obese type 2 diabetes with β-cell dysfunction in the golden (Syrian) hamster

Because of the advent of genome-editing technology, gene knockout (KO) hamsters have become attractive research models for diverse diseases in humans. This study established a new KO model of diabetes by disrupting the insulin receptor substrate-2 (Irs2) gene in the golden (Syrian) hamster. Homozygous KO animals were born alive but with delayed postnatal growth until adulthood. They showed hyperglycemia, high HbA1c, and impaired glucose tolerance. However, they normally responded to insulin stimulation, unlike Irs2 KO mice, an obese type 2 diabetes (T2D) model. Consistent with this, Irs2 KO hamsters did not increase serum insulin levels upon glucose administration and showed β-cell hypoplasia in their pancreas. Thus, our Irs2 KO hamster provide a unique T2D animal model that is distinct from the obese T2D models. This model may contribute to a better understanding of the pathophysiology of human non-obese T2D with β-cell dysfunction, the most common type of T2D in East Asian countries, including Japan.

Advancing Animal Models of Human Type 1 Diabetes.

Multiple rodent models have been developed to study the basis of type 1 diabetes (T1D). However, nonobese diabetic (NOD) mice and derivative strains still provide the gold standard for dissecting the basis of the autoimmune responses underlying T1D. Here, we review the developmental origins of NOD mice, and how they and derivative strains have been used over the past several decades to dissect the genetic and immunopathogenic basis of T1D. Also discussed are ways in which the immunopathogenic basis of T1D in NOD mice and humans are similar or differ. Additionally reviewed are efforts to "humanize" NOD mice and derivative strains to provide improved models to study autoimmune responses contributing to T1D in human patients.

Bidirectional modulation of TCA cycle metabolites and anaplerosis by metformin and its combination with SGLT2i

BackgroundMetformin and sodium-glucose-cotransporter-2 inhibitors (SGLT2i) are cornerstone therapies for managing hyperglycemia in diabetes. However, their detailed impacts on metabolic processes, particularly within the citric acid (TCA) cycle and its anaplerotic pathways, remain unclear. This study investigates the tissue-specific metabolic effects of metformin, both as a monotherapy and in combination with SGLT2i, on the TCA cycle and associated anaplerotic reactions in both mice and humans.MethodsMetformin-specific metabolic changes were initially identified by comparing metformin-treated diabetic mice (MET) with vehicle-treated db/db mice (VG). These findings were then assessed in two human cohorts (KORA and QBB) and a longitudinal KORA study of metformin-naïve patients with Type 2 Diabetes (T2D). We also compared MET with db/db mice on combination therapy (SGLT2i + MET). Metabolic profiling analyzed 716 metabolites from plasma, liver, and kidney tissues post-treatment, using linear regression and Bonferroni correction for statistical analysis, complemented by pathway analyses to explore the pathophysiological implications.ResultsMetformin monotherapy significantly upregulated TCA cycle intermediates such as malate, fumarate, and α-ketoglutarate (α-KG) in plasma, and anaplerotic substrates including hepatic glutamate and renal 2-hydroxyglutarate (2-HG) in diabetic mice. Downregulated hepatic taurine was also observed. The addition of SGLT2i, however, reversed these effects, such as downregulating circulating malate and α-KG, and hepatic glutamate and renal 2-HG, but upregulated hepatic taurine. In human T2D patients on metformin therapy, significant systemic alterations in metabolites were observed, including increased malate but decreased citrulline. The bidirectional modulation of TCA cycle intermediates in mice influenced key anaplerotic pathways linked to glutaminolysis, tumorigenesis, immune regulation, and antioxidative responses.ConclusionThis study elucidates the specific metabolic consequences of metformin and SGLT2i on the TCA cycle, reflecting potential impacts on the immune system. Metformin shows promise for its anti-inflammatory properties, while the addition of SGLT2i may provide liver protection in conditions like metabolic dysfunction-associated steatotic liver disease (MASLD). These observations underscore the importance of personalized treatment strategies.

Acidic Nanoparticles Restore Lysosomal Acidification and Rescue Metabolic Dysfunction in Pancreatic β-Cells under Lipotoxic Conditions.

Type 2 diabetes (T2D), a prevalent metabolic disorder lacking effective treatments, is associated with lysosomal acidification dysfunction, as well as autophagic and mitochondrial impairments. Here, we report a series of biodegradable poly(butylene tetrafluorosuccinate-co-succinate) polyesters, comprising a 1,4-butanediol linker and varying ratios of tetrafluorosuccinic acid (TFSA) and succinic acid as components, to engineer lysosome-acidifying nanoparticles (NPs). The synthesized NPs are spherical with diameters of ≈100 nm and have low polydispersity and good stability. Notably, TFSA NPs, which are composed entirely of TFSA, exhibit the strongest degradation capability and superior acidifying properties. We further reveal significant downregulation of lysosomal vacuolar (H+)-ATPase subunits, which are responsible for maintaining lysosomal acidification, in human T2D pancreatic islets, INS-1 β-cells under chronic lipotoxic conditions, and pancreatic tissues of high-fat-diet (HFD) mice. Treatment with TFSA NPs restores lysosomal acidification, autophagic function, and mitochondrial activity, thereby improving the pancreatic function in INS-1 cells and HFD mice with lipid overload. Importantly, the administration of TFSA NPs to HFD mice reduces insulin resistance and improves glucose clearance. These findings highlight the therapeutic potential of lysosome-acidifying TFSA NPs for T2D.

Fasting and Glucose Metabolism Differentially Impact Peripheral Inflammation in Human Type 2 Diabetes.

Cytokines produced by peripheral T-helper 1/17 cells disproportionately contribute to the inflammation (i.e., metaflammation) that fuels type 2 diabetes (T2D) pathogenesis. Shifts in the nutrient milieu could influence inflammation through changes in T-cell metabolism. We aimed to determine whether changes in glucose utilization alter cytokine profiles in T2D. Peripheral blood mononuclear cells (PBMCs), CD4+ T-cells, and CD4+CD25- T-effector (Teff) cells were isolated from age-matched humans classified by glycemic control and BMI. Cytokines secreted by CD3/CD28-stimulated PBMCs and Teff were measured in supernatants with multiplex cytokine assays and a FLEXMAP-3D. Metabolic activity of stimulated CD4+ T-cells was measured by a Seahorse XFe96 analyzer. In this study, we demonstrated that T-cell stimulated PBMCs from non-fasted people with T2D produced higher amounts of cytokines compared to fasting. Although dysglycemia characterizes T2D, cytokine production by PBMCs or CD4+ T-cells in T2D was unaltered by hyperglycemic media. Moreover, pharmacological suppression of mitochondrial glucose oxidation did not change T-cell metabolism in T2D, yet enhanced cytokine competency. In conclusion, fasting and glucose metabolism differentially impact peripheral inflammation in human T2D, suggesting that glucose, along with fatty acid metabolites per our previous work, partner to regulate metaflammation. These data expose a major disconnect in the use of glycemic control drugs to target T2D-associated metaflammation.

Role for the Carotid Chemoreceptors in Glucose Tolerance in Human Type 2 Diabetes

Objectives: The carotid body (CB) chemoreceptors have been implicated in the development and progression of type 2 diabetes (T2D). CB denervation can prevent the development and worsening of T2D in pre-clinical models — although these data have yet to be translated to humans. We examined CB chemosensitivity in T2D, as well as the contribution of the CB to glucose tolerance. We hypothesized: 1) individuals with T2D would exhibit exaggerated CB sensitivity to hypoxia (hypoxic ventilatory response, HVR), 2) attenuation of CB chemoreceptor activity (i.e., hyperoxia) would improve glucose tolerance in T2D, and 3) the magnitude of the effect of hyperoxia on glucose tolerance would be related to the level of CB chemosensitivity. Methods: HVR was assessed in sixteen adults with T2D (6M/10F, 55±11 yrs, HbA1c 7.7±1.4%) and twenty-one healthy controls (9M/12F, 50±13 yrs, HbA1c 5.2±0.4%)(NCT05219994). A subset (n=9 per group) completed two additional visits randomized to normoxia (0.21 FiO2) and hyperoxia (1.0 FiO2). During each visit, blood glucose and plasma insulin were measured every 15 min for 2 hrs following consumption of a 75 g glucose drink and responses were calculated as area under the curve (AUC). Pearson correlations between HVR and the difference in AUC glucose and insulin between visits (ΔAUC = hyperoxia-normoxia) were conducted. Results: HVR was augmented in T2D compared to control (control, -0.47±0.39; T2D, -0.83±0.50 L/min/%; p=0.02). There was no effect of hyperoxia on AUCglucose (control, p=0.77; T2D, p=0.73) or AUCinsulin (control, p=0.70; T2D, p=0.41). Correlations were observed between HVR and ΔAUCglucose (R=0.67, p=0.047) and ΔAUCinsulin (R=-0.55, p=0.16)] in adults with T2D, but not in controls [ΔAUCglucose (R=-0.32, p=0.40), ΔAUCinsulin (R=-0.18, p=0.67)]. Conclusions: Individuals with T2D exhibit exaggerated CB sensitivity to hypoxia. Glucose tolerance was unaffected by attenuation of CB chemoreceptor activity; however, when examined in relation to CB sensitivity, glucose tolerance improved with hyperoxia in T2D adults with the highest HVR. Present data advance our understanding of the pathophysiology of T2D and support a potential role for the CB chemoreceptors in glucose tolerance in human T2D. MizzouForward Undergraduate Research Training Grant, University of Missouri Research Council, University of Missouri Alumni Association Richard Wallace Research Incentive Fund. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Stat5b/Ezh2 axis governs high PD-L1 expressing tolerogenic dendritic cell subset in autoimmune diabetes

Dendritic cells (DCs) are specialized antigen-presenting cells that play an important role in inducing and maintaining immune tolerance. The altered distribution and/or function of DCs contributes to defective tolerance in autoimmune diseases such as type 1 diabetes (T1D). In human T1D and in NOD mouse models, DCs share some defects and are often described as less tolerogenic and excessively immunogenic. In the NOD mouse model, the autoimmune response is associated with a defect in the Stat5b signaling pathway. We have reported that expressing a constitutively active form of Stat5b in DCs of transgenic NOD mice (NOD.Stat5b-CA), re-established their tolerogenic function, restored autoimmune tolerance and conferred protection from diabetes. However, the role and molecular mechanisms of Stat5b signaling in regulating splenic conventional DCs tolerogenic signature remained unclear. In this study, we reported that, compared to immunogenic splenic DCs of NOD, splenic DCs of NOD.Stat5b-CA mice exhibited a tolerogenic profile marked by elevated PD-L1 and PD-L2 expression, reduced pro-inflammatory cytokine production, increased frequency of the cDC2 subset and decreased frequency of the cDC1 subset. This tolerogenic profile was associated with increased Ezh2 and IRF4 but decreased IRF8 expression. We also found an upregulation of PD-L1 in the cDC1 subset and high PD-L1 and PD-L2 expression in cDC2 of NOD.Stat5b-CA mice. Mechanistically, we demonstrated that Ezh2 plays an important role in the maintenance of high PD-L1 expression in cDC1 and cDC2 subsets and that Ezh2 inhibition resulted in PD-L1 but not PD-L2 downregulation which was more drastic in the cDC2 subset. Additionally, Ezh2 inhibition severely reduced the cDC2 subset and increased the cDC1 subset and Stat5b-CA.DC pro-inflammatory cytokine production. Together our data suggest that the Stat5b-Ezh2 axis is critical for the maintenance of tolerogenic high PD-L1-expressing cDC2 and autoimmune tolerance in NOD.Stat5b-CA mice.

Factors Governing B Cell Recognition of Autoantigen and Function in Type 1 Diabetes.

Islet autoantibodies predict type 1 diabetes (T1D) but can be transient in murine and human T1D and are not thought to be directly pathogenic. Rather, these autoantibodies signal B cell activity as antigen-presenting cells (APCs) that present islet autoantigen to diabetogenic T cells to promote T1D pathogenesis. Disrupting B cell APC function prevents T1D in mouse models and has shown promise in clinical trials. Autoantigen-specific B cells thus hold potential as sophisticated T1D biomarkers and therapeutic targets. B cell receptor (BCR) somatic hypermutation is a mechanism by which B cells increase affinity for islet autoantigen. High-affinity B and T cell responses are selected in protective immune responses, but immune tolerance mechanisms are known to censor highly autoreactive clones in autoimmunity, including T1D. Thus, different selection rules often apply to autoimmune disease settings (as opposed to protective host immunity), where different autoantigen affinity ceilings are tolerated based on variations in host genetics and environment. This review will explore what is currently known regarding B cell signaling, selection, and interaction with T cells to promote T1D pathogenesis.

TLR5-deficiency controls dendritic cell subset development in an autoimmune diabetes-susceptible model.

The incidence of the autoimmune disease, type 1 diabetes (T1D), has been increasing worldwide and recent studies have shown that the gut microbiota are associated with modulating susceptibility to T1D. Toll-like receptor 5 (TLR5) recognizes bacterial flagellin and is widely expressed on many cells, including dendritic cells (DCs), which are potent antigen-presenting cells (APCs). TLR5 modulates susceptibility to obesity and alters metabolism through gut microbiota; however, little is known about the role TLR5 plays in autoimmunity, especially in T1D. To fill this knowledge gap, we generated a TLR5-deficient non-obese diabetic (NOD) mouse, an animal model of human T1D, for study. We found that TLR5-deficiency led to a reduction in CD11c+ DC development in utero, prior to microbial colonization, which was maintained into adulthood. This was associated with a bias in the DC populations expressing CD103, with or without CD8α co-expression, and hyper-secretion of different cytokines, both in vitro (after stimulation) and directly ex vivo. We also found that TLR5-deficient DCs were able to promote polyclonal and islet antigen-specific CD4+ T cell proliferation and proinflammatory cytokine secretion. Interestingly, only older TLR5-deficient NOD mice had a greater risk of developing spontaneous T1D compared to wild-type mice. In summary, our data show that TLR5 modulates DC development and enhances cytokine secretion and diabetogenic CD4+ T cell responses. Further investigation into the role of TLR5 in DC development and autoimmune diabetes may give additional insights into the pathogenesis of Type 1 diabetes.

Redox regulation of m6A methyltransferase METTL3 in β-cells controls the innate immune response in type 1 diabetes.

Type 1 diabetes (T1D) is characterized by the destruction of pancreatic β-cells. Several observations have renewed the interest in β-cell RNA sensors and editors. Here, we report that N 6-methyladenosine (m6A) is an adaptive β-cell safeguard mechanism that controls the amplitude and duration of the antiviral innate immune response at T1D onset. m6A writer methyltransferase 3 (METTL3) levels increase drastically in β-cells at T1D onset but rapidly decline with disease progression. m6A sequencing revealed the m6A hyper methylation of several key innate immune mediators, including OAS1, OAS2, OAS3 and ADAR1 in human islets and EndoC-βH1 cells at T1D onset. METTL3 silencing enhanced 2'-5'-oligoadenylate synthetase levels by increasing its mRNA stability. Consistently, in vivo gene therapy to prolong Mettl3 overexpression specifically in β-cells delayed diabetes progression in the non-obese diabetic mouse model of T1 D. Mechanistically, the accumulation of reactive oxygen species blocked upregulation of METTL3 in response to cytokines, while physiological levels of nitric oxide enhanced METTL3 levels and activity. Furthermore, we report that the cysteines in position C276 and C326 in the zinc finger domains of the METTL3 protein are sensitive to S-nitrosylation and are important to the METTL3-mediated regulation of oligoadenylate synthase mRNA stability in human β-cells. Collectively, we report that m6A regulates the innate immune response at the β-cell level during the onset of T1D in humans.

The Potential of the Adzuki Bean (Vigna angularis) and Its Bioactive Compounds in Managing Type 2 Diabetes and Glucose Metabolism: A Narrative Review.

Type 2 diabetes (T2D) is a common noncommunicable disease. In the United States alone, 37 million Americans had diabetes in 2017. The adzuki bean (Vigna angularis), a legume, has been reported to possess antidiabetic benefits. However, the extent and specific mechanisms through which adzuki bean consumption may contribute to T2D prevention and management remain unclear. Therefore, the aim of this narrative review is to analyze current evidence supporting the utilization of adzuki beans in the diet as a strategy for preventing and managing T2D. Animal studies have demonstrated a positive impact of adzuki beans on managing T2D. However, supporting data from humans are limited. Conversely, the potential of adzuki bean consumption in preventing T2D via modulating two T2D risk factors (obesity and dyslipidemia) also lacks conclusive evidence. Animal studies have suggested an inconsistent and even contradictory relationship between adzuki bean consumption and the management of obesity and dyslipidemia, in which both positive and negative relationships are reported. In sum, based on the existing scientific literature, this review found that the effects of adzuki bean consumption on preventing and managing T2D in humans remain undetermined. Consequently, human randomized controlled trials are needed to elucidate the potential benefits of the adzuki bean and its bioactive components in the prevention and management of T2D.

Effect of Plasma Fibrinogen Levels on the Risk of Stroke in Patients with Type 2 Diabetes: A Systematic Review.

Aims In this systematic review, we assessed the literature on the association between fibrinogen levels and stroke in patients with type 2 diabetes (T2D). Methods MEDLINE and Ovid searches of English reports were performed on the relation between fibrinogen, stroke, and T2D in humans. The search was completed on May 4, 2023. Studies were eligible when T2D patients ≥18 years had stroke confirmed by computed tomography or magnetic resonance imaging, plasma fibrinogen was measured, and a relation between fibrinogen and stroke in T2D patients was reported. Screening of reports and extraction of data were done independently by two authors, and study quality was assessed by predefined issues. Results Five studies of different designs were included. Three studies reported on significantly increased fibrinogen levels in T2D patients with stroke compared with T2D patients without stroke. Two studies did not observe a significant association between fibrinogen levels and stroke risk. Conclusion No consistent association was observed between fibrinogen levels and risk of stroke in T2D patients. Due to differences in study design, low sample size, and poorly defined study participants, larger and better-defined studies are needed to elucidate the role of fibrinogen as a stroke risk marker in T2D patients.

Disrupted RNA editing in beta cells mimics early-stage type 1 diabetes

A major hypothesis for the etiology of type 1 diabetes (T1D) postulates initiation by viral infection, leading to double-stranded RNA (dsRNA)-mediated interferon response and inflammation; however, a causal virus has not been identified. Here, we use a mouse model, corroborated with human islet data, to demonstrate that endogenous dsRNA in beta cells can lead to a diabetogenic immune response, thus identifying a virus-independent mechanism for T1D initiation. We found that disruption of the RNA editing enzyme adenosine deaminases acting on RNA (ADAR) in beta cells triggers a massive interferon response, islet inflammation, and beta cell failure and destruction, with features bearing striking similarity to early-stage human T1D. Glycolysis via calcium enhances the interferon response, suggesting an actionable vicious cycle of inflammation and increased beta cell workload.

Mendelian randomization analyses suggest a causal role for circulating GIP and IL-1RA levels in homeostatic model assessment-derived measures of β-cell function and insulin sensitivity in Africans without type 2 diabetes

BackgroundIn vitro and in vivo studies have shown that certain cytokines and hormones may play a role in the development and progression of type 2 diabetes (T2D). However, studies on their role in T2D in humans are scarce. We evaluated associations between 11 circulating cytokines and hormones with T2D among a population of sub-Saharan Africans and tested for causal relationships using Mendelian randomization (MR) analyses.MethodsWe used logistic regression analysis adjusted for age, sex, body mass index, and recruitment country to regress levels of 11 cytokines and hormones (adipsin, leptin, visfatin, PAI-1, GIP, GLP-1, ghrelin, resistin, IL-6, IL-10, IL-1RA) on T2D among Ghanaians, Nigerians, and Kenyans from the Africa America Diabetes Mellitus study including 2276 individuals with T2D and 2790 non-T2D individuals. Similar linear regression models were fitted with homeostatic modelling assessments of insulin sensitivity (HOMA-S) and β-cell function (HOMA-B) as dependent variables among non-T2D individuals (n = 2790). We used 35 genetic variants previously associated with at least one of these 11 cytokines and hormones among non-T2D individuals as instrumental variables in univariable and multivariable MR analyses. Statistical significance was set at 0.0045 (0.05/11 cytokines and hormones).ResultsCirculating GIP and IL-1RA levels were associated with T2D. Nine of the 11 cytokines and hormones (exceptions GLP-1 and IL-6) were associated with HOMA-S, HOMA-B, or both among non-T2D individuals. Two-stage least squares MR analysis provided evidence for a causal effect of GIP and IL-RA on HOMA-S and HOMA-B in multivariable analyses (GIP ~ HOMA-S β = − 0.67, P-value = 1.88 × 10−6 and HOMA-B β = 0.59, P-value = 1.88 × 10−5; IL-1RA ~ HOMA-S β = − 0.51, P-value = 8.49 × 10−5 and HOMA-B β = 0.48, P-value = 5.71 × 10−4). IL-RA was partly mediated via BMI (30-34%), but GIP was not. Inverse variance weighted MR analysis provided evidence for a causal effect of adipsin on T2D (multivariable OR = 1.83, P-value = 9.79 × 10−6), though these associations were not consistent in all sensitivity analyses.ConclusionsThe findings of this comprehensive MR analysis indicate that circulating GIP and IL-1RA levels are causal for reduced insulin sensitivity and increased β-cell function. GIP’s effect being independent of BMI suggests that circulating levels of GIP could be a promising early biomarker for T2D risk. Our MR analyses do not provide conclusive evidence for a causal role of other circulating cytokines in T2D among sub-Saharan Africans.

Remission of type 2 diabetes: a real perspective for clinical pratice

The Type 2 diabetes (T2D) is probably the biggest challenges of global public health. In United States, 4% of all Gross Domestic Product is spent with the diabetes complications. Despite the progress on studies to refrain the diabetes complications, the most effort is target for iniciatives like a search with new pharmacological oportunities and there is less interest in the cientific comunity and governments to study plausible and applicable strategies of lifestylechanges in diabetes. Even so, the publication of Diabetes Prevention Programstudy, that demonstrated the expressive reduction in the primary outcome, diagnosis of diabetes, was a Mark that starts a series of studies looking for the remission of T2D. The DiRECT study is the most strong evidence to demonstrate the remission of T2D in humans with lifestyle changes with results until 89% in patients that reduced their weight in 15% of initial. The objective of this review is present and discuss the Lifestyle Medicine as a real possibility for Diabetes Type 2 Remission.