Calorie restriction (CR) is a well known intervention associated with multifaceted anti-aging and pro-longevity health benefits. It induces complex physiological cellular and molecular adaptations, resulting in the fine-tuning of metabolic and immune responses in both homeostatic and diseased states. It has thus been extensively studied both preclinically and clinically, uncovering its therapeutic potential against inflammatory conditions, particularly autoimmune diseases. CR mimetics (CRMs), that is, molecules that mimic CR's effects, have also been widely investigated to counteract inflammatory states associated with numerous diseases, including autoimmunity. However, a comprehensive overview of how CR and CRMs modulate different aspects of immune responses, thereby potentially modifying autoimmunity, is still lacking. Here, we reviewed the latest progress on the impacts of CR and CRMs on the immune system and the current evidence on their potential translation in the clinical management of people with autoimmune diseases. First, we summarized different types of CR and CRMs and their main mechanisms of action. We next reviewed comprehensively how CR and CRMs modulate immune cells and discussed up-to-date preclinical and clinical advances in using CR and CRMs in the context of some of the most common autoimmune diseases. Finally, challenges faced in CR-related research and its translation into the clinic are discussed. SIGNIFICANCE STATEMENT: Calorie restriction (CR) encompasses various approaches for daily or intermittent reduction in calorie intake while maintaining adequate nutrient intake. It acts through cell-intrinsic and -extrinsic pathways to modulate immune cell functions. CR is emerging as a strategy for autoimmune disease management. CR's effects could be partially mimicked by molecules called CR mimetics, which are proposed to achieve CR's effects without reducing food intake. CR and CR mimetics have been tested as promising potential therapeutics in preclinical and clinical autoimmune disease studies.

Regulatory T cells (Tregs) are essential for maintaining immune homeostasis, playing crucial roles in modulating autoimmune conditions and contributing to the suppressive tumor microenvironment. Their cellular metabolism governs their generation, stability, proliferation, and suppressive function. Enhancing Treg metabolism to boost their suppressive function offers promising therapeutic potential for alleviating inflammatory symptoms in autoimmune diseases. Conversely, inhibiting Treg metabolism to reduce their suppressive function can enhance the efficacy of traditional immunotherapy in cancer patients. This review explores recent advances in targeting Treg metabolism in autoimmune diseases and the metabolic adaptations of Tregs within the tumor microenvironment that increase their immunosuppressive function.

Immunometabolism is an emerging field that explores the intricate interplay between immune cells and metabolism. Regulatory T cells (Tregs), which maintain immune homeostasis in immunometabolism, play crucial regulatory roles. The activation, differentiation, and function of Tregs are influenced by various metabolic pathways, such as the Mammalian targets of rapamycin (mTOR) pathway and glycolysis. Correspondingly, activated Tregs can reciprocally impact these metabolic pathways. Tregs also possess robust adaptive capabilities, thus enabling them to adapt to various microenvironments, including the tumor microenvironment (TME). The complex mechanisms of Tregs in metabolic diseases are intriguing, particularly in conditions like MASLD, where Tregs are significantly upregulated and contribute to fibrosis, while in diabetes, systemic lupus erythematosus (SLE), and rheumatoid arthritis (RA), they show downregulation and reduced anti-inflammatory capacity. These phenomena suggest that the differentiation and function of Tregs are influenced by the metabolic environment, and imbalances in either can lead to the development of metabolic diseases. Thus, moderate differentiation and inhibitory capacity of Tregs are critical for maintaining immune system balance. Given the unique immunoregulatory abilities of Tregs, the development of targeted therapeutic drugs may position them as novel targets in immunotherapy. This could contribute to restoring immune system balance, resolving metabolic dysregulation, and fostering innovation and progress in immunotherapy.

Type 1 diabetes (T1D) is an autoimmune disease characterized by the specific destruction of insulin-producing beta cells in the pancreas by the immune system, including CD4 cells which orchestrate the attack and CD8 cells which directly destroy the beta cells, resulting in the loss of glucose homeostasis.

This comprehensive document delves into the complex interplay between the immune system and beta cells, aiming to shed light on the mechanisms driving their destruction in T1D. Insights into the genetic predisposition, environmental triggers, and autoimmune responses provide a foundation for understanding the autoimmune attack on beta cells. From the role of viral infections as potential triggers to the inflammatory response of beta cells, an intricate puzzle starts to unfold. This exploration highlights the importance of beta cells in breaking immune tolerance and the factors contributing to their targeted destruction. Furthermore, it examines the potential role of autophagy and the impact of cytokine signaling on beta cell function and survival.

This review collectively represents current research findings on T1D which offers valuable perspectives on novel therapeutic approaches for preserving beta cell mass, restoring immune tolerance, and ultimately preventing or halting the progression of T1D. By unraveling the complex dynamics between the immune system and beta cells, we inch closer to a comprehensive understanding of T1D pathogenesis, paving the way for more effective treatments and ultimately a cure.

Diabetes is a heterogeneous metabolic disease characterized by elevated blood glucose levels resulting from the destruction or malfunction of pancreatic β cells, insulin resistance in peripheral tissues, or both, and results in a non-sufficient production of insulin. To adjust blood glucose levels, diabetic patients need exogenous insulin administration together with medical nutrition therapy and physical activity. With the aim of improving insulin availability in diabetic patients as well as ameliorating diabetes comorbidities, different strategies have been investigated. The first approaches included enhancing endogenous β cell activity or transplanting new islets. The protocol for this kind of intervention has recently been optimized, leading to standardized procedures. It is indicated for diabetic patients with severe hypoglycemia, complicated by impaired hypoglycemia awareness or exacerbated glycemic lability. Transplantation has been associated with improvement in all comorbidities associated with diabetes, quality of life, and survival. However, different trials are ongoing to further improve the beneficial effects of transplantation. Furthermore, to overcome some limitations associated with the availability of islets/pancreas, alternative therapeutic strategies are under evaluation, such as the use of mesenchymal stem cells (MSCs) or induced pluripotent stem cells for transplantation. The cotransplantation of MSCs with islets has been successful, thus providing protection against proinflammatory cytokines and hypoxia through different mechanisms, including exosome release. The use of induced pluripotent stem cells is recent and requires further investigation. The advantages of MSC implantation have also included the improvement of diabetes-related comorbidities, such as wound healing. Despite the number of advantages of the direct injection of MSCs, new strategies involving biomaterials and scaffolds have been developed to improve the efficacy of mesenchymal cell delivery with promising results. In conclusion, this paper offered an overview of new alternative strategies for diabetes management while highlighting some limitations that will need to be overcome by future approaches.

Ramadan Iftar meal typically causes glucose excursions. Dipeptidyl peptidase-4 inhibitors increase glucagon-like peptide-1 and thus, decrease blood glucose levels with low risk of hypoglycemia.

To investigate the efficacy and safety of vildagliptin as an add-on therapy on glucose excursions of Iftar Ramadan meals among adolescents and young adults with type 1 diabetes mellitus (T1DM) using advanced hybrid closed-loop (AHCL) treatment.

Fifty T1DM patients on MiniMed™ 780G AHCL were randomly assigned either to receive vildagliptin (50 mg tablet) with iftar meal during Ramadan month or not. All participants received pre-meal insulin bolus based on insulin-to-carbohydrate ratio (ICR) for each meal constitution.

Vildagliptin offered blunting of post-meal glucose surges (mean difference - 30.3 mg/dL [- 1.7 mmol/L] versus - 2.9 mg/dL [- 0.2 mmol/L] in control group; p < 0.001) together with concomitant exceptional euglycemia with time in range (TIR) significantly increased at end of Ramadan in intervention group from 77.8 ± 9.6% to 84.7 ± 8.3% (p = 0.016) and time above range (180-250 mg/dL) decreased from 13.6 ± 5.1% to 9.7 ± 3.6% (p = 0.003) without increasing hypoglycemia. A significant reduction was observed in automated daily correction boluses and total bolus dose by 23.9% and 16.3% (p = 0.015 and p < 0.023, respectively) with less aggressive ICR settings within intervention group at end of Ramadan. Coefficient of variation was improved from 37.0 ± 9.4% to 31.8 ± 7.1%; p = 0.035). No severe hypoglycemia or diabetic ketoacidosis were reported.

Adjunctive vildagliptin treatment mitigated postprandial hyperglycemia compared with pre-meal bolus alone. Vildagliptin significantly increased TIR while reducing glycemic variability without compromising safety. Trial registration This trial was registered under ClinicalTrials.gov Identifier no. NCT06021119.

Type 1 diabetes (T1D) is a polygenic disease and does not follow a mendelian pattern. Inborn errors of immunity (IEIs), on the other hand, are caused by damaging germline variants, suggesting that T1D and IEIs have nothing in common. Some IEIs, resulting from mutations in genes regulating regulatory T-cell homeostasis, are associated with elevated incidence of T1D. The genetic spectrum of IEIs is gradually being unraveled; consequently, molecular pathways underlying human monogenic autoimmunity are being identified. There is an appreciable overlap between some of these pathways and the genetic variants that determine T1D susceptibility, suggesting that after all, IEI and T1D are 2 sides of the same coin. The study of monogenic IEIs with a variable incidence of T1D has the potential to provide crucial insights into the mechanisms leading to T1D. These insights contribute to the definition of T1D endotypes and explain disease heterogeneity. In this review, we discuss the interconnected pathogenic pathways of autoimmunity, β-cell function, and primary immunodeficiency. We also examine the role of environmental factors in disease penetrance as well as the circumstantial evidence of IEI drugs in preventing and curing T1D in individuals with IEIs, suggesting the repositioning of these drugs also for T1D therapy.

Type 1 diabetes mellitus (T1D) is the leading metabolic disorder in children worldwide. Over time, incidence rates have continued to rise with 20 million individuals affected globally by the autoimmune disease. The current standard of care is costly and time-consuming requiring daily injections of exogenous insulin. T1D is mediated by autoimmune effector responses targeting autoantigens expressed on pancreatic islet β-cells. One approach to treat T1D is to skew the immune system away from an effector response by taking an antigen-specific approach to heighten a regulatory response through a therapeutic vaccine. An antigen-specific approach has been shown with soluble agents, but the effects have been limited. Micro or nanoparticles have been used to deliver a variety of therapeutic agents including peptides and immunomodulatory therapies to immune cells. Particle-based systems can be used to deliver cargo into the cell and microparticles can passively target phagocytic cells. Further, surface modification and controlled release of encapsulated cargo can enhance delivery over soluble agents. The induction of antigen-specific immune tolerance is imperative for the treatment of autoimmune diseases such as T1D. This review highlights studies that utilize particle-based platforms for the treatment of T1D.

Insulin represents a life-saving treatment in patients with type 1 diabetes, and technological advancements have improved glucose control in an increasing number of patients. Despite this, adequate control is often still difficult to achieve and insulin remains a therapy and not a cure for the disease. β-cell replacement strategies can potentially restore pancreas endocrine function and aim to maintain normoglycemia; both pancreas and islet transplantation have greatly progressed over the last decades and, in subjects with extreme glycemic variability and diabetes complications, represent a concrete and effective treatment option. Some issues still limit the adoption of this approach on a larger scale. One is represented by the strict selection criteria for the recipient who can benefit from a transplant and maintain the lifelong immunosuppression necessary to avoid organ rejection. Second, with regard to islet transplantation, up to 40% of islets can be lost during hepatic engraftment. Recent studies showed very preliminarily but promising results to overcome these hurdles: the ability to induce β-cell maturation from stem cells may represent a solution to the organ shortage, and the creation of semi-permeable membranes that envelope or package cells in either micro- or macro- encapsulation strategies, together with engineering cells to be hypo-immunogenic, pave the way for developing strategies without immunosuppression. The aim of this review is to describe the state of the art in β-cell replacement with a focus on its efficacy and clinical benefits, on the actual limitations and still unmet needs, and on the latest findings and future directions.

Rapid insulin release plays an essential role in maintaining blood-glucose homeostasis in mammalians. Patients diagnosed with type-I diabetes mellitus experience chronic and remarkably high blood-sugar levels, and require lifelong insulin injection therapy, so there is a need for more convenient and less invasive insulin delivery systems to increase patients' compliance and also to enhance their quality of life. Here, an endoplasmic-reticulum-localized split sec-tobacco etch virus protease (TEVp)-based rapamycin-actuated protein-induction device (RAPID) is engineered, which is composed of the rapamycin-inducible dimerization domains FK506 binding protein (FKBP) and FKBP-rapamycin binding protein fused with modified split sec-TEVp components. Insulin accumulation inside the endoplasmic reticulum (ER) is achieved through tagging its C-terminus with KDEL, an ER-retention signal, spaced by a TEVp cleavage site. In the presence of rapamycin, the split sec-TEVp-based RAPID components dimerize, regain their proteolytic activity, and remove the KDEL retention signal from insulin. This leads to rapid secretion of accumulated insulin from cells within few minutes. Using liver hydrodynamic transfection methodology, it is shown that RAPID quickly restores glucose homeostasis in type-1-diabetic (T1DM) mice treated with an oral dose of clinically licensed rapamycin. This rapid-release technology may become the foundation for other cell-based therapies requiring instantaneous biopharmaceutical availability.

Type 1 diabetes (T1D) is an autoimmune disease mediated by T cells and is becoming a serious public health threat. Despite the increasing incidence rate of T1D worldwide, our understanding of why T1D develops and how T cells lose their self-tolerance in this process remain limited. Recent advances in immunometabolism have shown that cellular metabolism plays a fundamental role in shaping T cell responses. T cell activation and proliferation are supported by metabolic reprogramming to meet the increased energy and biomass demand, and deregulation in immune metabolism can lead to autoimmune disorders. Specific metabolic pathways and factors have been investigated to rectify known deficiencies in several autoimmune diseases, including T1D. Most therapeutic strategies have concentrated on aerobic glycolysis to limit T cell responses, whereas glycolysis is the main metabolic pathway for T cell activation and proliferation. The use of metabolic inhibitors, especially glycolysis inhibitors may largely leave T cell function intact but primarily target those autoreactive T cells with hyperactivated metabolism. In this review, we provide an overview of metabolic reprogramming used by T cells, summarize the recent findings of key metabolic pathways and regulators modulating T cell homeostasis, differentiation, and function in the context of T1D, and discuss the opportunities for metabolic intervention to be employed to suppress autoreactive T cells and limit the progression of β-cell destruction.

The most effective and physiological way to treat hyperglycemia is to restore beta-cell function and to rescue production of endogenous insulin. Increasing evidence suggests that both type 1 and type 2 diabetes are characterized by a significant defect in beta-cell mass, leading to the manifestation of the disease. Novel alternative approaches are needed to spare and expand beta-cell mass in patients with diabetes. This review sets out to describe the latest findings on how to restore the beta-cell mass and function in both forms of diabetes to modulate their progression.

Type 1 diabetes (T1D) results from the loss of immune tolerance to pancreatic beta-cells leading to their destruction. Immune intervention therapies tested in T1D so far delayed progression but failed to restore tolerance, which partly explains their lack of durable clinical efficacy.

The role of beta-cells and islets themselves in dialogue with their micro- and macro-environment including the immune system and the intestinal microbiome is increasingly evident. Indeed, islets can both maintain and break immune tolerance. Some recent immune therapies in cancer that block immune regulation also break tolerance. Induction of immune tolerance requires activating immune activation too, whereas immune suppression precludes this process. Immunotherapy alone my not suffice without engaging islets to restore tolerance and preserve beta-cell function.

New insight into the role of islet tissue and its interaction with its environment in preserving or breaking tolerance has contributed to understand the development of islet autoimmunity and T1D. Knowing which factors in islets and the immune system contribute to maintaining, breaking, and restoring the balance in the immune system is critical to prevent initiation and reverse disease progression, and guides the design of novel tolerogenic strategies for durable therapeutic intervention and remission that target both the immune system and distressed islets.