Diabetes is associated with numerous comorbidities, one of which is increased vulnerability to infections. This review will focus on how diabetes mellitus (DM) affects the immune system and its various components, leading to the impaired proliferation of immune cells and the induction of senescence. We will explore how the pathology of diabetes-induced immune dysfunction may have similarities to the pathways of “inflammaging”, a persistent low-grade inflammation common in the elderly. Inflammaging may increase the likelihood of conditions such as rheumatoid arthritis (RA) and periodontitis at a younger age. Diabetes affects bone marrow composition and cellular senescence, and in combination with advanced age also affects lymphopoiesis by increasing myeloid differentiation and reducing lymphoid differentiation. Consequently, this leads to a reduced immune system response in both the innate and adaptive phases, resulting in higher infection rates, reduced vaccine response, and increased immune cells’ senescence in diabetics. We will also explore how some diabetes drugs induce immune senescence despite their benefits on glycemic control.

Diabetes is a chronic disease that induces many comorbidities, including cardiovascular disease, nephropathy, and liver damage. Many mechanisms have been suggested as to how diabetes leads to these comorbidities, of which increased oxidative stress in diabetic patients has been strongly implicated. Limited knowledge of antioxidative antidiabetic drugs and substances that can address diabetic comorbidities through the nuclear factor erythroid 2–related factor 2 (Nrf2) pathway calls for detailed investigation. This review will describe how diabetes increases oxidative stress, the general impact of that oxidative stress, and how oxidative stress primarily contributes to diabetic comorbidities. It will also address how treatments for diabetes, especially focusing on their effects on the Nrf2 antioxidative pathway, have been shown to similarly affect the Nrf2 pathway of the heart, kidney, and liver systems. This review demonstrates that the Nrf2 pathway is a common pathogenic component of diabetes and its associated comorbidities, potentially identifying this pathway as a target to guide future treatments.

Diabetes mellitus (DM) is a metabolic disorder characterized by chronic hyperglycemia as a result of insufficient insulin levels and/or impaired function as a result of autoimmune destruction or insulin resistance. While Type 1 DM (T1DM) and Type 2 DM (T2DM) occur through different pathological processes, both result in β-cell destruction and/or dysfunction, which ultimately lead to insufficient β-cell mass to maintain normoglycemia. Therefore, therapeutic agents capable of inducing β-cell proliferation is crucial in treating and reversing diabetes; unfortunately, adult human β-cell proliferation has been shown to be very limited (~0.2% of β-cells/24 h) and poorly responsive to many mitogens. Furthermore, diabetogenic insults result in damage to β cells, making it ever more difficult to induce proliferation. In this review, we discuss β-cell mass/proliferation pathways dysregulated in diabetes and current therapeutic agents studied to induce β-cell proliferation. Furthermore, we discuss possible combination therapies of proliferation agents with immunosuppressants and antioxidative therapy to improve overall long-term outcomes of diabetes.

Islet cell transplantation has become a favorable therapeutic approach in the treatment of Type 1 Diabetes due to the lower surgical risks and potential complications compared to conventional pancreas transplantation. Despite significant improvements in islet cell transplantation outcomes, several limitations hamper long-term graft survival due to tremendous damage and loss of islet cells during the islet cell transplantation process. Oxidative stress has been identified as an omnipresent stressor that negatively affects both the viability and function of isolated islets. Furthermore, it has been established that at baseline, pancreatic β cells exhibit reduced antioxidative capacity, rendering them even more susceptible to oxidative stress during metabolic stress. Thus, identifying antioxidants capable of conferring protection against oxidative stressors present throughout the islet transplantation process is a valuable approach to improving the overall outcomes of islet cell transplantation. In this review we discuss the potential application of antioxidative therapy during each step of islet cell transplantation.

The limited supply and rising demand for kidney transplantation has led to the use of allografts more susceptible to ischemic reperfusion injury (IRI) and oxidative stress to expand the donor pool. Organ preservation and procurement techniques, such as machine perfusion (MP) and normothermic regional perfusion (NRP), have been developed to preserve allograft function, though their long-term outcomes have been more challenging to investigate. We performed a systematic review and meta-analysis to examine the benefits of MP and NRP compared to traditional preservation techniques. PubMed (MEDLINE), Embase, Cochrane, and Scopus databases were queried, and of 13,794 articles identified, 54 manuscripts were included (n = 41 MP; n = 13 NRP). MP decreased the rates of 12-month graft failure (OR 0.67; 95%CI 0.55, 0.80) and other perioperative outcomes such as delayed graft function (OR 0.65; 95%CI 0.54, 0.79), primary nonfunction (OR 0.63; 95%CI 0.44, 0.90), and hospital length of stay (15.5 days vs. 18.4 days) compared to static cold storage. NRP reduced the rates of acute rejection (OR 0.48; 95%CI 0.35, 0.67) compared to in situ perfusion. Overall, MP and NRP are effective techniques to mitigate IRI and play an important role in safely expanding the donor pool to satisfy the increasing demands of kidney transplantation.