The Effects of Type 2 Diabetes Mellitus on Organ Metabolism and the Immune System

Abstract

Metabolic abnormalities such as dyslipidemia, hyperinsulinemia, or insulin resistance and obesity play key roles in the induction and progression of type 2 diabetes mellitus (T2DM). The field of immunometabolism implies a bidirectional link between the immune system and metabolism, in which inflammation plays an essential role in the promotion of metabolic abnormalities (e.g., obesity and T2DM), and metabolic factors, in turn, regulate immune cell functions. Obesity as the main inducer of a systemic low-level inflammation is a main susceptibility factor for T2DM. Obesity-related immune cell infiltration, inflammation, and increased oxidative stress promote metabolic impairments in the insulin-sensitive tissues and finally, insulin resistance, organ failure, and premature aging occur. Hyperglycemia and the subsequent inflammation are the main causes of micro- and macroangiopathies in the circulatory system. They also promote the gut microbiota dysbiosis, increased intestinal permeability, and fatty liver disease. The impaired immune system together with metabolic imbalance also increases the susceptibility of patients to several pathogenic agents such as the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Thus, the need for a proper immunization protocol among such patients is granted. The focus of the current review is to explore metabolic and immunological abnormalities affecting several organs of T2DM patients and explain the mechanisms, whereby diabetic patients become more susceptible to infectious diseases.

Keywords: SARS-CoV-2; immunometabolism; infectious diseases; insulin resistance; obesity; systemic low-level inflammation; type 2 diabetes mellitus.

Figure 1

Effects of T2DM on body organs. T2DM is an inflammatory state that affects circulatory system, gastrointestinal tract, pancreatic beta cells, liver, and skeletal muscles and makes them dysfunctional. NFALD, non-alcoholic fatty liver disease; NASH, non-alcoholic steatohepatitis; ER, endoplasmic reticulum.

Figure 2

Blood vessels in healthy individuals and T2DM patients. (A) normal blood flow in healthy individuals. (B) A close view of HDL binding to its receptors on the surface of ECs that results in the activation of anti-inflammatory cascades. (C) Blood vessels in T2DM patients. During the progression of the disease, red blood cells become glycated, while activated ECs synthesize elevated levels of adhesion molecules and chemokines that facilitate monocytes recruitment, adhesion, and transmigration across the endothelium toward the subendothelial region. Monocytes are then differentiated into macrophages and eventually, by excess lipid uptake, generate foam cells. Subsequently, further immune cell infiltration into the atherosclerotic lesion occurs, where their inflammatory cytokines promote platelet activation, EC apoptosis, and increased generation of ROS and Ox-LDL. (D) interactions between oxLDL and its receptor aggravate ROS generation, NF-κB activation and inflammation. EC, endothelial cell; RBC, red blood cell; PLT, platelet; HDL, high-density lipoprotein; Ox-LDL, Oxidized low-density lipoprotein; ROS, reactive oxygen species; eNOS, endothelial nitric oxide synthase; NO, Nitric oxide; LOX-1, lectin-type oxidized LDL receptor 1.