**1. Introduction**

Diabetes caused by chronic hyperglycemia due to failure of the pancreatic beta cells to produce adequate insulin or ineffective utilisation of the produced insulin by the body is a severe health issue worldwide [1]. Diabetes exists in two major forms: type 1 (T1D) and type 2 (T2D) diabetes. Type 1 diabetes is caused by the body's immune system damaging the pancreas thereby making the body incapable to produce sufficient insulin. Impaired regulation and use of glucose due to insulin resistance or inefficiency in insulin production by the body leads to Type 2 diabetes. Family history is the well risk factors for Type 1 diabetes whileobesity, advancing

age, family history, sedentary lifestyle, ethnicity and certain medications are the risk factors associated with Type 2 diabetes. Diabetes affects the brain, kidney, heart, and eyes as an acute condition that rises the risk of various diseases brought on by damage to the macro and microvasculature [2]. Patients with diabetes are also more prone to infections. Numerous studies have shown that individuals with diabetes are more likely to develop diseases of the lower respiratory tract, including pulmonary tuberculosis (TB) urinary tract infections, and pneumonia and infections of the skin and internal organ tissues [3]. Diabetes patients typically have poor outcomes from infection treatment. Diabetes patients are more financially burdened by infection because of the high cost of therapy, the time of treatment, and the associated consequences.

Around 425 million people worldwide have diabetes, according to the International Diabetes Federation [2]. Both developed and developing nations expect this number to rise. By 2045, there could be 629 million diabetes patients worldwide if adequate care and control are not implemented. Around 5 million persons perished from diabetes in 2017; 850 million USD were spent on diabetic care. In developing nations, especially those with tropical climates have high prevalence of communicable disease, along with whooping number of diabetics, which inevitably results in increased incidence of infectious diseases posing huge burden on the nation's economy [4].

Due to decreased insulin synthesis by islet cells in the pancreas and insufficient insulin action (insulin resistance), T2D accounts for over 90% of all cases of diabetes. The condition causes the blood glucose levels to rise. Obesity, inactivity, and ageing are all linked to insulin resistance in T2D. In order to counteract insulin resistance, the pancreatic islets expand their cell mass and produce more insulin [5]. When this attempt falls short of making up for insulin resistance, T2D develops. Pancreatic cell damage due to years of insulin resistance leads above half of T2D patients to take insulin therapy. In T2D, long-term chronic insulin resistance has a number of negative effects, such as atherosclerosis and microvascular problems such nephropathy, neuropathy, and retinopathy [6].

## **2. Glucose intolerance and insulin resistance**

Following a meal, blood islet cells produce and release insulin in response to elevated blood glucose levels. Lower blood glucose level results due to increased glucose uptake by cells as a result of the insulin binding to its receptors present on the cell membranes. This process causes the translocation of glucose transporters to the cell membrane. Hyperglycemia is a condition where the pancreas either fails to generate enough insulin, produces insufficient insulin, or both. It has been observed that TNF levels elevated in adipose tissue of obese mice have been linked to insulin resistance in these experimental models [7]. Additionally, increased levels of interleukin (IL)-6, plasminogen activator inhibitor, C-reactive protein and other inflammatory mediators in the plasma of obese mice exaggerates the damage associated with these factors. Suppression of insulin receptor substrate (IRS-1) is brought on by TNF, ceramide, diacylglyceride, free fatty acids, hypoxia, reactive oxygen species (ROS), and c-Jun N-terminal kinase I (JNK1) in liver and adipose tissue (**Figure 1**). Additionally, TNF- causes insulin resistance by impairing the activity of the gamma subunit of the peroxisome proliferator-activated receptor [8].

Tyrosine phosphorylation at IRS-1 and -2 results from the binding of insulin with its receptor. IKK and JNK1, the mediators of inflammatory and stress responses, phosphorylate IRS substrates on serine, which inhibits insulin signalling. The

*Perspective Chapter: Immunosuppression in Patients with Diabetes Mellitus DOI: http://dx.doi.org/10.5772/intechopen.107362*

#### **Figure 1.**

*Oxidative stress promotes a cascade of responses leading to adipogenesis.*

transcriptional activation of several genes linked to the inflammatory response is also caused by JNK1 and IKK, which leads to insulin resistance. JNK1 and IKK signalling pathways are activated by the influx of more free fatty acids and glucose [9]. The transcription inflammation associated genes causes the phosphorylation and activation of IKK that further encourages the ubiquitination and destruction pathways in proteasome thereby translocating NF into the nucleus. IKK also blocks insulin signalling pathways in adipocytes by phosphorylating IRS-1 serine residues [10]. TNF-induced JNK activation phosphorylates IRS-1 to suppress insulin signalling. The transducers and activators of Janus kinase/signal transcription (JAK/STAT) pathway also results in the suppression of insulin signalling. STAT's tyrosine is phosphorylated by JAK kinases, which causes STAT to dimerize and go to the nucleus and phosphorylate IRS-1 at Ser636 and Ser307.The Glut-4 translocation to cell membranes is eventually hampered by this suppression of insulin signalling, which results in hyperglycemia [11].
