**4. Diabetes mellitus**

Diabetes mellitus is primarily a metabolic dysfunction resulting in a significant reduction in the cellular ability to metabolize glucose because of either the lack of insulin or insulin inactivity (insulin resistance) [62, 63]. Diabetes mellitus is expected to affect 700 million worldwide by 2040 [64]. The compromised ability of the cells to metabolize glucose results in increased cellular and plasma levels of glucose,

a condition known as hyperglycemia. Hyperglycemia induces tissue damage mainly through the increased influx of glucose through the polyol pathway and increased formation of advanced glycation end products (AGE*s*) and subsequent increased expression of AGE receptors and their ligand [65, 66]. Overproduction of reactive oxygen species (ROS) due to hyperglycemia through mitochondria acts as the main trigger for the activation of the polyol pathway, formation of AGEs and increase in AGE receptor expression [67].

Diabetes mellitus has been categorized in two primary forms: Type 1 Diabetes Mellitus (T1DM) and Type 2 Diabetes Mellitus (T2DM). T1DM has been characterized by a mutation in the insulin gene or immune cell-mediated destruction of β cell resulting in either the synthesis of abnormal insulin protein that fails to activate insulin receptors or a complete lack of endogenous insulin secretion [63]. T1DM patients are usually diagnosed early in their life. The only possible medical treatment referred to these patients is the multiple daily doses of synthetic insulin. T2DM on the other hand is much more complicated and requires a thorough diagnostic approach [62, 68–70]. T2DM is considered one of the most common metabolic disorders globally. Major risk factors for T2DM include a sedentary lifestyle, lack of exercise, excessive use of a high-carb and high-fat diet, overweight and obesity [71]. Poor lifestyle and dietary habits have been attributed to the global incidence of type 2 diabetes in the last 2 decades. Obesity, visceral fat deposition and increased body mass index (BMI) play a central role in the pathophysiology of type 2 diabetic patients [62]. Quality, quantity and type of food have been debated to be the primary cause of this global incident. A healthy diet with the appropriate amount of nutrients and fiber and a certain level of physical activity has been advised globally to counter the incidence of T2DM in young adults.

The development of T2DM is mainly caused by the significant decline in insulin secretion from β cells or the inability of insulin-responsive tissues (muscles, fat and liver) to respond to insulin, mainly because of defective insulin signaling resulting in hyperinsulinemia and subsequent insulin resistance [72–75]. Failure of the insulin hormone to activate insulin receptors at the cellular level has been attributed to be the major cause of hyperinsulinemia and insulin resistance [76, 77]. Insulin binding to insulin receptors at the plasma membrane activates a signaling cascade that initiates glucose metabolism inside the cells. Insulin-bound insulin receptors or activated insulin receptors go through internalization at the plasma membrane, a phenomenon known as insulin receptor endocytosis [1, 78]. Following the activation, the endocytosis of the insulin receptor is the primary physiological mechanism through which the duration and intensity of insulin signaling are controlled. Hyperinsulinemia accelerates insulin receptor endocytosis and affects the presence of adequate functional insulin receptors at the plasma membrane resulting in insulin resistance [79]. Apart from accelerated insulin receptor endocytosis, insulin-stimulated insulin receptor kinase activity is also decreased in diabetic patients [80]. Compromised insulin signaling fails to activate glucose metabolic enzymes like glucokinase and hexokinase resulting in hyperglycemia. High plasma glucose levels initiate glucosestimulated insulin secretory (GSIS) response from β cells resulting in the rise of plasma insulin levels. The rising insulin levels should be normalized over time because of the renal insulin clearance mechanism. But compromised renal insulin clearance rate in diabetic subjects results in abnormally high plasma levels of insulin (hyperinsulinemia) [81, 82].

Hyperinsulinemia and hyperglycemia in theory cannot trigger alpha cells to secrete glucagon. But it has been observed that T2DM patients with insulin resistance, *DOI: http://dx.doi.org/10.5772/intechopen.105616 Gut Microbiota Potential in Type 2 Diabetes*

hyperinsulinemia and hyperglycemia also have abnormally high plasma levels of glucagon [83]. Hinting toward the disturbance in the alpha and β cell interplay through the inability of the insulin to block glucagon gene transcription [84]. T2DM is also characterized by a decrease in GLP-1 secretion from L cells of the small intestine [85, 86]. Indicating a pathophysiological role of the gut in the development and progression of type 2 diabetes [87, 88]. GLP-1 receptor agonists which induce an increase in insulin secretion from β cells and inhibit glucagon secretion are the major treatment option for T2DM patients to combat hyperglycemic conditions [89–91].
