**3. Pathogenesis and risk factors of Type 1 diabetes**

368 Type 1 Diabetes – Complications, Pathogenesis, and Alternative Treatments

acids, monoglycerides and phospholipids. These micelles solubilise lipids and transport

In the past, bile acids were considered to have three basic physiological functions (Kuhajda

However, recent studies have expanded the role of bile acids to include endocrine signalling to regulate glucose, lipid and their own homeostasis and influence energy expenditure and

This chapter aims to explore the changes in gut physiology and metabolic pathways which are associated with diabetes. It also aims to identify current and potential applications of

Glucose is a major source of energy with the normal range (normoglycemia) being 3.5-7.8 mmol/l (Cubeddu & Hoffmann 2002). When the body is at absolute rest (the basal state), glucose consumption is equal to its production (Overkamp et al. 1997; Zisser et al. 2007). When glucose is absorbed into the circulation and the body has no immediate need for energy, glucose is stored in the liver and muscles as glycogen (Overkamp et al. 1997). In healthy individuals, glycogen synthesis (glyconeogenesis) in tissues is stimulated by insulin. When the amount of glucose in the blood gets low, glycogen breaks down in the liver to glucose (glycogenolysis). In healthy individuals, feedback processes ensure that glucose levels are under homeostatic control by balancing glyconeogenesis and glycogenolysis. The liver can also convert lactate to glucose via a process known as gluconeogenesis to further supply the required glucose to the blood when levels are low. Glyconeogenesis, glycogenolysis and gluconeogenesis are controlled by anabolic hormones released from the Islets of Langerhans in the pancreas such as glucagon (released from the -cells) and insulin (released from the β-cells). These hormones bind to specific receptors to trigger a chain of reactions that control glucose homeostasis. GLUT-2 (mainly in beta-cells) and GLUT-4 (mainly in skeletal muscles) are the dominant glucose transporters. In general, insulin activates to become fully functional pores that are able to transport glucose molecules into

The pancreas produces large quantities of insulin which it stores in intracellular secretary granules (Al-Salami et al. 2007). Upon stimulation from rising levels of glucose, these granules release their insulin into the mesenteric veins (Juhl et al. 2002; Just et al. 2008). Insulin secretion is different in healthy and diabetic individuals. In healthy individuals, there are two phases of insulin secretion; first phase insulin secretion (FPIS) which starts immediately after the initial stimulus of raised glucose levels and second phase insulin secretion (SPIS) which starts shortly after FPIS, and has a shorter duration but greater magnitude. FPIS occurs from -cells of the pancreas as a direct response to high influx of extracellular glucose. In T1D patients, FPIS and SPIS do not exist since there is a complete lack of insulin production while, in T2D patients, FPIS is impaired and further exposure to glucose results in a reduction in insulin secretion in SPIS due to the desensitization of

them across biological membranes (Hamada et al. 2006; Leng et al. 2003).

3. Facilitation of the absorption of fat soluble vitamins such as A, D and K.

2. Facilitation of the digestion of dietary fats (emulsifying agents);

bile acids and probiotics in the prevention and treatment of the disease.

et al. 2006a; Kuhajda et al. 2006b; Mikov & Fawcett 2006b):

1. Elimination of excess cholesterol;

gut microfloral composition (48, 53, 88).

tissues (Rosa et al. 2011; Stuart et al. 2009).


**2. Glucose regulation and insulin secretion** 

Recent studies have shown that the inflammation which leads to the destruction of β-cells is initiated in the gut (Devendra et al. 2004). It is likely to occur within the first three months of life (Notkins & Lernmark 2001) due to different diabetic-causing xenobiotics (diabetogenics) that include gluten (Akerblom et al. 2002), cow milk protein (Barbeau et al. 2007), viruses such as rubella (Vaarala 2006), and food-toxins such as alloxan, streptozotocin and N-nitroso compounds (Vaarala 2006; Ziegler et al. 2003). Although the pathogenesis of T1D remains unclear, the generally accepted explanation is that T1D is a chronic autoimmune disease triggered in genetically susceptible individuals by a primary insult initiated in the gut (Ghosh et al. 2004). T2D develops in adult life probably due to environmental factors (Moore et al. 2003b) that lead to tissue desensitization to insulin. Continuous stimulation of betacells through hyperglycemia or certain types of antidiabetic drugs such as sulphonylureas can lead to tissue exhaustion and eventual cessation of insulin production due to tissue damage which results in the development of T1D (Fajans 1987).

The associated-disturbances in the compositions of bile and gut microflora are reported in the literature. However whether the changes in bile and microfloral compositions are caused by diabetes, or diabetes develops as a result of disturbed bile and gut microflora, remains to be determined.
