CHAPTER 7 7.0. Appendices
1.1. Diabetes mellitus
1.2.4. Insulin regulatory and counteregulatory hormones
~-cells are located in the islets of Langerhans in the pancreas. Other cell types present in islets include a, 8 and pancreatic polypeptide (PP) cells. Glucagon, secreted by the pancreatic a-cells, is a major counter-regulatory hormone involved in regulation of glucose homeostasis (Hussain, Daniel and Habener, 2000). Glucagon increases glycaemia by mediating hepatic glycogenolysis (Robertson and Harmon, 2006).
Studies have shown that diabetics have basal or increased plasma glucagon concentrations. Furthermore, suppression of this hormone is associated with reduction of plasma glucose concentration (Cherrington, Lacy and Chiasson, 1976). 8-cells also secrete somatostatin which plays an inhibitory role in the secretion of several hormones, including insulin (Robertson and Harmon, 2006).
Counteregulatory effects of epinephrine are due to its direct effects on target tissues and its effects on other participating hormones. For example, adrenaline stimulates increased glucagon secretion by activating ~-adrenergic receptors on a-cells of pancreatic islets (Guy, Sandoval, Richardson, Tate and Davis, 2005). Due to its effects on muscle, epinephrine also decreases insulin mediated glucose uptake as a result of glucose-6-phosphate-dependent inhibition of hexokinase (Raz, Katz and
Glycogenolysis and inhibition of glycogen synthesis, by both epinephrine and glucagon, are mediated via increased generation of cAMP which activates protein kinase A. Protein kinase A inactivates glycogen synthase and activates phosphorylase (Hodis, Kutinova-Canova, Potmesil, Kamenikova, Kmonickova, Zidek, Farghali, 2007).
Glucocorticoids antagonise effects of insulin. Excessive levels of glucocorticoids may cause insulin resistance and central obesity (Liu, Nakagawa, Wang, Sakurai, Tripathi, Lutfy and Friedman, 2005). In addition, glucocorticoids enhance hepatic gluconeogenesis and impair effects of insulin to reduce glucose production in type II diabetes (Delaunay, Khan, Cintra, Davani, Ling, Andersson, Ostenson, Gustafsson, Efendic and Okret, 1997; Liu et ai., 2005). In states of intensive glycaemic control resulting in hypo glycaemia, hormones antagonistic to insulin action are released to restore normoglycaemia (Ross, Warren, Kelnar and Frier, 2005). Hence, counteregulatory hormones may offer benefits in specific conditions.
Adiponectin is an adipocyte derived peptide which improves insulin sensitivity via several mechanisms. It modulates fatty acid oxidation, inhibits fatty acid synthesis and uptake in the liver and enhances glucose and fatty acid oxidation in the muscle (Mlinar, Marc, Janez and Pfeifer, 2007). These effects are mediated through stimulation of perixosome proliferator gamma receptors (PP AR-y) nuclear receptors and activation of AMP kinase (Mlinar et ai., 2007).
Like adiponectin, leptin is an adipocyte derived-hormone that circulates in plasma in free and bound form. Acting through its receptors located in the hypothalamus,
hippocampus, cortex, cerebellum, thalamus and choroids plexus, leptin decreases levels of circulating neuropepide Y resulting in reduced appetite (Mantzoros, 1999).
Leptin also modulates glucose homeostasis (Levy and Stevens, 2001). In insulin- deficient rats, administration of leptin restores normal glucose levels, enhances glucose metabolism in the post absorptive stages and improves hepatic insulin sensitivity during glucose clamp (Chinookoswong, Wang, and Shi, 1999). Leptin, therefore, acts agonistically to effects of insulin. Moreover, leptin modulates release of thyroid hormones which playa homeostatic role in glucose metabolism (Wang, Chinookoswong, Yin and Shi, 2000).
Thyroid hormones secreted by the thyroid glands also exert glucose homeostatic functions in synergy as well as antagonistic to insulin action. Thyroid hormones may increase glucose production via hepatic gluconeogenesis, to meet increased energy requirements by the body (Lenzen and Bailey, 1984). Thyroid hormones, however, enhance transcription of insulin sensitive glucose transporter-4 (GLUT-4) (Chidakel, Mentuccia and Celi, 2005). This allows increased uptake of glucose by tissue cells thereby offsetting initial increase in blood glucose (Lenzen and Bailey, 1984).
1.2.5. Insulin resistance
Insulin resistance largely caused by central obesity is a key component in the pathogenesis of type II diabetes mellitus. It is defined as the inability of insulin to curtail hepatic glucose production and promote glucose disposal in the peripheral
glucose uptake and glycogen synthesis in adipose, skeletal and hepatic tissues (DeFronzo, 1999; Kahn and Flier, 2000; Panunti, Jawa and Fonseca, 2004).
Adipose tissue secretes large quantities of tumour necrosis factor (TNF)-a. According to Mlinar et al., (2007), TNF -a is the main factor that stimulates increased levels of circulating free fatty acids into circulation. Increased intraportal free fatty acids impair insulin clearance. The mechanisms by which this is mediated are still unclear (Kahn and Flier, 2000). It is, however, suggested that accumulation of intramyocellular lipids in striated muscles suppresses glucose uptake, glycogen synthesis and glucose oxidation (Flordellis, Ilias and Papavassiliou, 2005). Moreover, TNF-a inhibits expression of PPAR-y, tyrosine phosphorylation on the insulin receptor and intermediates of insulin post-receptor signalling (Bailey, 2000).
In addition to TNF -a, adipose tissue also secretes resistin, which has been established as one of the possible links between excessive adiposity and insulin resistance (Liu, Fan, Qiu, Wang, Zhang, Gu, Zhang, Fei, Pan, Guo, Chen and Guo, 2008). This link, however, has been disputed by other investigators (De Courten, Degawa-Yamauchi, Considine and Tataranni, 2004).
Insulin resistance may manifest at the level of glucose entry into cells (Shepherd and Kahn, 1999). Indeed, in obesity insulin resistance is characterised by downregulation of glucose transporters (GLUT)-4 in skeletal muscles (Kahn and Flier, 2000). Insulin resistance is the main target of antihyperglycaemic agents because, if left unchecked, it results in the pathogenesis of a wide allay of disorders including hypertension,
dyslipidaemia, atherosclerosis, or the metabolic syndrome (Chakrabarti, Damarla, Mullangi, Sharma, Vikramadithyan and Rajagopalan, 2006).