6BBL03942 Endocrinology of Diabetes and GP Surgery

2. Insulin is a protein in nature. It is made of a dimer composed of two chains of amino acids which are held together by bonds of disulphide. It is made of 51 amino acids. It is made and released from beta cells of the pancreas. As echoed by Craft et al (2016), the levels of glucose in blood are kept within range by a loop mechanism (negative feedback) in an attempt to keep the body systems in balance. The feedback mechanism operates in a manner such that when the blood glucose levels are high, the body looks for ways of reducing these levels to normal. When levels of blood glucose rise, either from the digestion of a meal or from glycogen-glucose conversion, insulin hormone is released from a glandular group of cells within the pancreas called Langerhans where the b cells reside. The levels of glucose in blood are detected directly by beta cells of the pancreas. There are other causes of increase in blood sugar levels. These include the hormone adrenaline, steroids, infections and trauma (Shungin et al (2015)). GLUT 2 transporters form the transport channels where glucose enters the beta cells. This glucose is then phosphorylated by kinases and is converted to pyruvate in the cytoplasm. The breakdown of glucose involves a series of steps in a process called glycolysis into two molecules of pyruvate. The broken down glucose in form of pyruvate enters the mitochondria and is further broken down to water and carbon (IV) dioxide whereby ATP is formed by addition of phosphate molecules. The ATP from the mitochondria migrates into the cytoplasm, where it inhibits ATP sensitive potassium channels, reducing potassium efflux. This causes increased positive charge as potassium molecules are cations. This causes depolarization of the beta cell and calcium enters the cell via voltage gated calcium channels (Fajans et al (2016)). The calcium entry causes the release of secretory granules containing insulin hence triggering the release of insulin from b cells.  The liver has several functions in the body and is involved in glucose metabolism. There are several processes that occur in the liver as pertains glucose and these include the formation of glucose, (gluconeogenesis), the breakdown of glycogen, (glycogenolysis) and glycogen synthesis. Insulin being a hormone involved with glucose regulation therefore affects the liver. It causes the liver to convert excess glucose into glycogen and most of the body cells mainly the muscle cells and those found in fat tissue to uptake the glucose via GLUT 4 channels leading to low levels of glucose in blood. Insulin is also involved in protein synthesis where it encourages conversion of circulating amino acids into protein. Examples of such amino acids are leucine and arginine. A high level of these compounds thereby stimulates secretion of insulin as they act in a similar manner to glucose by generation of ATP once they are metabolized. This leads to closure of potassium sensitive pumps in the beta cells causing insulin release. (Humphrey et al (2015). Hypoglycemia (low blood sugar levels) on the other hand reduces insulin release. According to Sandler et al (2017), low blood glucose levels at the same time triggers the release of four hormones which counter the activities of insulin of which the principle hormone that counteracts this effect is glucagon. These hormones work hand in hand to ensure that glucose levels in blood are increased to normal hence homeostasis is achieved

3. The receptor pf insulin is a complex made of alpha and beta subunits. It is activated by either insulin or insulin like growth factors. As stated by Canfora et al (2015), binding of insulin or insulin like growth factors to the alpha subunit leads to a change in arrangements resulting into down cascade where tyrosine molecules within the beta subunit are phosphorylated. The resulting pathway causes a series of downward cascade involving a number of enzymes and amplification sequences that lead to glucose storage. Insulin stimulates glucose uptake by cells including myocytes and cells found in fat tissues (Anhê et al (2015)). It does so by inducing changes that lead to the migration of a transporter of glucose called GLUT 4 from the intracellular storage to the plasma membrane. Enzymes involved in the process including P 13 and kinase and AKT are known to play an essential role in GLUT 4 movement. According to Jung et al (2014), the activation of the receptor complex leads to a series of downward activation of a gene encoded protein (Cbl) through phosphorylation attached to second messenger CAP. The complex formed between the two proteins then translocate to lipid layers in the cell membrane. The former (Cbl) after this binds crk associated with an exchange factor C3G. The exchange factor then activates components of a larger family specifically tc10 that enhances movement of GLUT 4 to the cell membrane by activating an anonymous adaptor molecule.

4. Insulin signaling activation also inhibits the generation and release of glucose from the liver by inhibiting the enzymatic dependent process of its synthesis (gluconeogenesis) and the breakdown of glycogen which is stored by the organ (glycogenolysis). As stated by Becker et al (2015), it does so by directly controlling a number of metabolic regulatory enzymes involved in gluconeogenesis and glycogenolysis. This involves enzymes causing phosphorylation and dephosphorylation cascades and also is involved in regulating the expression of genes involved in gluconeogenesis. In gene transcription, there are promoters and inhibitors of transcription all classified in a bigger family referred to as transcription factors. The promoters that lead to increased expression of enzymes that promote gluconeogenesis and glycogenolysis are down regulated leading to a decrease in blood glucose levels. Transcription factors involved in insulin signaling pathway play a role in hepatic enzyme regulation in enzymes involving glucose. The process of gluconeogenesis contributes to increased blood glucose hence the action of insulin to downregulate the process leads to low sugar levels. In addition to these processes, insulin also stimulates glucose storage in the liver. This is done by stimulating glycogen synthesis in the liver. This process involves a number of processes that regulate liver enzymes including glycogen synthase. In one of this insulin signaling activation cascades, inactivation of some enzymes promote glycogen synthesis

5. Changes in diet and exercise in a diabetic patient helps in the maintenance of the condition and helps the body utilize the available insulin properly to regulate blood sugar levels.  As stated by Fang et al (2015), since diabetes is a result of increased blood glucose levels, avoiding sugary foods is crucial in regulating these levels. This includes foods rich in sodium, high cholesterol rich foods such as dairy products whose fat content is high and organ meats such as liver. Such food types involving fats should be avoided in diabetic patients. This is because increased circulating keto acids may worsen diabetes leading to coma especially in diabetic keto acidosis in type 1 diabetes patients. In as much as avoiding certain types of food is important, the intake of certain food types is also encouraged. These include fiber rich foods such as vegetables, fruits, nuts and legumes and good fats such as walnuts, olives and peanut oils. These kinds of foods help lower blood sugar levels quickly and maintain them at a normal range. Antidiabetics are also crucial elements in controlling diabetes since they promote increased secretion of insulin. Others down regulate hepatic activity in the process of gluconeogenesis. Exercise is as important as diet in the maintenance of diabetes. This is because muscles become more sensitive to insulin and absorb more glucose from blood upon exercising.

References

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Craft, S. and Rhoads, K., 2016. Insulin resistance syndrome and Alzheimer’s disease. In Insulin Resistance Syndrome and Neuropsychiatric Disease (pp. 104-118). CRC Press.

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Fajans, S.S., Floyd Jr, J.C., Knopf, R.F. and Conn, J.W., 2016, July. Effect of amino acids and proteins on insulin secretion in man. In Schering Symposium on Endocrinology, Berlin, May 26 to 27, 1967: Advances in the Biosciences (Vol. 1, p. 231). Elsevier.

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Humphrey, S.J., Azimifar, S.B. and Mann, M., 2015. High-throughput phosphoproteomics reveals in vivo insulin signaling dynamics. Nature biotechnology, 33(9), p.990.

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Becker, R.H., Dahmen, R., Bergmann, K., Lehmann, A., Jax, T. and Heise, T., 2015. New insulin glargine 300 units· mL− 1 provides a more even activity profile and prolonged glycemic control at steady state compared with insulin glargine 100 units· mL− 1. Diabetes care, 38(4), pp.637-643.

Fang, S., Suh, J.M., Reilly, S.M., Yu, E., Osborn, O., Lackey, D., Yoshihara, E., Perino, A., Jacinto, S., Lukasheva, Y. and Atkins, A.R., 2015. Intestinal FXR agonism promotes adipose tissue browning and reduces obesity and insulin resistance. Nature medicine, 21(2), p.159.