Clinical and Metabolic Consequences of Type 1 and Type 2 Diabetes - Term Paper Example

Medical Biochemistry Introduction and Background Control of the amount of glucose circulating in the body is essentially done through the interaction between nutrient, neural and hormonal regulation. The interplay between insulin, glucagons and circulating glucose reflect the critical homeostatic mechanism involved in this interaction. Based on the changes in dietary patterns of individuals, in a normal healthy body glucose production by the liver is regulated and so is the case with the uptake of glucose by the muscles and other tissues. The two crucial mediators in this regulatory process are insulin and glucagon. Insulin is a hormone produced by the beta cells of the Islets of Langerhans in the pancreas, which is responsible for uptake of insulin into the tissues. It also assists in lowering hepatic glucose production, by which plasma glucose levels are reduced. Any deficiency in the availability of insulin for this homeostatic function can lead to dire consequences in human body including chronic disease from the improper metabolism of carbohydrates, fats and proteins. Diabetes Mellitus is the name of the chronic disease given to the deficiency in the availability of insulin. It is classified into two. Type 1 diabetes mellitus is a catabolic disorder in which the insulin availability is very low or absent, which is caused by the destruction of the beta cells and presents at younger ages, usually before the age of forty years (Hussain & Vincent, 2007). In genetically prone individuals the insulin producing beta cells immune-mediated destruction of the beta cells occurs leading to an absence or very low availability of insulin and the disease Type-1 diabetes (Gandhi et al, 2008). Type 2 Diabetes Mellitus on the other hand is a progressive disease that results from a set of complex metabolic disorders originating from coexisting defects in multiple organ sites that include insulin resistance in muscle and adipose tissue, gradually reducing pancreatic insulin secretion, lack of regulation in hepatic glucose production, inappropriate glucagons secretion and reduced production of gastrointestinal incretins (Barr, Myslinski & Scarborough, 2008). Clinical Consequences of Type 1 and Type 2 Diabetes The islets of Langerhans in such individuals are normally enlarged and degranulated. During the course of the disease, the islets of Langerhans become individually smaller and are reduced in numbers and demonstrate evidence of a lymphocytic infiltrate. This is representative of the hallmark of the thyrogastric immune group of disorders. There also arises the question of concomitant glucagons deficiency in type 1 diabetes. There is evidence to show that glucagon secretion is elevated when diabetes remains uncontrolled, which acts to potentate hyperglycaemia. . Normalisation of glucose levels in the blood invariably causes a reduction in plasma glucogen levels. . Insufficient control of hyperglycaemia in type diabetes could lead to long-term vascular and neurological complications typical of continued state of hyperglycaemia, which could lead to morbidity and mortality associated with these complications. The continued state of hyperglycaemia makes patients with type 1 diabetes prone to severe micro-vascular complications, which include proliferative retinopathy and chronic kidney disease that result in blindness and premature death (Makinen et al, 2008). Type 1 diabetes occurs in the younger populations and there is consistent evidence to suggest that type 1 diabetes results in cognitive impairments particularly with children diagnosed with type 1 diabetes. The usual reason attributed for this connection between cognitive impairment and type 1 diabetes, is the greater susceptibility for the developing brain to be damaged by the recurrent hypoglycaemic insults caused to it in type 1 diabetes (Ho et al, 2008). The clinical consequences of type 2 diabetes can be classified into two as microvascular diseases based on impact of type 1 diabetes on the finer blood vessels and macrovascular diseases based on impact of type 1 diabetes on the larger blood vessels. The microvascular diseases include retinopathy, renal disease and polyneuropathy, while the macrovascular diseases include stroke, myocardial infarction and peripheral artery disease. Macrovascular disease is more life threatening than microvascular disease. The increased presentation of macrovascular disease in type 2 diabetes is linked to the lipid disorders of insulin resistance, increased tumour necrosis factor (TNF) and the promotion of thrombosis, glycation of proteins and hypertension associated with type 2 diabetes (Barr, Myslinski & Scarborough, 2008). Usually type 2 diabetes is associated with the development of chronic heart disease (CHD) at a an age earlier than is normally found in individuals without type 2 diabetes. In type 2 diabetes patients CHD is found to be more severe, with a higher probability of mortality. In addition individuals with type 2 diabetes show a higher tendency for clot formation due to platelet abnormalities, thereby enhancing blood coagulation. Peripheral arterial disease associated with type 2 diabetes increases the risk of lower extremity amputation (Barr, Myslinski & Scarborough, 2008). Severe skin problems that include ulcers and infections are common in patients with type 2 diabetes. Prolonged hyperglycaemia as a result of type diabetes can cause accumulation of end products of glycolysis, changes in the vascular supply and changes in the function of nerve collagen and muscle function. All these factors make for higher risk of several musculoskeletal problems in patients with type 3 diabetes. These problems include Dupuytrene contracture, flexor tenosynovitis, plantar fasciitis, adhesive capsulitis of the shoulder, osteoporosis and diffuse idiopathic skeletal hyperstosis (Barr, Myslinski & Scarborough, 2008). Neuropathies are commonly seen in type 2 diabetes patients, the most common of which is distal symmetrical poly-neuropathy that affects the longest nerves and then advances proximally. Diabetic autonomic neuropathy and mono-neuropathy are the other neuropathies commonly linked to type 2 diabetes. Peripheral neuropathy requires serious consideration as it is detected late and is the cause of loss of lower limbs from amputation and plantar ulcers. Peripheral neuropathy is also the cause of the development of functional problems that have an impact on the gait and balance, leading to frequent falls. These mobility impairments that come from peripheral neuropathy are a major cause of disability seen in patients with type 3 diabetes (Barr, Myslinski & Scarborough, 2008). The failure of the kidney marks the final stages of nephropathy. There is no cure for end stage kidney disease, unless kidney transplant is a viable solution. Otherwise the only intervention strategy is dialysis. Type 2 diabetes is found to be the most common cause of kidney failure and nephropathy can occur even when good glycaemic control is maintained. Insulin resistance may be of greater significance insulin deficiency in the development of nephropathy, as C-peptide levels are also higher in such cases, suggesting to higher levels insulin (Barr, Myslinski & Scarborough, 2008). Among the early clinical consequences of type 2 diabetes is diabetic retinopathy. Diabetic retinopathy occurs fast in type 2 diabetes because the blood vessels of the retina are very susceptible to microvascular damages associated with type 2 diabetes. In a similar manner diabetic macular oedema is commonly seen in type 2 diabetes. The changes that occur in diabetic macular oedema result from thickening of the retina accompanied with hard lipid exudates near or around the centre of the macula (Barr, Myslinski & Scarborough, 2008). Insulin resistance and type 2 diabetes, along with obesity are central to the development of fatty liver disease or steatosis. Hyperinsulinaemia makes for increased transport of fatty acids from adipose tissues to the liver. The additional stress on the liver from the increased synthesis of the fatty acids makes it susceptible to fatty liver disease. Severe hyperglycaemia is a crisis event that occurs with type 2 diabetic patients and is associated with the enhanced mortality and morbidity rates in type e diabetes. There are two states that result in severe hyperglycaemia. The first is diabetic ketoacidosis (DKA), which results from total insulin deficiency and the ketosis from the breakdown of free fatty acid. The second is hyperosmolar hyperglycaemic state, which stems from insulin deficiency with nil or minimal ketosis. Severe hypoglycaemic shock is another crisis event that can occur with diabetic patients, when the blood glucose levels drop below 50-70mg/dL. This drop in blood glucose level deprives the brain of glucose and if not attended to can progress to unconsciousness, convulsions and coma (Barr, Myslinski & Scarborough, 2008). Metabolic Consequences of Type 1 and Type 2 Diabetes In the case of type 1 diabetes the application of the metabolic consequences to explain the co-occurrence of insulin resistance and macrovascular and microvascular changes is fraught with controversy (Makinen et al, 2008). In spite of this criticism, the framework of the metabolic syndrome enables a better understanding of the pathophysiology of insulin resistance and the metabolic changes that are associated with it and the vascular changes consequences. It is generally accepted that free fatty acids (FFA) and tumour necrosis factor (TNF) have a significant role to play in the development of insulin resistance. Both impair the intracellular insulin signalling transduction pathway. FFA and TNF are produced in abundance in obese individuals, while there is a reduction in the production of adiponectin and anti-inflammatory adipokine. Thus there is an imbalance in the production of pro and anti-inflammatory adipokines, as is seen in the case of adipocyte dysfunction. This imbalance is believed to be the driving force behind insulin resistance and obesity as a risk factor for type 2 diabetes. In recent times there has been better understanding of the role played by the newly discovered adipokines like resistin, visfatin and retinol-binding protein in the development and pathogenesis of insulin resistance. The insulin resistance that result from the adipocyte dysfunction induces several metabolic changes that include hyperglycaemia, dyslipidaemia and hypertension, which are all contributing factors to micro-vascular and macro-vascular changes and enhanced cardiovascular risk. Furthermore adipocyte dysfunction that results in high TNF-alpha concentrations and reduced levels of adiponectin has a direct influence on the vascular endothelium, which results in endothelial dysfunction and atherosclerosis. Adipocyte dysfunction thus acts as the link between obesity and diabetes and atherosclerosis (Wassink, Olijhoek & Visseren, 2007). There is increasing acceptance that atherogenic dyslipidaemia in diabetes comprises high fasting and postprandial triglycerides, low HDL-C and a greater proportion of small dense LDL particles that a closely associated with each other metabolically. Postprandial lipemia has been found to be regular and additive phenomenon in type 2 diabetes patients in their consumption of habitual diets, from an examination of the triglyceride profiles. Triglyceride values taken after lunch were above 2.25mmol/l for several hours and furthermore the nadir value prior to lunch was comparable to the maximum triglyceride value in non-diabetic subjects. Emerging evidence shows convincingly the role of non-fasting triglycerides that are carried in VLDL and chlymicrons as a risk factor for cardiovascular diseases and death. The overproduction of large VLDL1 by the liver along with the accumulation of apoB-48-containing triglyceride-rich lipoproteins (TRLs) is seen prior to hyperglycaemia, demonstrating the importance of insulin resistance as an early pathogenic defect. Multiple insulin action sites present in the liver, adipose tissue, muscle and intestine show resistance to insulin. In combination these disturbances in the action of insulin lead to the overproduction of atherogenic VLDL and chylomicron remnant particles. Such a situation leads to the vascular wall endothelium being exposed to severe cholesterol influx that causes endothelial dysfunction, oxidative stress and prothrombotic state after meals during a twenty-four hour period. This summarizes the current knowledge of diabetic postprandial metabolic dysfunction (Matikainen & Taskinen, 2008). Glucagon-like peptide (GLP-1) is created in the body by post-translational processing of glucagons and is secreted by the intestinal L-cells., when food is consumed. Impaired GLP-1 secretion has been found in type 2 diabetes patients, which reduces the sensitivity to insulin. The importance of GLP-1 in enhancing secretion of insulin through beta-cell functioning, enhancing the feeling of satiety and thereby reducing increased food intake and delaying gastric emptying is accepted universally. In type 2 diabetes patients the reduced availability of GLP-1 leads to reduced production of insulin sensitivity to insulin on one side and increased intake of food on the other leading to metabolic stress on the liver and increased consequences of the disease (Lee, et al, 2007). Literary References Barr, E., Myslinski, J. M. & Scarborough, P. 2008, 'Type 2 Diabetes: Pathophysiology and resulting complications', Physical Therapy, vol.16, no.2, pp.34-46. Gandhi, Y. G., Murad, H. M., Flynn, N. D., Elamin, B. M. Erwin, J. P., Montori, M. V. & Kudva, C. Y. 2008, 'Immuno Therapeutic Agents in Type1 Diabetes: A Systematic Review and Meta-Analysis of Randomized Trials', Clinical Endocrinology, vol.69, no.2, pp.244-252. Ho, S. M., Weller Bapp, J. N., Ives, F. J., Carne, L. C., Murray, K., vanden Driessen, I. R., Nguyen, P. T., Robins, D. P., Bulsara, M., Davis, A. E. & Jones, W. T. 2008, 'Prevalence of Structural Central Nervous System Abnormalities in Early-Onset Type 1 Diabetes Mellitus', The Journal of Paediatrics, vol.153, no.3, pp.385-390. Hussain, N. A. & Vincent, T. M. 2007, 'Diabetes Mellitus, Type -1', emedicine [Online] Available at: http://www.emedicine.com/med/TOPIC546.HTM (Accessed November 9, 2008). Lee, Y., Shin, S., Shigihara, T., Hahm, E., Liu, M., Han, J., Yoon, J. & Jum, H. 2007, 'Glucagon-Like Peptide-1 Gene Therapy in Obese Diabetic Mice Results in Long-Term Cure of Diabetes by Improving Insulin Sensitivity and Reducing Hepatic Gluconeogenesis, Diabetes, vol.56, no.6, pp.1671-1679. Makinnen, V., Forsblom, C., Thorn, M. L., Waden, J., Gordin, D. Heikkila, Q., Heitala, K., Kyllonen, L., Kyto, J., Rosengard-Barlund, M., Saraheimo, M., Tolonen, T., Parkkonen, M., Kashi, K., Ala-Korpela, M., & Groop, P. 2008, 'Metabolic Phenotypes, Vascular Complications and Premature Deaths in a Population of 4,197 Patients With Type 1 Diabetes', Diabetes, vol. 47, no.9, pp.2480-2487. Matikainen, N. & Taskinen, M. 2008, 'Postprandial Triglyceride-rich Lipoproteins in Insulin Resistance and Type 2 Diabetes', Future Lipidology, vol.2, no.5, pp.531-543. Wassink, A. M., Olijhoek, J. K. & Visseren, F. L. 2007, 'The metabolic syndrome: metabolic changes with vascular consequences', European journal of clinical investigation, vol.37, no.1, pp.8-17. Read More