Discuss the physiological consequences of Insulin deficiency.

Outline:

·        Role of Insulin in metabolism

·        Causes of Insulin deficiency

·        Diagnosis of Insulin deficiency

·        Acute complications

·        Chronic complications

Essay:

            Insulin is an anabolic hormone secreted by the b cells of the pancreatic islet. It affects almost every tissue though it acts mainly on the liver, muscle and adipose tissue. Insulin induces efficient storage of excessive nutrients while suppressing mobilization of endogenous substrates. It increases glucose uptake by tissue and increase glycogen synthesis in the liver and muscles. It reduces free fatty acid release from the adipose tissue by inhibiting hormone sensitive lipase, enhances deposition of triacylglycerols in circulating VLDLs by inducing lipoprotein lipase, and increase lipid synthesis. It increases transport of amino acids into cells and stimulates protein synthesis.

            The constellation of abnormalities caused by insulin deficiency is called diabetes mellitus, of which there are two types, type I and type II. Type I diabetes is usually caused by autoimmune destruction of the b cells. In type II diabetes, the b cells fail to secrete enough insulin. Insulin resistance occurs when tissues fail to respond normally to insulin. Type II diabetes is frequently accompanied by target organ insulin resistance that results in a decreased responsiveness to both endogenous and exogenous insulin.

            Diabetes is characterized by polyuria, polydipsia and weight loss in spite of polyphagia and glucosuria. The clinical diagnosis for diabetes is a random blood glucose level of more than 7.8mM. Blood glucose level 2 hours after a oral glucose tolerance test is more than 11 mM. The amount of glycated hemoglobin is more than 6% of the total hemoglobin.

            Insulin deficiency results in widespread biochemical abnormalities. The fundamental defects to which most of the abnormalities can be traced are: reduced entry of glucose into various peripheral tissues and increased liberation of glucose into the circulation from the liver. Therefore, there is an extracellular glucose excess, and an intracellular glucose deficiency.

            Hyperglycemia by itself can cause symptoms resulting from the hyperosmolality of the blood. In addition, there is glycosuria because the renal capacity for glucose reabsorption is exceeded. Excretion of the osmotically active glucose molecules entails the loss of large amounts of water. The resultant dehydration activates the mechanisms regulating water intake, leading to polydipsia. In diabetes, energy requirements can only be met by drawing on protein and fat reserves. Insulin-mediated uptake of glucose into tissues is greatly reduced and glycogen depletion is a common consequence of intracellular glucose deficit. The low insulin:glucagon ratio activates mechanisms that greatly increase the catabolism of protein and fat. Cortisol and catecholamines are involved too. Insulin inhibits the release of neuropeptide Y, a hormone which stimulates the satiety center, inducing appetite. In the absence of insulin, there is an increased appetite and intake of food, but weight loss is observed due to the breakdown of endogenous proteins for generating energy as the body is unable to utilize incoming nutrients.

            One of the consequences of increased fat catabolism is ketoacidosis. Breakdown of fats produce acetyl CoA for generation of reducing equivalents in the tricarboxylic acid cycle. When there is excess acetyl CoA in the body, some of it is converted to the ketone bodies acetoacetate and b-hydroxybutyrate in the liver. These circulating ketone bodies are an important source of energy in fasting. Most of the hydrogen ions liberated from ketone bodies are buffered, but severe metabolic acidosis still develops. The low plasma pH stimulates the respiratory center, producing the rapid, deep respiration called Kussmaul breathing. The urine is acidic and the patient may have an acetone breath. In severe acidosis, total body sodium is markedly depleted. The electrolyte and water losses lead to dehydration, hypovolemia, and hypotension. Finally, the acidosis and dehydration depresses consciousness to the point of coma. However, the blood glucose can be elevated to such a degree that independent of plasma pH, the hyperosmolality of the plasma causes unconsciousness (hyperosmolar coma). Brain edema is seen in a significant number of patients with diabetic acidosis, and it can cause edema.

            Chronic complications of diabetes are microangiopathy, retinopathy, nephropathy and neuropathy. Increased level of glucose enhances the non-enzymic glycation of proteins, forming advanced glycation endproducts which can bind to receptors in macrophages present in endothelial cells. In the long run, this causes the thickening of the basement membrane of small capillaries. If this happens in the kidneys, the end result is diabetic nephropathy with the thickening of renal glomeruli, leading eventually to glomerulosclerosis, renal insufficiency and renal failure. In the retina, blockage of small capillaries impaired blood flow, increases hydrostatic pressure, causing leakage of proteins and red cells into the retina, affecting vision. The growth of new capillaries and fibrous tissue as a result of small vessel occlusion causes vitreous hemorrhage and retinal detachment. This condition is called diabetic retinopathy. The small vessels of the limbs are especially susceptible to occlusion and this can lead to tissue ischemia and ischemic gangrene.

            Diabetic neuropathy may be due to ischemic infarction of a peripheral nerve. If the nerve affected is a sensory nerve, the symptoms are months and years of paresthesias, tinglings, itching and increased pain. Involvement of nerves of the autonomic system can result in postural hypotension, increased occurrence of diarrhea and impotence. Diabetes also predispose the individual to atherosclerosis, myocardial infarction and stroke.