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	Diabetes - Errors of Metabolism Introduction: Diabetes, because of its frequency, is probably the most important metabolic disease. It affects every cell in the body and the biochemical processes of carbohydrate, lipid, and protein metabolism. The term diabetes came from Greek words meaning "siphon" or "run through". In medicine, it signifies the excretion of an excessive urine volume. Diabetes is characterized by the polytriad: polyuria (excessive urination), polydypsia (excessive thirst), and polyphagia (excessive hunger). There are several types of diabetes indicated by qualifying terms: 1) Diabetes Insipidus - ("lacks flavor") is a relatively rare chronic disease characterized by the excretion of large quantities of dilute urine but free from sugar and other abnormal constituents. The pituitary gland fails to produce the hormone vasopressin which controls reabsorption of water from the kidneys. 2) Renal Diabetes is a benign form of glucosuria due to a low-sugar threshold in the kidneys. Blood glucose levels are normal but the kidney fails to reabsorb the normal amount of glucose back into the blood. Glucose above the threshold is excreted in the urine. 3) Diabetes Mellitus (Latin for sweet) is the most familiar type of diabetes and most of the time is referred to as "diabetes" without the qualifier. The fundamental cause of diabetes mellitus is a low level or complete lack of the hormone insulin from the pancreas. From a practical standpoint, there are two types of diabetes mellitus: Type I - where the pancreas secretes no insulin, and Type II where there is some insulin available from the pancreas. The types do not necessarily correspond to the ages suggested although most incidences of Type I occur before the age of 20.
Fill in the following chart listing - positive or negative for each test condition.  Condition  Glucosuria  Acetonuria  Hyperglycemia  Normal   Answer negative   Answer negative   Answer negative  Renal diabetes   Answer positive   Answer negative   Answer negative  Diabetes insipidus   Answer negative   Answer negative   Answer negative  Diabetes mellitus   Answer positive   Answer positive   Answer positive	Laboratory Diagnosis: The laboratory diagnosis of diabetes depends on finding glucose in the urine (glucosuria), however the appearance of glucosuria may result from a variety of causes. In diabetes mellitus, glucose appears in the urine because a hyperglycemia condition exists in the blood. Therefore, the glucose concentration should also be measured in the blood. Glucosuria can occur temporarily from emotional stress or pain, hyperthyroidism, alimentary hyperglycemia, and meningitis. Apparently, the kidney acts as a safety valve against the excessive accumulation of glucose in the blood. If the glucose level becomes too high, then the renal threshold in the kidneys may be exceeded. The renal threshold is a concentration level above which all glucose is not reabsorbed in the blood, but the excess above the threshold concentration remains in the urine. A threshold is analogous to a dam and only when the water level becomes too high, does the water spill over the dam. Many other substances in the blood have their own threshold levels and when the threshold is exceeded, the substance appears in the urine. In renal diabetes, the threshold is abnormally low and glucose appears in the urine at a much lower concentration than normal. The relationships between glucosuria and the renal threshold are illustrated in the diagram on the left. Another relatively easy laboratory test can be made for ketone bodies in the urine. The condition is known as acetonuria from the acetone present. Ketones bodies result in diabetes mellitus for the very same reasons as given for starvation. Ketone bodies are not normally found in urine nor are they present with the other types of diabetes listed. Ketone bodies are present in various amounts depending upon the severity of the diabetes mellitus. Glucose Tolerance Test: In order to measure the metabolic response of a patient to glucose, the glucose tolerance test was devised. The test consists of giving 100 g of glucose in place of breakfast and then testing the concentrations of glucose in the blood and urine at specific timed intervals. This test establishes when the blood glucose reaches its highest concentration, when glucosuria occurs, and how rapidly the blood glucose concentration returns to normal. In normal persons, the venous blood sugar value usually does not exceed 200 mg/100 ml blood and returns below 120 mg in two hours. In diabetes mellitus, the glucose level peaks above 200 mg and does not return below 120 mg after two hours. In renal diabetes, the blood glucose curve is normal. Glucose tolerance curves may produce different results at different times on the same person.
Click for larger image  Quiz: Why must insulin be injected rather than taken in an oral form? Hint: What type of compound is insulin? What about digestion?   Answer Insulin is a protein. It would be hydrolyzed during digestion and never reach the blood stream.	Metabolic Disorders from Diabetes Mellitus: The key defect which leads to diabetes mellitus is the lack of insulin. Insulin, a polypeptide, interacts with the cell membrane to assist the entry of glucose into the cell. In addition, either directly or indirectly, insulin increases the rate of glycolysis, glycogenesis, lipogenesis, and the synthesis of protein. Insulin decreases the rate of glycogenolysis and gluconeogenesis in the liver. In the absence of insulin, the opposite effects are produced. Normally, more than 80% of the energy produced by the body is derived from the combustion of carbohydrates. If carbohydrate metabolism is severely limited, the cell begins to oxidize fat reserves for energy. In addition, proteins are degraded to amino acids which in turn are converted to glucose. If excessive fat metabolism occurs in conjunction with inadequate carbohydrate metabolism, there are inadequate amounts of oxaloacetic acid with which to react with acetyl CoA from the fatty acid spiral. An excess of acetyl CoA leads to a build up of ketone bodies leading to ketosis and since ketone bodies are also acids, this leads to a condition known as acidosis. Severe acidosis, if not counteracted, can result in coma and death. A diabetic coma is accompanied by labored breathing, a dry parched mouth and tongue, acetone on the breath, a rapid pulse, low blood pressure and often vomiting.The metabolic disorders associated with diabetes mellitus are summarized in the graphic on the left. Long term complications of the diabetic condition includes arteriosclerosis and other cardiovascular circulatory problems, changes in eye retina and eye cataracts, nervous system problems, and kidney diseases caused by overwork of removing excess glucose and water. Gangrene may easily develop as a result of the circulatory problems mentioned earlier. Treatments: Since Type I diabetes mellitus can only be treated with daily injections of insulin, the amount of insulin must be carefully regulated. An overdose of insulin may result in insulin shock. Type II diabetes may be treated with oral drugs such as sulphonureas such as tolbutamide and chlorpropamide. The principal action is on beta islet cells, stimulating the secretion of insulin. These are not insulin substitutes but work by stimulating the pancreas to secrete insulin. Biguanides, orally active hypoglycaemic agents, appear to act by increasing glucose uptake into the tissues. They may also increase glycolysis and decrease gluconeogenesis. Troglitazone is an example of a thiazolidine dione which is an oral drug approved for treating non-insulin dependent diabetes mellitus. It acts as an insulin sensitiser. It may be used alone (monotherapy) or in combination with sulphonylureas.