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Pathophysiology of Diabetes


This diagram shows the various players involved and events that occur during glucose homeostasis. Liver gets a load of carbohydrates, fat and proteins from the diet. These macronutrients are converted to glycogen if excess, or converted into glucose by gluconeogenesis. The liver eventually also breaks down glycogen through glycogenolysis, if required. Pancreas releases insulin depending on the level of glucose in the blood. Insulin allows the move of glucose from extracellular fluid into the intracellular space, that lowers blood glucose. Insulin also inhibits hepatic glucose output (gluconeogenesis and glycogenolysis). Insulin increases glycogen production as well. All actions of insulin are thus towards lowering of glucose concentrations in the blood.

In contrast, Glucagon that comes from alpha cells of the pancreas has an action that is the opposite of insulin. It stimulates glycogen breakdown into glucose thus causing hyperglycaemia.

Glycogen is also present in skeletal muscle, but not much as the amount in the liver. Skeletal muscle cells are primary utilisers of glucose.

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Type 1 DM is noted for its absolute lack of insulin. It makes up about 5-10% of the overall worldwide diabetic population. The B cells of the pancreas lose their ability to secrete insulin, due to some inciting event like a post viral autoimmune reaction. This type of DM occurs usually in children and adolescents. In this type of a diabetic there is very little role of insulin resistance. Usually this type also presents as a medical emergency like ketoacidosis.

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Type 2 DM is the most common form of diabetes in the world. 95% of all diabetics are of this type. Insulin resistance and impaired insulin secretion play a dual role in its pathogenesis. As against Type 1 DM, this type has a relative lack of Insulin. It is usually associated with obesity and has a strong genetic component linked to its causation. Ketosis is not a usual feature of presentation for these type of diabetics.

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There are two main mechanisms of hyperglycaemia in Type 2 DM. One is insulin resistance and the other is impaired insulin secretion. Insulin resistance usually precedes impaired insulin secretion. Major reason for insulin resistance is obesity.

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This slide shows the various risk factors that could lead to insulin resistance. From rare mutations of the insulin receptor to acquired causes of obesity, which are more common, elevated glucose levels per se is also another reason for insulin resistance.

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On this slide, the black line represents the normal glucose response to a meal. After eating, there is a rapid rise in the blood glucose level from it's basal level (70 - 110) to a postprandial high of 40 - 50 points above basal. One of the things that keeps the glucose from rising too high in the non-diabetic body is the immediate corresponding surge of insulin into the blood stream. This immediate surge is called the first phase response. It is followed by a slower, slightly longer 2nd phase insulin response. The combination of the 1st and 2nd phase responses prevents the glucose from rising too high and brings it back down to basal level, usually within two hours after a meal.

The patient with T2DM has lost the 1st phase response, making it difficult to control the post meal glycemic excursion. Second phase insulin is slower and blunted, so it is common for the glucose levels to remain elevated for several hours after a meal.

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Insulin resistance by itself does not cause diabetes. As long as the pancreatic beta cell can compensate for the insulin resistance by producing more insulin; glucose levels will remain normal. It is only when the beta cell becomes impaired and insulin secretion is inadequate to compensate for insulin resistance that glucose levels rise. Initially there may be adequate insulin production in the fasting state but an inability for the pancreas to cope with the stress of high carbohydrate intake resulting in postprandial hyperglycaemia.

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Consequences of the Metabolic Syndrome: Insulin Resistance

Insulin resistance is central to the etiologic process of a metabolic syndrome that includes impaired glucose tolerance, hyperinsulinaemia, dyslipidemia, hypertension and premature atherosclerosis. (Reaven, 1994) The compensatory hyperinsulinaemia that precedes the development of Type 2 diabetes predisposes to hypertension and to increases in plasma triglycerides, small dense LDL and PAI-1 (plasminogen activator inhibitor-1), plus decreased HDL levels-all factors that raise the risk of coronary heart disease. (DeFronzo, 1991; Bloomgarden, 1998). This cluster of abnormalities occurs in individuals with no overt diabetes mellitus, although glucose intolerance may be present. (Facchini, 1992). Hyperuricaemia has been shown to significantly correlate with insulin resistance (Facchini, 1991) and with higher plasma triglycerides, low HDL levels and higher blood pressure. (Zavaroni, 1993).

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Six-year follow-up data from the United Kingdom Prospective Diabetes Study (UKPDS) demonstrated the decline in ß-cell function as T2DM progresses. At the time of diagnosis, ß-cell function is already reduced by about 50% and continues to decline regardless of therapy.

Severe ß-cell failure means insulin deficiency and a subsequent requirement for insulin therapy. Treatment may already be late by the time we start it as the load of B cells is reduced.

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Major effects of Insulin

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Insulin is an anabolic hormone. Its main action is across major metabolic pathways. In glucose metabolism, it stimulates glucose uptake into cells and allows the liver to convert excess glucose to glycogen. With lack of insulin hyperglycaemia occurs. The body uses kidneys to get extra glucose out of the body. Once glucose spills over into glomerulus, it pulls water with it so it acts as an osmotic diuretic. Thus the key symptom of diabetes is frequent urination (polyuria). Due to excess urination, patients get a dry mouth so thirst is another symptom (polydipsia). Polyphagia or excess appetite as intracellular glucose is low, thus signalling the hypothalamus to eat is another common symptom.

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Insulin also prevents lipolysis and prevents the elevation of FFA in the blood.

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Insulin is needed for protein anabolism, it prevents protein catabolism and insulin deficiency can lead to muscle wasting.

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The symptoms and signs of diabetes are diverse. These may be present as a combination in a patient. In some patients, there may be none, thus regular checking of high risk patients is recommended.

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Atypical diabetes and Secondary Diabetes

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Very rare. Seen ONLY in men. No cases in women yet. No cases in Caucasians yet. Here the ß-cells stop functioning temporarily, but do not die, so they could show up with ketonaemia at one week and the next week they are fine and the next week patients are back with ketones. Very labile and difficult to treat because if we increase their insulin, they may go into severe hypoglycaemia as all of the sudden their beta cells start working again. Causation is idiopathic currently.

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A lot of patients with LADA end up with false diagnosis of T2DM. If one treats with oral agents there would be no response. Some patients also display positive anti islet antibodies like Type 1 DM. These patients will require insulin at an earlier age than what is expected for a Type 2 DM patient.

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MODY is a rare form of diabetes which is different from both Type 1 and Type 2 diabetes and runs strongly in families. MODY is caused by a mutation (or change) in a single gene. If a parent has this gene mutation any child they have, has a 50% chance of inheriting it from them. If a child does inherit the mutation, they will generally go on to develop MODY before they are 25, whatever their weight, lifestyle, ethnic group etc.

The key features are:

Being diagnosed with diabetes under the age of 25. Having a parent with diabetes, with diabetes in two or more generations. Not necessarily needing insulin.

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Behave like Type 1 diabetes. Here all of the pancreas is involved instead of just the B cells. Evidence of endocrine and exocrine failure.

Alcohol abuse is the leading cause.

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Most researchers believe that gestational DM is same as Type 2 DM and is triggered by the stress of the pregnancy (specifically the weight gain).

High % of patients who have gestational DM are at risk for future Type 2 DM. This type of diabetes can not only have deleterious effects on the mother but it can also affect the foetus. Insulin is the best choice for treatment as many oral drugs are not tested enough for their safety in use in this population. Metformin and Glibenclamide have some evidence of safety.

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