Metabolic Features of Diabetes Mellitus PDF

Lecture-3 Metabolic Features of Diabetes Mellitus I -Hyperglycaemia If plasma glucose concentration exceeds about 10 mmol/L, glycosuria would be expected. High urinary glucose concentrations produce an osmotic diuresis and therefore polyuria. Cerebral cellular dehydration due...

Lecture-3 Metabolic Features of Diabetes Mellitus I -Hyperglycaemia If plasma glucose concentration exceeds about 10 mmol/L, glycosuria would be expected. High urinary glucose concentrations produce an osmotic diuresis and therefore polyuria. Cerebral cellular dehydration due to hyperosmolality, secondary to hyperglycaemia, causes thirst (polydipsia). A prolonged osmotic diuresis may cause excessive urinary electrolyte loss. These ‘classic’ symptoms are suggestive of diabetes mellitus. Diabetic patients on insulin may show the following conditions. The ‘dawn’ phenomenon is the physiological response of the elevation of blood glucose concentration in the early morning prior to breakfast due to nocturnal spikes in GH concentration and a rise in plasma cortisol concentration that increase hepatic gluconeogenesis. Conversely, in some diabetic patients nocturnal hypoglycaemia may evoke a rebound counter- regulatory hyperglycaemia called the Somogyi phenomenon. Patient blood glucose checking at 02.00– 04.00 h, or continuous glucose monitoring if available, may distinguish these conditions, as the Somogyi phenomenon reveals hypoglycaemia. 2-Abnormalities in lipid metabolism These may be secondary to insulin deficiency. Lipolysis is enhanced and plasma NEFA concentrations rise. In the liver, NEFAs are converted to acetyl CoA and ketones, or are re-esterified to form endogenous triglycerides and incorporated into VLDLs; the latter accumulate in plasma because lipoprotein lipase, which Is necessary for VLDL catabolism, requires insulin for optimal activity. High-density lipoprotein cholesterol concentration tends to be low in type 2 diabetes. If insulin deficiency is very severe, there may also be chylomicronaemia. The rate of cholesterol synthesis is also increased, with an associated increase in plasma LDL concentrations. Consequently, patients with diabetes may show high plasma triglyceride, raised cholesterol and low HDL cholesterol concentrations. 1  Acute Metabolic Complications of Diabetes Mellitus Patients with diabetes mellitus may develop various metabolic complications that require emergency treatment,including coma, and these include the following :- Hypoglycaemia This is probably the most common cause of coma seen in diabetic patients. Hypoglycaemia is most commonly caused by accidental overadministration of insulin or sulphonylureas or meglitinides. Precipitating causes include too high a dose of insulin or hypoglycaemicdrug; conversely, the patient may have missed a meal or taken excessive exercise after the usual dose of insulin or oral hypoglycaemic drugs. Hypoglycaemia is particularly dangerous, and some patients lack awareness of this; that is to say, they lose warning signs such as sweating, dizziness and headaches. Driving is a major hazard under such circumstances. Patients should monitor their own.blood glucose closely, carry glucose preparations.. Diabetic ketoacidosis Diabetic ketoacidosis may be precipitated by infection, acute myocardial infarction or vomiting. The patient who reasons ‘no food, therefore no insulin’ could mistakenly withhold insulin. In the absence of insulin, there is increased lipid and protein breakdown, enhanced hepatic gluconeogenesis and impaired glucose entry into cells. The clinical consequences of diabetic ketoacidosis are due to: _ hyperglycaemia causing plasma hyperosmolality, _ metabolic acidosis, _ glycosuria. Plasma glucose concentrations are usually in the range 20–40 mmol/L, but may be considerably higher, although euglycaemic diabetic ketoacidosis has been described when plasma glucose concentrations are only slightly elevated. Hyperglycaemia causes glycosuria and hence an osmotic diuresis. Water and electrolyte loss due to vomiting, which is common in this syndrome, increases fluid depletion. There may be haemoconcentration and reduction of the glomerular filtration rate enough to cause uraemia due to renal circulatory insufficiency. The extracellular hyperosmolality causes a shift of water out of the cellular compartment and severe cellular dehydration occurs. Loss of water from cerebral cells is probably the reason for the confusion and coma. Thus there is both cellular and extracellular volume depletion. The rate of lipolysis is increased because of decreased insulin activity; more free fatty acids are produced than can be metabolized by peripheral tissues. The free fatty acids are either converted to ketones by the liver or, of less immediate clinical importance, incorporated as endogenous triglycerides into VLDL, sometimes causing severe hypertriglyceridaemia. Hydrogen ions, produced with ketones other than acetone, are buffered by plasma bicarbonate. However, when their rate of production exceeds the rate of bicarbonate generation, the plasma bicarbonate falls. Hydrogen ion secretion causes a fall in urinary pH. 2 The deep, sighing respiration (Kussmaul’s respiration) and the odor of acetone on the breath are classic features of diabetic ketoacidosis. Plasma potassium concentrations may be raised, secondarily to the metabolic acidosis, before treatment is started. This is due to failure of glucose entry into cells in the absence of insulin and because of the low glomerular filtration rate. Despite hyperkalaemia, there is a total body deficit due to increased urinary potassium loss in the presence of an osmotic diuresis. During treatment, plasma potassium concentrations may fall as potassium re-enters cells, sometimes causing severe hypokalaemia unless potassium is prescribed. Plasma sodium concentrations may be low (hyponatraemia) or low-normal at presentation, partly because of the osmotic effect of the high extracellular glucose concentration, which draws water from the cells and dilutes the sodium. Hyperosmolal Non-Ketotic Coma In diabetic ketoacidosis there is always plasma hyperosmolality due to the hyperglycaemia, and many of the symptoms, including those of confusion and coma, are related to it. However, the term ‘hyperosmolal’ coma or ‘pre-coma’ is usually confined to a condition in which there is marked hyperglycaemia but no detectable ketoacidosis. The reason for these different presentations is not clear. It has been suggested that insulin activity is sufficient to suppress lipolysis but insufficient to suppress hepatic gluconeogenesis or to facilitate glucose transport into cells. Hyperosmolal non-ketotic (HONK) coma now may be referred to as hyperosmolar hyperglycaemic state (HHS) and may be of sudden onset. It is more common in older patients. Plasma glucose concentrations may exceed 50 mmol/L. The effects of glycosuria are as described earlier, but hypernatraemia due to predominant water loss is more commonly found than in ketoacidosis and aggravates the plasma hyperosmolality. Cerebral cellular dehydration, which contributes to the coma, may also cause hyperventilation, and a respiratory alkalosis, although sometimes plasma lactic acid may rise, evoking a metabolic acidosis and hence, a mixed acid–base disturbance may occur. There may also be an increased risk of thrombosis. 3  Pathogenesis of Chronic Complications of Diabetes Mellitus Patients with both type 1 and type 2 diabetes are at high risk for the development of chronic complications. Diabetes-specific microvascular pathology in the retina, renal glomerulus, and peripheral nerve produces retinopathy, nephropathy, and neuropathy. As a result of these microvascular complications, diabetes is the most frequent cause of new cases of blindness in the industrialized world in persons between 25 and 74 years and the leading cause of end-stage renal disease. Diabetes is also associated with a marked increase in atherosclerotic macrovascular disease involving cardiac, cerebral, and peripheral large vessels. The consequence is that patients with diabetes have a high rate of myocardial infarction (the major cause of mortality in diabetes), stroke, and limb amputation. Prospective clinical studies document a strong relationship between hyperglycemia and the development of microvascular complications. Both hyperglycemia and insulin resistance appear to be important in the pathogenesis of macrovascular complications. Progress has been made in our understanding of the molecular mechanisms underlying derangements produced by hyperglycemia. Four main hypotheses have been proposed to explain how hyperglycemia causes the neural and vascular pathology. These include: 1- Increased aldose reductase (or polyol pathway) flux 2- Activation of protein kinase C 3- Increased hexosamine pathway flux 4- Enhanced formation of advanced glycation end products (AGE); Inhibitors of each of these have been shown to ameliorate diabetes-induced abnormalities in cell culture and animal models. Overproduction of superoxide by the mitochondrial electron transport chain integrates these four apparently disparate mechanisms. Clinical trials are under way using novel therapies specifically directed at the signaling molecules (such as protein kinase C) or employing antioxidants to neutralize the effects of the oxidants. Monitoring of Diabetes Mellitus Glycosuria Glycosuria can be defined as a concentration of urinary glucose detectable using relatively insensitive, but specific, screening tests. These tests often depend on the action of an enzyme, such as glucose oxidase, incorporated into a diagnostic strip. Glycosuria, occurs only when the plasma, and therefore glomerular filtrate, concentrations exceed the tubular reabsorptive capacity. This may be because the plasma and glomerular filtrate concentrations are more than about 10 mmol/L, and therefore the normal tubular reabsorptive capacity is significantly exceeded. 4  Very rarely, if the glomerular filtration rate is much reduced, there may be no glycosuria despite plasma glucose concentrations more than 10 mmol/L. A diagnosis of diabetes mellitus should never be made on the basis of glycosuria. Blood glucose Blood glucose concentrations may be measured using glucose testing reagent strips. The colour change ofthe strip can be assessed visually or by using a portable glucose meter and the reaction often involves an enzyme determination of glucose, for example glucose oxidase. Glycated haemoglobin Glycated haemoglobin (HbA1c) is formed by nonenzymatic glycation of haemoglobin and is dependent on the mean plasma glucose concentrations and on the lifespan of the red cell; falsely low values may be found in patients with haemolytic disease. Measurement of blood HbA1c may not reveal potentially dangerous short-term swings and nor does HbA1c detect hypoglycaemic episodes and thus plasma glucose estimations may also be useful. This was expressed as a percentage of total blood haemoglobin concentration and gives a retrospective assessment of the mean plasma glucose concentration during the preceding 6–8 weeks. The higher the glycated haemoglobin, the poorer the mean diabetic or glycaemic control. Glycated haemoglobin used to be expressed in percentage units but now is expressed as mmol/mol Intervention trials for type 1 and type 2 diabetes have shown that trying to optimize glycemic control, as judged by HbA1c ˂ 6.5 % reduces the risk of microvascular diabetic complications. Fructosamine The measurement of plasma fructosamine concentrations may be used to assess glucose control over a shorter time course than that of HbA1c (about 2–4 weeks), but the assay has methodological limitations. Fructosamine reflects glucose bound to plasma proteins, predominantly albumin, which has a plasma half-life of about 20 days but is problematic in patients with hypoalbuminaemia, for example due to severe proteinuria. This assay may sometimes be useful in pregnancy and also if haemoglobin variants, for example HbS or HbC, exist that may interfere with certain HbA1c assays. 5