Insulin deficiency: Phys effects
The widespread biochemical effects of insulin result in equally vast physiologic abnormalities when insulin is deficient. Reduced entry of glucose into peripheral tissues and increased release of glucose from the liver leads to hyperglycemia , which in turn leads to several physiologic consequences. Elevated blood glucose concentration leads to a filtered load of glucose that exceeds the kidney’s reabsorptive capacity. Unreabsorbed glucose acts as an osmotic diuretic in the urine, leading to extracellular fluid volume contraction and resulting hypotension, as well as a decrease in total body sodium and potassium. A decreased insulin:glucagon ratio stimulates catabolism of protein and fat , which can lead to increased production and decreased clearance of VLDL leading to hypertriglyceridemia, as well as increase in the by-product acetyl CoA. Excess acetyl CoA in the body from breakdown of fats leads to formation of ketone bodies acetoacetate and b-hydroxybutyrate in the liver. The body is able to buffer some of the hydrogen ions in the setting of ketoacidosis, but metabolic acidosis still develops, leading to increased ventilation rate as a compensatory mechanism. Potassium shifts out of cells in the setting of hyperglycemia and acidosis, and thus normal or even increased serum potassium levels are often seen, despite total body depletion.
While insulin deficiency can lead to serious acute complications, there are chronic consequences as well, which are often seen in longtime diabetics. Increased levels of glucose lead to glycosylation of proteins and, consequently, advanced glycosylation end products (AGE) that bind to receptors present in endothelial cell macrophages. Chronic hyperglycemia can also lead to abnormal stimulation of signaling cascades, increased production of ROS, and abnormal activation of hemodynamic regulatory systems. Microvascular and macrovascular derangements result, leading to such complications as diabetic nephropathy, retinopathy, neuropathy, and atherosclerosis.