Without insulin the synthesis of glycogen in the liver is depressed, and there is an increase in glucose synthesis through the gluconeogenic pathway. At the same time there is a decreased uptake of glucose by the muscle and adipose cells and an increased catabolism of glycogen in muscle cells. An increase in proteolysis also occurs, with the release of amino acids from muscle cells and an increase in lipolysis, with the release of fatty acids and glycerol from the adipose cells. Certain amino acids and the glycerol released from the cells serve as substrate for gluconeogenesis in the liver. Therefore, hyperglycemia and hyperlipemia occur in the absence of insulin; such hyperglycemia may result in part from excessive amounts of glucagon.
Without insulin, fatty acids become the major fuel for energy metabolism in the TCA cycle. However, when an excess of acetyl CoA accumulates due to the lack of other substrate required by the TCA cycle, cholesterol and ketone bodies are synthesized in the liver. The ketone bodies are acetoacetic and betahydroxy butyric acids and acetone. Acetoacetic acid and betahydroxy butyric acids can be metabolized for energy to some extent by brain and muscle cells. However, in the absence of insulin the quantity in the circulation exceeds the body's capacity to metabolize them, leading to ketonemia.
When the amount of glucose filtered by the glomeruli of the kidney exceeds the capacity of the renal tubules to reabsorb it, it is excreted in the urine. This usually occurs at blood glucose levels of 160 mg per 100 ml or higher. Since glucose requires water for excretion, an increase in urine volume results, \vith the loss of body water and the electrolvte sodium.
At the same time, there is an increase in the amount of urea nitrogen to be excreted due to the deamina tion of amino acids, so that their carbon structures can serve as substrate for gluconeogenesis. Also, when cellular proteins are catabolized and their amino acids transported to the liver for gluconeogenesis, potassium is lost from the cells. The increasing amounts of both urea and potassium in the circulation again require water for excretion by the kidneys.
Finally the ketone bodies, betahydroxy butyric acid, acetoacetic acid, and acetone, in excess of what the body can use require water for excretion by the kidney. Acetone is volatile and is also excreted by the lungs. This attempt by the kidney to excrete an abnormal quantity of metabolites leads to cellular dehydration and the depletion of body water and electrolytes. At the same time there is an increase in blood hydrogen ion concentration (metabolic acidosis). All of these metabolic events lead to circulatory failure. If treatment is not instituted promptly to reestablish carbohydrate metabolism and fluid and electrolyte balance, death may ensue.
Patients with noninsulin-dependent diabetes do not usually develop ketoacidosis. It appears that, since these patients frequently have hyperinsulinism, and insulin is antilipolytic, excessive amounts of fatty acids are not released from the adipose cell. However, this does not mean that these diabetics do not experience hyperlipemia. In the presence of insulin and excessive amounts of glucose, there is an increase of triglyceride synthesis in the liver with secretion into the circulation.
Other metabolic problems
It has been observed that disease of the small and large blood vessels occurs more frequently in diabetics than in nondiabetics. Hypertriglyceridemia is a common finding in the untreated patient. In the diabetic there is a tendency to recurrent myocardial infarction with an increase in the incidence of congestive heart failure. Small blood vessel diseases, such as retinopathy, peripheral vascular disease, and nephropathy, also occur more frequently than in the nondiabetic. Diabetic retinopathy is a major cause oflegal blindness or visual impairment. Diabetic nephropathy and atherosclerosis are the major causes of death among diabetics. Siperstein has observed a thickening in the capillary basement membrane in diabetics, and Spiro has identified an abnormality in the mucopolysaccharides in the basement membrane, which may account for the vascular complications of diabetes. The polyol pathway of glucose metabolism is also involved in some of the complications of the disease.
