Cortisol and Growth Hormone: promotes hepatic glucose production and antagonizes the peripheral effects of insulin on glucose disposal, primarily in the muscle.

Normally, there is a precise balance between insulin and the counter-regulatory hormones that allows for fairly constant glucose levels at all times.

DKA can be viewed as a state of absolute or relative insulin deficit and increased levels of counter-regulatory hormones (glucagon, catecholamines, cortisol, growth hormone). As discussed above, under normal conditions these hormones balance out their actions on the fat cells and the liver allowing for well regulated management of glucose and lipids within the liver and adipose tissues. In cases where the counter-regulatory hormones outweigh the effects of insulin, for whatever reason, DKA supervenes.

In some ways, DKA can be seen as starvation in the midst of plenty. Clearly, there is an excess of glucose, the normal substrate used for energy production. Unfortunately, without the presence of insulin, the glucose goes largely unused since most cells are unable to transport glucose into the cell without the presence of insulin. Many of the cells in the body feel as though they are starving and they innocently activate homeostatic mechanisms to provide even greater quantities of glucose, thus resulting in greater hyperglycemia. In response to the sense of starvation, other alternative fuels, such as ketoacids and fatty acids, are produced.

Despite these fuels, the majority of cells remain "hungry" and continue to order more food production.

In the setting of insulin deprivation three organs are primarily affected, the liver, the fat cell, and the muscle. When insulin levels decrease in DKA, large quantities of fatty acids are released from the fat cell, into the blood. These free fatty acids are taken up by the liver where, in the setting of decreased insulin and increased glucagon, become the precursors for ketoacid production. In addition, the elevated free fatty acid levels increase gluconeogenesis within the liver, increasing the glucose levels even more. If there were no free fatty acids there would be no DKA.

In Type 1 DM, there is insulin deficiency, and the precise balance is altered. Glucose is no longer able to pass from the serum to the cells, and the cells perceive a fuel shortage, therefore stimulating intact mechanisms to increase the supply of fuel. As a result, counterregulatory hormones increase, the liver releases more glucose, and blood glucose values rise.

Major components of the pathogenesis of diabetic ketoacidosis are reductions in effective concentrations of circulating insulin and concomitant elevations of counterregulatory hormones (catecholamines, glucagon, growth hormone and cortisol). These hormonal alterations bring about three major metabolic events:

(1) hyperglycemia resulting from accelerated gluconeogenesis and decreased glucose utilization,

(2) increased proteolysis and decreased protein synthesis; and increased lipolysis and ketone production.

This will lead to an increase in the blood glucose levels, but the glucose cannot pass into cells without insulin. Hyperglycemia initially causes the movement of water out of cells, with subsequent intracellular dehydration, extracellular fluid expansion and hyponatremia

When the blood glucose levels rise over a certain threshold, excess glucose spills over into the urine. Glucose in the urine pulls extra water with it and creates an "osmotic diuresis", and the symptoms of polyuria and polydipsia ensue.

In this diuresis, the water losses exceed sodium chloride losses. Urinary losses then lead to progressive dehydration and volume depletion, which causes diminished urine flow and greater retention of glucose in plasma. The net result of all these alterations is hyperglycemia with metabolic acidosis and an increased plasma anion gap (see figure 4).

Biochemical Basis of changes seen in DKA and HHS

Carbohydrate Metabolism
When insulin is deficient (absolute or relative), hyperglycemia develops as a result of three processes: increased gluconeogenesis, accelerated glycogenolysis, and impaired glucose utilization by peripheral tissues. Increased hepatic glucose production results from the high availability of gluconeogenic precursors, such as amino acids (alanine and glutamine; as a result of accelerated proteolysis and decreased protein synthesis), lactate (as a result of increased muscle glycogenolysis), and glycerol (as a result of increased lipolysis), and from the increased activity of gluconeogenic enzymes. These include PEPCK, fructose-1,6-biphosphatase, pyruvate carboxylase, and glucose-6-phosphatase, which are further stimulated by increased levels of stress hormones in DKA and HHS. From a quantitative standpoint, increased glucose production by the liver represents the major pathogenic disturbance responsible for hyperglycemia in these patients, and gluconeogenesis plays a greater metabolic role than glycogenolysis.

Although the detailed biochemical mechanisms for gluconeogenesis are well established, the molecular basis and the role of counterregulatory hormones in DKA are the subject of debate; very few studies have attempted to establish a temporal relationship between the increase in the level of counterregulatory hormones and the metabolic alterations in DKA. However, studies of insulin withdrawal in previously controlled patients with type 1 diabetes indicate that a combination of increased catecholamines and glucagon (and a decreased level of free insulin) in a well-hydrated individual may be the initial event. Furthermore, in the absence of dehydration, vomiting, or other stress situations, ketosis is usually mild, while glucose levels increase with simultaneous increases in serum potassium.

Animal studies have shown that catecholamines stimulate glycogen phosphorylase via -receptor stimulation and subsequent production of cAMP-dependent protein kinase. Decreased insulin in the presence of an ambient level of glucagon, which is usually higher in diabetic than in nondiabetic individuals, leads to a high glucagon-to-insulin ratio, which inhibits production of an important metabolic regulator: fructose-2,6-biphosphate. Reduction of this intermediate stimulates the activity of fructose-1,6-biphosphatase (an enzyme that converts fructose-1,6-biphosphate to fructose-6-phosphate) and inhibits phosphofructokinase, the rate-limiting enzyme in the glycolytic pathway. Gluconeogenesis is further enhanced through stimulation of PEPCK by the increased ratio of glucagon to insulin in the presence of increased cortisol in DKA. In addition, the rapid decrease in the level of available insulin also leads to decreased glycogen synthase. These interactions can be summarized as follows:

The final step of glucose production occurs by conversion of glucose-6-phosphate to glucose, which is catalyzed by another rate-limiting enzyme of gluconeogenesis, hepatic glucose-6-phosphatase, which is stimulated by increased catabolic hormones and decreased insulin levels. Major substrates for gluconeogenesis are lactate, glycerol, alanine (in the liver), and glutamine (in the kidney). Alanine and glutamine are provided by the process of excess proteolysis and decreased protein synthesis, which occurs as a result of increased catabolic hormones and decreased insulin.

In DKA and HHS, hyperglycemia causes an osmotic diuresis due to glycosuria, resulting in loss of water and electrolytes, hypovolemia, dehydration, and decreased glomerular filtration rate, which further increase the severity of hyperglycemia. Although increased hepatic gluconeogenesis is the main mechanism of hyperglycemia in severe ketoacidosis, recent studies have shown a significant portion of gluconeogenesis may be accomplished via the kidney.

Decreased insulin availability and partial insulin resistance, which exist in DKA and HHS by different mechanisms, also contribute to decreased peripheral glucose utilization and add to the overall hyperglycemic state in both conditions.

Proposed biochemical changes that occur during DKA leading to increased gluconeogenesis and lipolysis and decreased glycolysis. Note that lipolysis occurs mainly in adipose tissue. Other events occur primarily in the liver (except some gluconeogenesis in the kidney). Lighter arrows indicate inhibited pathways in DKA. F-6-P, fructose-6-phosphate; G-(X)-P, glucose-(X)-phosphate; HK, hexokinase; HMP, hexose monophosphate; PC, pyruvate carboxylase; PFK, phosphofructokinase; PEP, phosphoenolpyruvate; PK, pyruvate kinase; TCA, tricarboxylic acid; TG, triglycerides.