Lipid and Ketone Metabolism
The increased production of ketones in DKA is the result of a combination of insulin deficiency and increased concentrations of counterregulatory hormones, particularly epinephrine, which lead to the activation of hormone-sensitive lipase in adipose tissue.

The increased activity of tissue lipase causes a breakdown of triglyceride into glycerol and free fatty acids (FFAs). Although glycerol is used as a substrate for gluconeogenesis in the liver and the kidney, the massive release of FFAs assumes pathophysiological predominance in the liver, the FFAs serving as precursors of the ketoacids in DKA.

In the liver, FFAs are oxidized to ketone bodies, a process predominantly stimulated by glucagon. Increased concentration of glucagon in DKA reduces the hepatic levels of malonyl-CoA by blocking the conversion of pyruvate to acetyl-CoA through inhibition of acetyl-CoA carboxylase, the first rate-limiting enzyme in de novo fatty acid synthesis. Malonyl-CoA inhibits carnitine palmitoyl-transferase (CPT)-I, the rate-limiting enzyme for transesterification of fatty acyl-CoA to fatty acyl-carnitine, allowing oxidation of fatty acids to ketone bodies. CPT-I is required for movement of FFA into the mitochondria, where fatty acid oxidation takes place. The increased fatty acyl-CoA and CPT-I activity in DKA leads to increased ketogenesis in DKA.

In addition to increased production of ketone bodies, there is evidence that clearance of ketones is decreased in patients with DKA. This decrease may be due to low insulin concentration, increased glucocorticoid level, and decreased glucose utilization by peripheral tissues.

Water and Electrolyte Metabolism
The development of dehydration and sodium depletion in DKA and HHS is the result of increased urinary output and electrolyte losses. Hyperglycemia leads to osmotic diuresis in both DKA and HHS. In DKA, urinary ketoanion excretion on a molar basis is generally less than half that of glucose. Ketoanion excretion, which obligates urinary cation excretion as sodium, potassium, and ammonium salts, also contributes to a solute diuresis.

The extent of dehydration, however, is typically greater in HHS than in DKA. At first, this seems paradoxical because patients with DKA experience the dual osmotic load of ketones and glucose. The more severe dehydration in HHS, despite the lack of severe ketonuria, may be attributable to the more gradual onset and longer duration of metabolic decompensation and partially to the fact that patients presenting with HHS typically have an impaired fluid intake.

Other factors that may contribute to excessive volume losses include diuretic use, fever, diarrhea, and nausea and vomiting. The more severe dehydration, together with the older average age of patients with HHS and the presence of other comorbidities, almost certainly accounts for the higher mortality of HHS. In addition, osmotic diuresis promotes the net loss of multiple minerals and electrolytes (Na, K, Ca, Mg, Cl, and PO4). Although some of these can be replaced rapidly during treatment (Na, K, and Cl), others require days or weeks to restore losses and achieve balance.

The severe derangement of water and electrolytes in DKA and HHS is the result of insulin deficiency, hyperglycemia, and hyperketonemia (in DKA). In DKA and HHS, insulin deficiency per se may also contribute to renal losses of water and electrolytes because insulin stimulates salt and water reabsorption in the proximal and distal nephron and phosphate reabsorption in the proximal tubule.

During severe hyperglycemia, the renal threshold of glucose and ketones is exceeded. Thereby, urinary excretion of glucose in DKA and HHS may be as much as 200 g/day, and urinary excretion of ketones in DKA may be ~20-30 g/day, with total osmolar load of ~2,000 mOsm. The osmotic effects of glucosuria result in impairment of NaCl and H2O reabsorption in the proximal tubule and loop of Henle.

Moreover, the ketoacids formed during DKA ( -hydroxybutyric and acetoacetic) are strong acids that fully dissociate at physiological pH. Thus, ketonuria obligates excretion of positively charged cations (Na, K, NH4+). The hydrogen ions are titrated by plasma bicarbonate, resulting in metabolic acidosis. The retention of ketoanions leads to an increase in the plasma anion gap.

The average losses of electrolytes and water in DKA and HHS are summarized below.

During HHS and DKA, intracellular dehydration occurs as hyperglycemia and water loss lead to increased plasma tonicity, leading to a shift of water out of cells.

Thus, patients with a better history of food, salt, and fluid intake prior to and during DKA have better preservation of kidney function, greater ketonuria, lower ketonemia, and lower anion gap and are less hyperosmolar. These patients may, therefore, present with greater degrees of hyperchloremic metabolic acidosis.

On the other hand, patients with a history of diminished fluid and solute intake during the development of acute metabolic decompensation, plus loss of fluid through nausea and vomiting, typically present with greater degrees of volume depletion, increased hyperosmolarity, and impaired renal function and greater retention of glucose and ketoanions in plasma. The greater retention of plasma ketoanions is reflected in a greater increment in the plasma anion gap. Such patients may present with greater alteration of sensoria, which is more commonly found in HHS than DKA. However, in HHS, as mentioned above, the inability to take fluid (often in elderly patients) plus other pathogenic mechanisms leads to greater hyperosmolarity.

Potassium
Potassium deserves special attention in the patient with DKA. As a rule, the total body potassium levels in the patient with DKA are decreased. However, the patient may be hyperkalemic or have a normal serum potassium level at presentation. This falsely normal or elevated plasma potassium level is multifactorial. First, the osmotic pull of the extracellular fluid shifts water and potassium out of the intracellular fluid of the muscle cells. The shift is then further increased by the breakdown of intracellular protein which liberates more potassium. Additionally, potassium moves out of cells in exchange for hydrogen ions which are present in excess during DKA. Finally, in the absence of insulin potassium is unable to move back into cells once it has been pulled out. All of this potassium that is pulled from the intracellular arena is initially brought to the kidneys, where it is lost in the osmotic pull present due to the extreme glycosuria. When the patient finally becomes so dehydrated that they cannot maintain adequate glomerular filtration, the potassium present in the extracellular fluid appears as a normal or increased amount, despite severe total body depletion.