Glycolysis

adipocyte liver

With the increase in hepatic glucose production, ketogenesis, and peripheral insulin resistance stimulated by elevations in counterregulatory hormone concentrations, acidosis and dehydration worsen. These changes then accelerate the development of DKA by stimulating further increases in the concentrations of counterregulatory hormones. A vicious cycle is created and is responsible for the eventual development of severe ketoacidosis.

Other physiologic processes also contribute to worsening acidosis and dehydration (Fig. 3). Intestinal ileus occurs as a consequence of acidosis, potassium depletion, and diminished splanchnic perfusion caused by dehydration. Intestinal ileus causes abdominal pain and vomiting, which impairs a patient's ability to compensate for osmotic diuresis by increased intake of fluids. More substantial dehydration eventually leads to diminished tissue perfusion, which enhances acidosis via accumulation of lactic acid [45,46]. Severe dehydration eventually compromises renal function and diminishes the capacity for clearance of glucose and ketones, which causes concentrations of both to rise further. Ongoing osmotic diuresis and ketonuria in the setting of acidosis also result in urinary losses of electrolytes, particularly potassium, sodium, chloride, calcium, phosphate, and magnesium. Urinary losses of sodium and potassium as ketone salts may result in excess chloride retention, such that hyperchloremic acidosis is superimposed on the increased anion gap acidosis [47]. Elevated aldosterone concentrations that result from dehydration also serve to further enhance potassium loss [46]. Typical electrolyte deficits in patients who have DKA include approximately 5 to 13 mmol/kg of sodium, 3 to 5 mmol/kg of potassium, and 0.5 to 1.5 mmol/kg of phosphate [48,49].

Clinical manifestations of diabetic ketoacidosis

Classic symptoms of DKA include polyuria, polydipsia, weight loss, abdominal pain, nausea, and vomiting. Abdominal tenderness, absence of bowel sounds, and guarding may be present and may mimic the acute abdomen [50].

Fig. 1. (A) Early in the development of DKA, a decrease in the concentration of insulin relative to glucagon results in stimulation of glycogenolysis by promoting conversion of glycogen synthase a to inactive glycogen synthase (3 and conversion of phosphorylase (3 to active phosphorylase a. Gluco-neogenesis is also stimulated but plays a lesser role in the increase in hepatic glucose output at this stage than does glycogenolysis. An increase in the ratio of glucagon to insulin stimulates a decrease in fructose 2,6 bisphosphate concentrations mediated by phosphorylation of 6-phosphofructo-2-kinase/ fructose-2,6-bisphosphatase. The decreased concentration of fructose 2,6 bisphosphate inactivates the rate-limiting enzyme for glycolysis (6-phosphofructo-1-kinase) and stimulates gluconeogenesis via activation of fructose-2,6-bisphosphatase. Decreased insulin concentrations also result in a lower peripheral glucose uptake by muscle and adipose tissue with diminished transport of GLUT4 to the cell membrane. (B) Later in the development of DKA, elevated concentrations of other counterregu-latory hormones (eg, cortisol, noripinephrine, epinephrine, growth hormone) further increase hepatic glucose output and decrease peripheral glucose uptake. ( -Adrenergic agonists enhance glycogenolysis and promote release of gluconeogenic substrate from muscle. Elevated cortisol and growth hormone concentrations cause further declines in peripheral glucose uptake and augment gluconeogenesis.

R- adrenergic agonists

Fig. 2. Decreased insulin concentrations result in increased activity of hormone-sensitive lipase in adipose tissue with release of FFA. As concentrations of stress hormones (eg, cortisol, growth hormone (GH), catecholamines) increase later in the course of DKA, hormone-sensitive lipase activity is further stimulated. FFAs are taken up by the liver, where they are esterified to fatty acyl-CoA. Transport of the CoA ester across the mitochondrial membrane for (-oxidation requires trans-esterification with carnitine, which is accomplished by carnitine palmityl transferase 1 (CPT-1). Once inside the mitochondria, esterification to carnitine is reversed, and fatty acyl-CoA undergoes (-oxidation to form ketones (AcAc) and ((-OHB). CPT-1 is regulated by the concentration of malonyl CoA, which inhibits CPT-1 activity. Malonyl CoA is produced from acetyl-CoA by acetyl-CoA carboxylase (ACC), whose activity is increased by insulin and decreased by glucagon and (-adrenergic agents. Glucagon also decreases the concentration of malonyl CoA by diminishing the rate of glycolysis and the rate of production of citrate, the substrate for malonyl CoA production.

R- adrenergic agonists

HSL 1 I CPT1

» mitochondria

ß- adrenergic agonists

hepatocyte adipocyte

Fig. 2. Decreased insulin concentrations result in increased activity of hormone-sensitive lipase in adipose tissue with release of FFA. As concentrations of stress hormones (eg, cortisol, growth hormone (GH), catecholamines) increase later in the course of DKA, hormone-sensitive lipase activity is further stimulated. FFAs are taken up by the liver, where they are esterified to fatty acyl-CoA. Transport of the CoA ester across the mitochondrial membrane for (-oxidation requires trans-esterification with carnitine, which is accomplished by carnitine palmityl transferase 1 (CPT-1). Once inside the mitochondria, esterification to carnitine is reversed, and fatty acyl-CoA undergoes (-oxidation to form ketones (AcAc) and ((-OHB). CPT-1 is regulated by the concentration of malonyl CoA, which inhibits CPT-1 activity. Malonyl CoA is produced from acetyl-CoA by acetyl-CoA carboxylase (ACC), whose activity is increased by insulin and decreased by glucagon and (-adrenergic agents. Glucagon also decreases the concentration of malonyl CoA by diminishing the rate of glycolysis and the rate of production of citrate, the substrate for malonyl CoA production.

Tachycardia is frequent, and signs of hypoperfusion, such as delayed capillary refill time and cool extremities, are also common. Other signs of dehydration also may be present, including dry mucous membranes, absence of tears, and poor skin turgor. Hypothermia also has been described [51]. Although profound aci-dosis may depress myocardial contractility and vascular smooth muscle tone, the occurrence of these effects to a clinically relevant degree has not been demonstrated in DKA [52], and hypotension in children who have DKA is rare. Tachypnea occurs in response to metabolic acidosis as a result of stimulation of chemoreceptors in the central nervous system (CNS). Tachypnea may be extreme and may cause DKA to be initially misdiagnosed as respiratory illness. Acetone (produced from nonenzymatic decarboxylation of acetoacetate [AcAc]) typically causes a fruity breath odor, which may be a helpful initial clue to the diagnosis of DKA. Despite profound systemic acidosis, most children who have DKA present with normal mentation or only minimal depression of mental status. The lack of substantial neurologic depression reflects the fact that brain pH in patients who inadequate insulin secretion/ counter-regulatory hormone excess

^¡J^fatty acid oxidation '0' gluconeogenesis '^glycogenosis TT peripheral glucose uptake

Diabetes 2

Diabetes 2

Diabetes is a disease that affects the way your body uses food. Normally, your body converts sugars, starches and other foods into a form of sugar called glucose. Your body uses glucose for fuel. The cells receive the glucose through the bloodstream. They then use insulin a hormone made by the pancreas to absorb the glucose, convert it into energy, and either use it or store it for later use. Learn more...

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