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Diabetic ketoacidosis (DKA) and hyperosmolar hyperglycemic state (HHS) represent two extremes in the spectrum of marked decompensated diabetes. DKA and HHS are still important causes of morbidity and mortality among patients with diabetes even with major agreements about their diagnostic criteria and treatment protocols . The annual incidence of DKA from population-based studies is estimated to range from 4 to 8 episodes per 1,000 patient admissions with diabetes . The incidence of DKA continues to increase with DKA accounting for about 115,000 hospitalizations in the United States in 2003 (figure 1 a). The rate of hospital admissions for HHS is lower than DKA and is less than 1% of all diabetic-related admissions . Decompensated diabetes imposes a heavy burden in terms of economics and patient outcomes. DKA is an economically burdensome with the average cost of $13,000 per patient per hospitalization .Therefore, the annual expenditure for the care of patients with DKA may exceed $1 billion. The mortality rate for DKA has been falling over the years. Age adjusted mortality rates in the U.S. have dropped by 22% between 1980 and 2001 (from 32 to 20 per 100,000 diabetic population respectively)(4)(figure 1b). Contrary to DKA mortality, the mortality rate of HHS has remained high, ~ 15%, compared to less than 5% in patients with DKA . Severe dehydration, older age, and the presence of comorbid conditions in patients with HHS, account for the higher mortality in these patients .
Figure1a.Incidence of DKA 1980-2003
Figure1b.Mortality rate of DKA 1980-2001 
DKA consists of the biochemical triad of hyperglycemia, ketonemia and metabolic high anion gap acidosis  (Figure 2). The terms hyperglycemic hyperosmolar nonketotic state and hyperglycemic hyperosmolar nonketotic coma have been replaced with the term hyperglycemic hyperosmolar state (HHS)  to show the facts that 1)the hyperglycemic hyperosmolar state may consist of moderate to variable degrees of clinical ketosis detected by nitroprusside method and 2) alterations in consciousness may often be present without coma .
Figure2.The triad of DKA (hyperglycemia, acidemia, and ketonemia) and other conditions with which the individual components are associated. From Kitabchi and Wall 
Both DKA and HHS are characterized by absolute or relative insulinopenia. Clinically, they differ only by the severity of dehydration, ketosis and metabolic acidosis .
DKA most often occurs in patients with type 1 diabetes mellitus (T1DM). It also occurs in type 2 diabetes under conditions of extreme stress such as serious infection, trauma, cardiovascular or other emergencies, and, less often, as a presenting manifestation of type 2 diabetes, a disorder called ketosis-prone type 2 diabetes . Similarly, whereas HHS occurs most commonly in T2DM, it can be seen in T1DM in conjunction with DKA .Pathogenesis
The underlying defects in DKA and HHS are 1) reduced net effective action of circulating insulin as a result of decreased insulin secretion (DKA) or ineffective action of insulin in HHS  2)elevated levels of counterregulatory hormones: glucagon , catecholamines , cortisol , and growth hormone , resulting in increased hepatic glucose production and impaired glucose utilization in peripheral tissues 3)dehydration and electrolytes abnormalities mainly due to osmotic diuresis caused by glycosuria (figure 3).
Figure 3. Pathogenesis of DKA and HHS
Diabetic KetoacidosisIn DKA, there is severe alteration of carbohydrate, protein, and lipid metabolism (1). In general, the body is shifted into a major catabolic state with breakdown of glycogen stores, hydrolysis of triglycerides from adipose tissues and mobilization of aminoacids from muscle .The released triglycerides and amino acids from the peripheral tissues will be the substrates for the production of glucose and ketone bodies by the liver .Hyperglycemia and ketone bodies production play central roles in developing this metabolic decompensation .Hyperglycemia
The hyperglycemia in DKA is the result of three events: (a) increased gluconeogenesis; (b) increased glycogenolysis, and (c) decreased glucose utilization by liver, muscle and fat. Decreased insulin and elevated cortisol levels also result in decreased protein synthesis and increased proteolysis with increased production of amino acids (alanine and glutamine), which serve as substrates for gluconeogenesis . Furthermore, muscle glycogen is catabolized to lactic acid via glycogenolysis. The lactic acid is transported to the liver in the Cori cycle where it serves as carbon skeleton for gluconeogenesis . Increased levels of glucagon, cathecholamines and cortisol with concurrent insulinopenia stimulate gluconeogenic enzymes especially phosphoenol pyruvate carboxykinase (PEPCK) . Decreased glucose utilization is further exaggerated by increased levels of circulating catecholamines and FFA .KetogenesisExcess catecholamines coupled with effective insulinopenia promote triglyceride breakdown (lipolysis) to free fatty acids (FFA) and glycerol, the latter provides carbon skeleton for gluconeogenesis while the former provides the substrate for the formation of ketone bodies . The key regulatory site for fatty acid oxidation is known to be carnitine palmitoyltransferase 1(CPT1)which is inhibited by malonyl CoA in normal nonfasted state but the increase ratio of glucagons and other counter regulatory hormones to insulin disinhibit the fatty acid oxidation and the incoming fatty acids from fat tissue can be converted to ketone bodies . Increased production of ketone bodies (acetoacetate, and - hydroxybutyrate) leads to ketonemia . There is also decreased clearance of ketone bodies in DKA, which contributes to ketonemia . These ketoacids are buffered by extracellular and cellular buffers resulting in their loss and subsequent anion gap metabolic acidosis . Studies in diabetic and pancreatectomized patients have demonstrated the cardinal role of hyperglucagonemia and insulinopenia in the genesis of DKA (Figure 4).. In the absence of stressful situations such as dehydration, vomiting or intercurrent illness, ketosis is usually mild .
Figure4.Proposed Biochemical Alterations in Diabetic Ketoacidosis Leading to Increased Gluconeogenesis, Lipolysis, Ketogenesis and Decreased Glycolysis. 
Elevated levels of pro-inflammatory cytokines and lipid peroxidation markers, as well as procoagulant factors such as plasminogen activator inhibitor-1 (PAI-1) and C-reactive protein (CRP) have been demonstrated in DKA. The levels of these factors return to normal with insulin therapy and correction of hyperglycemia . This inflammatory and procoagulant state may explain the well-known association between hyperglycemic crisis and thrombotic state.
Hyperglycemic Hyperosmolar State
The pathogenesis of DKA and HHS are similar, however, in HHS: 1) there is enough insulin to prevent lipolysis and ketogenesis but not adequate to cause glucose utilization (as it takes 1/10 as much insulin to suppress lipolysis as it does to stimulate glucose utilization)(47,48) 2) possible smaller increases in counterregulatory hormones 
The two most common precipitating factors in the development of DKA or HHS are inadequate or inappropriate insulin therapy or infection . Other factors include myocardial infarction, cerebrovascular accidents,pulmonary embolism, pancreatitis ,alcohol abuse and drugs  (Table 1) . In addition to the mentioned precipitating factors, numerous underlying medical illness and medications that provoke the release of counter regulatory hormones and/or compromise the access to water are likely to result in severe dehydration and HHS . Drugs such as corticosteroids, thiazides, sympathomimetic agents (e.g.,dobutamine and terbutaline )  and second generation antipsychotic agents  may precipitate the genesis of DKA or HHS. In young patients with type 1 diabetes, insulin omission due to fear of hypoglycaemia or weight gain, the stress of chronic disease, and eating disorders, may contribute in 20 % of recurrent DKA . Cocaine use also is associated with recurrent DKA . Mechanical problems with continuous subcutaneous insulin infusion (CSII) devices had also precipitated DKA , but with improvement in technology and better education of patients ,the incidence of DKA seems to have been reduced in pump users . Further studies are required to document reduction of DKA incidence with the use of CSII devices. There are also case reports of patients with DKA as the primary manifestation of acromegaly .
Table 1.Diagnostic Criteria and Typical Total Body Deficits of Water and Electrolytes in Diabetic Ketoacidosis (DKA) and Hyperglycemic Hyperosmolar Syndrome (HHS)
Increasing numbers of DKA cases have been reported in patients with DMT2. Available evidence shows that almost 50 % of newly diagnosed adult African American and Hispanic patients with DKA have type 2 diabetes .These patients who have ketosis prone type 2 diabetes develop sudden-onset impairment in insulin secretion and action, resulting in profound insulinopenia . Clinical and metabolic features of these patients include a high rate of obesity, a strong family history of diabetes, a measurable pancreatic insulin reserve and low prevalence of au