**3. Pathogenesis**

There are some factors as a reason of acute metabolic complications in diabetic patiens. These factors are insulin deficiency as the initial primary event in progressive beta-cell fail‐ ure, its failure in a patient with established disease or its ineffectiveness when insulin action is antagonized by physiological stress such as sepsis and in the context of counterregulatory hormone (catecholamines, cortisol, glucagon, and growth hormone) excess. These hormonal changes increase glucose production from glycogenolysis and gluconeogenesis and impair glucose utilization by peripheral tissues, resulting in hyperglycemia, osmotic diuresis, elec‐ trolyte loss, dehydration, decreased glomerular filtration (further compounding hyperglyce‐ mia) and hyperosmolarity. [26, 30-35].

The combination of insulin deficiency and increased counterregulatory hormones in DKA also leads to the release of free fatty acids into the circulation from adipose tissue (lipolysis). This is augmented by transient insulin resistance due to the hormone imbalance itself as well as the elevated free fatty acid concentrations [8,10,26,28-39]. Uncontrolled hepatic fatty acid oxidation in the liver to ketone bodies (beta-hydroxybutyrate and acetoacetate) results ketonemia and metabolic acidosis [40]. The pathogenesis causing to hyperglycemia and ke‐ toacidosis are schematized in Figure 1 [30].

A number of clinical studies showed that the hyperglycemia in patients with hyperglycemic cri‐ ses is associated with a severe inflammatory state characterized by an elevation of proinflam‐ matory cytokines tumor necrosis factor alpha (TNF-α) and interleukin-6, and -8 (IL-6,8), Creactive protein, reactive oxygen species, and lipid peroxidation, as well as cardiovascular risk factors, plasminogen activator inhibitor-1 and free fatty acids in the absence of obvious infec‐ tion or cardiovascular pathology. Insulin therapy and hydration recover these parameters to near-normal values within 24 hours [41]. Recent studies focused on the role of interleukin-1 be‐ ta (IL-1ß), interleukin-12 (IL-12) and interferon-gamma (IFN-γ). As demonstrated *in vitro,* these cytokines can directly influence beta cell function and viability [42]. Karavanaki et al. studied plasma levels of cytokines IL-1β, interleukin-2 (IL-2), IL-6, IL-8, and interleukin-10 (IL-10), TNF- α and also white blood cell count (WBC), high sensitivity C-reactive protein (hs-CRP), growth hormone (GH) and cortisol in 38 newly diagnosed T1DM children with DKA (mean age 7.68±3.07 years), prior to, during and 120 hours after DKA management, with the aim to moni‐ tor their levels at different time-points and in different degrees of DKA severity. Prior to DKA management the levels of IL- 6, IL-8, IL-10,WBC and cortisol were elevated, but all parameters were reduced within 120 hours after DKA management [43].

[17]. In a Turkish study conducted among the patients with diabetic adults who admitted to the hospital, the ratio of T1DM was found to be 6.6% and DKA was 38% of the group [18]. There is wide geographic variation in the frequency of DKA at onset of diabetes. The ratio inversely correlates with the regional incidence of T1DM. Frequencies range from 15 to 70% in Europe, Australia, and North America [11,19-25]. The most occurrence ages of DKA are between the 18-44 years (56%), than 45-65 years (24%) continues with only 18% of patients <20 years of age. Two-thirds of DKA patients are considered to have T1DM and 34% to have type 2 diabetes. DKA is the most common cause of death in children and adolescents with T1DM. Half of all deaths in diabetic patients younger than 24 years of age are caused from DKA [26,27]. In adult subjects with DKA, the overall mortality is usually given <1% (13), however mortality rates may increase over 5% in the elders and in patients with concomi‐

There are some factors as a reason of acute metabolic complications in diabetic patiens. These factors are insulin deficiency as the initial primary event in progressive beta-cell fail‐ ure, its failure in a patient with established disease or its ineffectiveness when insulin action is antagonized by physiological stress such as sepsis and in the context of counterregulatory hormone (catecholamines, cortisol, glucagon, and growth hormone) excess. These hormonal changes increase glucose production from glycogenolysis and gluconeogenesis and impair glucose utilization by peripheral tissues, resulting in hyperglycemia, osmotic diuresis, elec‐ trolyte loss, dehydration, decreased glomerular filtration (further compounding hyperglyce‐

The combination of insulin deficiency and increased counterregulatory hormones in DKA also leads to the release of free fatty acids into the circulation from adipose tissue (lipolysis). This is augmented by transient insulin resistance due to the hormone imbalance itself as well as the elevated free fatty acid concentrations [8,10,26,28-39]. Uncontrolled hepatic fatty acid oxidation in the liver to ketone bodies (beta-hydroxybutyrate and acetoacetate) results ketonemia and metabolic acidosis [40]. The pathogenesis causing to hyperglycemia and ke‐

A number of clinical studies showed that the hyperglycemia in patients with hyperglycemic cri‐ ses is associated with a severe inflammatory state characterized by an elevation of proinflam‐ matory cytokines tumor necrosis factor alpha (TNF-α) and interleukin-6, and -8 (IL-6,8), Creactive protein, reactive oxygen species, and lipid peroxidation, as well as cardiovascular risk factors, plasminogen activator inhibitor-1 and free fatty acids in the absence of obvious infec‐ tion or cardiovascular pathology. Insulin therapy and hydration recover these parameters to near-normal values within 24 hours [41]. Recent studies focused on the role of interleukin-1 be‐ ta (IL-1ß), interleukin-12 (IL-12) and interferon-gamma (IFN-γ). As demonstrated *in vitro,* these cytokines can directly influence beta cell function and viability [42]. Karavanaki et al. studied plasma levels of cytokines IL-1β, interleukin-2 (IL-2), IL-6, IL-8, and interleukin-10 (IL-10), TNF-

tant life-threatening illnesses [28,29].

mia) and hyperosmolarity. [26, 30-35].

toacidosis are schematized in Figure 1 [30].

**3. Pathogenesis**

252 Type 1 Diabetes

**Figure 1.** The pathogenesis causing to hyperglycemia and ketoacidosis in DKA (Data adapted from reference [17])

Recent studies have reported that an upregulated production of and interleukin-18 (IL-18) could be an important pathogenic event in the dysregulated production of IFN-γ and other type 1 cytokines thought to predispose T1DM [44-46] and the potential role of IL-18 in the pathophysiology of the chronic complications of diabetes mellitus [7-11]. But the potential role of IL-18 in the acute complications of diabetes mellitus such as DKA is controversial. Dong et al. compared serum IL-18 levels and other cytokines (IL-12 and IFN-γ) in newly di‐ agnosed T1DM with DKA, T1DM without DKA and age/sex-matched healthy controls. Se‐ rum IL-18 levels were significantly higher in patients than those in healthy controls. Serum IL-12 and IFN-γ levels were not different between patients and controls. But there was a positive correlation between serum IL-18 and islet cell antibody (ICA) and C-peptide levels, but not between serum IL-18 and HbA1C, insulin and glucose in T1DM. Serum IL-18 levels also correlated positively with serum IL-12 levels. Serum IL-18 levels was significantly high‐ er in patients with DKA than those in patients without DKA while C-peptide levels were markedly lower in patients with DKA. These results point that serum IL-18 levels are elevat‐ ed and correlated with C-peptide levels and ICA in patients with T1DM, with marked in‐ crease in T1DM with DKA. Clinicans should be aware of the risk of DKA in diabetic patients with high serum IL-18 [47]. The procoagulant and inflammatory states may be due to non‐ specific phenomena of stress and may partially explain the association of hyperglycemic cri‐ ses with a hypercoagulable state [48].

sociation between antipsychotic drugs, especially with atypical antipsychotics and hyperglycemia and even DKA have been reported in some cases [55,56]. Arefi et al. re‐ ported the first case of DKA due to nalidixic acid overdosage [57]. It has been available for the treatment of urinary tract infections for many years [58]. There are reports of hy‐ perglycemia, convulsions and glycosuria in overdosage of nalidixic acid [58-61]. Interfer‐ on-alpha (IFN-α), a natural protein with anti-viral, anti-proliferative and immunomodulatory effects is routinely administered in chronic hepatitis C (CHC). Clas‐ sical IFN-α has been correlated with the development of a variety of autoimmune disor‐ ders including Hashimoto thyroiditis, immune-mediated thrombocytopenia, hemolytic anemia, psoriasis, rheumatoid arthritis, systemic lupus erythematosus, primary biliary cirrhosis and sarcoidosis. It is unclear whether IFN-α treatment is associated with the de‐ velopment of T1DM. The prevalence of diabetes mellitus development in patients receiv‐ ing classical IFN-α for CHC is very low ranging from 0.08% to 0.7% [62,63]. Fabris et al. reviewed 9 relative studies; the prevalence of pancreatic auto-antibodies appeared to rise from 3% to 7% prior to and following initiation of IFN-α treatment [64]. Soultati et al. re‐ ported a 38 year-old female patient developed simultaneously DKA and hyperthyroidism 5 months following initiation of treatment with pegylated IFN-α and ribavirin for CHC. High titers of glutamic acid decarboxylase, antinuclear and thyroid (thyroid peroxidase and thyroglobulin) antibodies were detected [65]. Until 2005, 35 cases of IFN-α related T1DM had been reported in the medical literature [64,66-69]. DKA was reported in a few classical IFN-α related cases [70-73], in three pegylated IFN-α related cases [65,74,75]. The development of DKA and the permanent insulin dependency may be related with a rapidly developing T helper-1-mediated pathogenic mechanism [72]. Tacrolimus, a rever‐ sible calcineurin inhibitor, is known for its diabetogenic potential. The incidence of diabe‐ tes is less frequent among the patients of nephrotic syndrome in comparison to organ transplant recipients. DKA is even rarer. Sarkar et al. reported in a 12-year-old girl with steroid resistant nephrotic syndrome, DKA as the first presentation of new onset tacroli‐ mus induced transient T1DM despite a lower dose range and low trough level of the

Diabetic Ketoacidosis

255

http://dx.doi.org/10.5772/53199

Cocaine abuse causes recurrent DKA with several mechanisms, including therapeutic non‐ compliance, stimulation of adrenal release of epinephrine and norepinephrine and increased release of other counter regulatory hormones [30,77]. Cytomegalovirus infection [78,79], protease inhibitor treatment [80,81] and highly active antiretroviral therapy (via immune re‐

The acute DKA episode in T1DM evoluation should be done rapidly. The symptoms of poorly controlled diabetes may be present for several days, but the metabolic changes typical of ketoacidosis usually occurs within a short time (typically 24 h). Occasionally,

storation) may precipitate DKA in HIV-infected patients [82].

drug is being [76].

**5. Diagnosis**

**5.1. History and physical examination**
