Diabetes treatment oral hypoglycemic agents 2013,punar vivah 7 jan 2013 written update,epidemiology type 2 diabetes uk - Plans Download


Science, Technology and Medicine open access publisher.Publish, read and share novel research. Diabetic KetoacidosisMustafa Cesur1 and Irmak Sayin2[1] Ankara Guven Hospital, Department of Endocrinology and Metabolic Disease, Turkey[2] Ufuk University, Medical Faculty, Department of Internal Medicine, Turkey1. Table 2.Classification of DKAOne of the major laboratory findings in DKA is the elevation of total blood ketone concentration. Table 3.Typical total body deficits of water and electrolytes in DKA (*Per kg of body weight)Increased amylase and lipase has been reported in 16-25 % of patients with DKA.
Table 4.Differantial diagnosis of DKAAcute renal failure can be seen in ~5-7% of all adult hospitalizations [132,133].
Clinical and Home Testing - Daily home blood sugar monitoring should be done by both Type I and Type II diabetics. This site was created by Christian Sosa in fulfillment of requirements for the course CSS 335: Latino Health Issues taught by Dr. Oral medication is initiated when 2-3 months of diet and exercise alone are unable to achieve or maintain their optimal plasma glucose levels.
Sulfonylureas work primarily by stimulating pancreatic insulin secretion, which in turn reduces hepatic glucose output and increases peripheral glucose disposal. As the biguanides do not stimulate endogenous insulin secretion, hypoglycemia does not occur when they are used alone and therefore they are sometimes called anti-hyperglycemic agents rather hypoglycemic agents.
The use of phenformin has decreased considerably and it is usually metformin that is now used when a biguanide is prescribed. Acarbose is an alpha-glucosidase inhibitor that slows down the breakdown of disaccharides and polysaccharides and other complex carbohydrates into monosaccharides.
Thiazolidinediones are a new class of oral antidiabetic agents (commercially known as glitazones) that enhance insulin sensitivity in peripheral tissues. Rosiglitazone and Pioglitazone are now available for clinical use and are extremely potent in reducing peripheral insulin resistance. Prior to 1994, the Ohas available for the treatment of Type II diabetes was limited to some sulfonylureas and biguanides. The SU class of oral hypoglycemic agents (insulin secretagogues) has been in existence since tolbutamide was introduced in 1956.
However, after several months, blood levels of insulin return to pre-medication levels, yet blood glucose levels remain reduced.
The efficacy of the first- and second-generation sulfonylureas is similar, although second-generation agents are better formulated and, although costlier than the older sulfonylureas, have some advantages.
In addition, the pharmacokinetics of these second-generation agents allows for more effective once-a-day dosing, which enhances compliance.
Although some consider SUs to be dated compared with the newer oral hypoglycemic drugs, there remains a large number of patients that will continue to benefit from them.
Metformin works mainly by suppressing excessive hepatic glucose production, although it may increase glucose utilization in peripheral tissues to a lesser degree, by decreasing insulin resistance in muscle cells. Metformin has many characteristics that are ideal for treating type 2 diabetes, including weight loss, insulin sensitization, positive lipid effect, mild hypotensive effect, and low or no incidence of hypoglycemia. Treatment with metformin has beneficial effects on plasma lipids (it lowers triglyceride and low-density lipoprotein [LDL] cholesterol levels while increasing high-density lipoprotein [HDL] cholesterol) that are greater than expected from improved glucose control alone. Metformin is effective as monotherapy or in combination with sulfonylureas, alpha-glucosidase inhibitors, and insulin. Acarbose (Precose) is an alpha-glucosidase inhibitor that slows down the breakdown of disaccharides and polysaccharides and other complex carbohydrates into monosaccharides. Delaying the absorption of carbohydrates is a unique mechanism among oral diabetic medications for lowering HgbA1c levels.
One disadvantage with the use of acarbose is that it is to be taken along with the first bite of a meal.
Although Acarbose is the only available AGI in use in India, there are three AGIs in current use all over the world. Repaglinide from the meglitinide drug class, acts like an extremely short-acting SU (an insulin secretagogue) and is potentially useful as a SU replacement. The repaglinide-affected potassium channel appears to be glucose dependent, which may partially explain why repaglinide is associated with a much lower incidence of hypoglycemia. What makes repaglinide clinically different from the SUs is its ultra-short half-life (1 hour). Its biggest advantage over the other oral hypoglycemic medications is that it allows for flexible timing and missed meals. Repaglinide has been approved for use with metformin, and the combination appears to be a very effective. The thiazolidinedione (TZD) class of oral hypoglycemics ( popularly known as glitazones) was developed in 1997 and offers a new mechanism for treatment of type 2 diabetes.
The primary effect of TZDs is peripheral, with increasing insulin sensitivity and increased glucose uptake. TZDs are hepatically metabolized and thus can be used safely in patients with renal dysfunction. Both pioglitazone and rosiglitazone are approved for monotherapy and in combination with metformin, SUs, and insulin.
Besides their effect in lowering the blood glucose levels, both drugs also have notable effects on lipids. Januvia 100mg (Sitagliptin) is an oral hypoglycemic  medicine which belongs to the group of medicines called selective inhibitors of dipeptidyl peptidase-4. Januvia 100mg (Sitagliptin) is an oral hypoglycemic medicine which belongs to the group of medicines called selective inhibitors of dipeptidyl peptidase-4. Januvia increasesthe concentration of glucagon-like peptide-1 and glucose-dependent insulinotropic peptide in blood plasma. Januvia 100mg (Sitagliptin) is an oral hypoglycemic medicine, a selective inhibitor of dipeptidyl peptidase-4. Sitagliptin is different in structure and action mechanism from insulin, sulfonylureas and biguanide derivatives, analogues of glucagon-like peptide-1 agonists, PPAR-gamma (gamma receptor, peroxisome proliferator-activated) inhibitors of alpha-glycosidase, amylin analogues.
Inhibition of dipeptidyl peptidase-4 leads to increased concentrations of two known incretins: glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP).
Glucagon-like peptide-1 also contributes to the suppression of increased glucagon secretion by alpha-cells in the pancreas.
At low concentrations of glucose in the blood the acti listed above effects of incretins on the release of insulin and glucagon secretion are not observed.
Glucagon-like peptide-1 and glucose-dependent insulinotropic peptide do not affect the release of glucagon in response to hypoglycemia. Januvia prevents hydrolysis of the active forms of incretin GPP-1 and GIP by the enzyme dipeptidyl peptidase-4, increasing their plasma concentrations, increases insulin release and glucose-dependent secretion of glucagon. In patients with type II diabetes with hyperglycemia, these changes in insulin secretion and glucagon levels lead to lower glycated hemoglobin (NbA1s) and a decrease in plasma glucose concentration. In patients with diabetes mellitus type II, after receiving a standard therapeutic dose of Januvia, the inhibition of dipeptidyl peptidase-4 is observed for 24 hours.
Combination therapy: to improve glycemic control in combination with metformin or a PPAR-gamma agonists (eg, pioglitazone or rosiglitazone) when diet and exercise in combination with monotherapy do not provide the desired results.
Januvia tablets containing Sitagliptin 100ng are taken orally independently on food intake. Renal failure (in patients with moderate to severe renal impairment the dose adjustment is required). In clinical studies, the overall incidence of side effects, as well as the frequency of Januvia withdrawal because of side effects were similar to those on placebo.
Laboratory parameters: increase of uric acid concentration, the overall decrease in the concentration of alkaline phosphatase, an increase of leukocytes blood levels.
Sitagliptin had no clinically significant effect on the pharmacokinetics of metformin, rosiglitazone, glyburide, simvastatin, warfarin, oral contraceptives.
It was noted a slight increase in AUC (11%) and C max (18%) of digoxin This increase is not considered to be clinically significant.
The pathogenesis causing to hyperglycemia and ketoacidosis in DKA (Data adapted from reference [17])4. Protocols for the management of patients with DKA (Data adapted from reference 10) Table 5. A 15 years old male patient firstly diagnosed T1DM with DKA infected by rhino-orbita-cerebral mucormycozis (Picture from the reference [218])7.6.
IntroductionA chronic autoimmune destruction of the pancreatic beta cells results in decreasing endogenous insulin secretion and the clinical manifestation of type 1 diabetes mellitus (T1DM).
Assessment of increased ketonemia is usually performed by the nitroprusside reaction which provides a semiquantitative estimation of acetoacetate and acetone levels.
It shares the common feature of an increased anion gap metabolic acidosis but can be easily differentiated from DKA by the absence of hyperglycemia or ketonemia. However, the hypotension results from a loss of electrolyte solution and it is more physiological to replace with crystalloid. Carbohydrates are a simple sugar that the body easily converts to sugar and tends to build up in the body. 30-60 minute sessions of cardiovascular exercise is a good workout, although weight training is a great addition. Clinical testing should be done annually for Type I Diabetes and Type II Diabetes testing should be done annually after being diagnosed for 3-5 years. Progress of glucose homeostasis and treatment of the patients submitted to surgery.Table 4.
Comparison of weight loss, BMI reduction, percentage of excess BMI reduction and waist circumference reduction between the groups.BMI = body mass index. However, a trial of diet and exercise alone should be reserved for these patients with asymptomatic hyperglycemia.
The enzymatic generation and subsequent absorption of glucose is delayed and the postfood blood glucose values, which are characteristically high in patients with type II diabetes, are reduced.
Troglitazone was the first glitazone introduced to the market, and though widely used, it has now been withdrawn from the market as its use has been linked with hepatocellular injury and death secondary to liver failure. In the last few years, four new classes and at least 8 new oral agents have become available for the treatment. Initially, they work primarily by stimulating pancreatic insulin secretion, which in turn reduces hepatic glucose output and increases peripheral glucose disposal.
Both phenformin and metformin have been widely used here, although in recent times, the use of phenformin has decreased significantly and most people now use metformin when a biguanide is to be used. The combination of metformin and troglitazone has also been shown to be safe and effective, although this combination is not an USA FDA- approved indication and extensive published data on this combination is lacking.
The enzymatic generation and subsequent absorption of glucose is delayed and the postprandial blood glucose values, which are characteristically high in patients with type II diabetes, are reduced with acarbose.
The effectiveness of this mechanism is one of the physiologic characteristics of type 2 diabetes.
Repaglinide is taken just before or with meals, and the stimulation of the pancreas is limited only to a brief time around meals.
There are no clinical trials of repaglinide with the alpha-glucosidase inhibitors, and of the TZD class, only 1 clinical trial with troglitazone has been reported. The first, troglitazone was taken off the market in 1999 because of its association with hepatic toxicity. The current data show that pioglitazone has a minimal effect on low-density lipoprotein (LDL) cholesterol levels and a favorable effect on high-density lipoprotein (HDL) cholesterol and triglyceride levels. Blood sugar levels may show a significant reduction statistically in as little as two to four weeks, but the maximum effects are not seen until two or three months have passed. Thus, increases insulin secretion, reduces glucagon secretion and glycosylated hemoglobin levels in patients with diabetes mellitus type II.
It works by increasing the concentration of glucagon-like peptide-1 and glucose-dependent insulinotropic peptide in blood plasma. These incretins are secreted into the intestine and their concentration is increased in response to food intake. Reducing the concentration of glucagon, accompanied by increased levels of insulin helps reduce hepatic glucose production, resulting in a decrease of glycemia levels. Under physiological conditions, the activity of incretins is limited to dipeptidyl peptidase-4, which rapidly hydrolyzes incretins in inactive products. The dose of the medication is indicated individually by a health care provider and is based on severy of the disease, patients age, othet medical conditions treated.
Januvia should be stored at dry and protected from light place at a room temperature out of reach of children. The clinical onset of the disease is often acute in children and adolescents and diabetic ketoacidosis (DKA) is present in 20-74% of the patients [1-7]. The major complications of hypothermia are acute renal failure, aspiration pneumonia, rhabdomyolysis, acute respiratory distresss syndrome and acute pancreatitis [83]. The nitroprusside test (both in urine and in serum) is highly sensitive, but it does not recognize the main metabolic product in ketoacidosis; beta-hydroxybutyrate. Amylase elevations could be related with subtle injury to pancreatic acinar cells which causes release of this enzyme to the circulation, release of salivary gland amylase or suboptimal excretion in the urine [128].
A recent Cochrane review did not support the use of colloid in preference to crystalloid fluid [153].
If patients are symptomatic, oral antidiabetic agents or insulin should be initiated in concert with diet and exercise.
Clearly, the clinical choices today are more confusing and complicated than they were only a few years ago. Several have been identified, among them: sulfonylurea medications slow the rate at which the liver releases glucose into the bloodstream, and they increase the number of insulin receptors on cell membranes, thus increasing insulin efficiency. AGIs do not prevent the absorption of carbohydrates and complex sugars, but they do delay their absorption. Patients with type 2 diabetes demonstrate a delayed or sluggish insulin response from the pancreas to a glucose (a meal) load.
Miglitol and acarbose appear to be equally effective, but miglitol clearly is the preferred choice. Repaglinide, like the SUs, blocks the potassium channels on the pancreatic islet beta-cells, which causes an influx of calcium into the cell and increasing the secretion of insulin.


Because of the short duration, the patient does not have continuous high levels of insulin and the resulting adverse effects. Rosiglitazone and pioglitazone have been available since 1999, and have recently been introduced in the Indian market. Reports have suggested that rosiglitazone works better in women, but the reason for this is not known.
Rosiglitazone has a favorable effect on HDL cholesterol levels but a negative effect on LDL cholesterol levels.
It helps increase insulin secretion, causes reduction of glucagon secretion, glycosylated hemoglobin levels and blood glucose levels in patients with diabetes mellitus type II.
Usually the stadard reccomended dosage of Januvia is 100m once daily as monotherapy or in combination with other anti-diabetic medicines. The mechanism of hypothermia complicated by DKA is unclear, but the inability of glucose to endocytose due to insulin deficit which leads to a lack of substrate for cellular heat production has been proposed [84]. In conclusion this assay is insufficient to determine the severity of ketoacidosis [10,31].
There is little correlation between the presence, degree or isoenzyme type of hyperamylasemia and the presence of gastrointestinal symptoms (nausea, vomiting, and abdominal pain) or pancreatic imaging studies [129].
The pH and anion gap can be found usually mild abnormal, however blood sugar is typically normal. Buchwald, Evolution of operative procedures for the management of morbid obesity, Obes Surg. By delaying the absorption of glucose, the insulin response is more matched to the serum glucose, resulting in less postprandial hyperglycemia and a lowering of the HbA1c. Acarbose has occasionally been associated with liver toxicity and requires liver monitoring, whereas miglitol does not. There appears to be 2 similar potassium channels on islet beta-cells, one of which is predominantly affected by repaglinide and the other is predominantly affected by SUs. At normal or elevated blood glucose levels these incretins contribute to increase of insulin synthesis and secretion of its beta-cells of the pancreas by cAMP-associated signaling intracellular mechanisms. Even with appropriate intervention, DKA is associated with significant morbidity and possible mortality in diabetic patients in the pediatric age group [8]. A characteristic elevated J point on the electrocardiogram (ECG) (Osborn wave) may be observed when markedly hypothermia occurs [85-87]. Measurement of serum ?- hydroxybutyrate may be an alternative to determine ketoacidosis [96). Increase in lipase may be related with release of nonpancreatic lipolytic enzymes into the circulation due to malignant tumors, to acute cholecystitis or esophagitis. It was approved by the Research Ethics Committee of the University Hospital of the Federal University of Espirito Santo, Brazil (protocol no. The AGIs also demonstrate a lowering of total insulin output of the pancreas, increased insulin sensitivity, a variable but mild decrease in triglycerides, with no effect on patient weight.
The thermoregulatory system could be impaired in diabetic patients with autonomic neuropathy and reduced muscle mass or adipose tissue related with malnutrition. Other possible mechanism are; renal insufficiency, delayed blood withdrawal, hypertriglyceridemia or subclinical pancreatitis [130]. Lactic acidosis occasionally contributes to metabolic acidosis in patients hospitalized for either uncomplicated diabetes or DKA [137]. Kim, Oh, Results of laparoscopic sleeve gastrectomy (LSG) at 1 year in morbidly obese Korean patients. Foster-Schubert, Gastric bypass for obesity: mechanisms of weight loss and diabetes resolution. Miglitol has been clinically tested and found effective as a single agent and in combination with SUs, metformin, and insulin. The triad of uncontrolled hyperglycemia, metabolic acidosis and increased total body ketone concentration characterizes DKA [10]. The anion gap is calculated by subtracting the sum of chloride(Cl) and bicarbonate (HCO3) concentration from the sodium (Na) concentration: [Na - (Cl +HCO3)]. Pancreatic enzyme levels reach a peak 12-24 hours after initiation of treatment for DKA [131].
In order to homogenize the sample, we adopted the following inclusion criteria: female patients aged 20-60 years, with BMI 40-45 (inclusive), who agreed on giving written informed consent. Laferrere, Do incretins play a role in the remission of type 2 diabetes after gastric bypass surgery: what are the evidence?
Leonetti, et al.Effectiveness of laparoscopic sleeve gastrectomy (first stage of biliopancreatic diversion with duodenal switch) on co-morbidities in super-obese high-risk patients. Polonsky, Interactions between insulin resistance and insulin secretion in the development of glucose intolerance.
Souza, Mecanismos cirurgicos de controle do diabetes mellitus tipo 2 apos cirurgia bariatrica. There have been no trials comparing AGIs with TZDs or repaglinide; however, there are no obvious reasons that the AGIs could not be used with the TZDs, but there are some theoretical concerns in using them with repaglinide. In addition to possible acute complications, it may also influence the later outcome of diabetes [11].2. It occurs in the setting of decreased tissue oxygen delivery which triggers non-oxidative metabolism of glucose to lactic acid.
Mingrone, et al.The mechanism of diabetes control after gastrointestinal bypass surgery reveals a role of the proximal small intestine in the pathophysiology of type 2 diabetes. EpidemiologyWorldwide, an estimated 65 000 children under 15 years old develop T1DM each year, and the global incidence in children continues to increase at a rate of 3% a year [12,13]. Abdominal pain on presentation could be a result of the DKA or an indication of a precipitating cause of DKA, particularly in younger patients or in the absence of severe metabolic acidosis [91,92]. In clinical trials mixed acid–base disorders have been showed in DKA [97,98], but it is very rare the presentation of DKA with alkalaemia. Differential diagnosis Other causes of metabolic acidosis and ketosis must be differentiated from DKA. When co-existent with DKA, the anion gap typically exceeds that attributable to lactate alone. In patients with renal or cardiac failure, monitoring of serum osmolality and frequent assessment of cardiac, renal and mental status must be performed during fluid resuscitation to avoid iatrogenic fluid overload [10,37,148]. Bonanomi, et al.Laparoscopic sleeve gastrectomy as an initial weight-loss procedure for high-risk patients with morbid obesity.
The first case has been reported in 1970, defined as ‘diabetic ketoalkalosis’ [99] and it was followed by other case reports.
Laboratory findings The initial laboratory evaluation should include determination of plasma glucose, blood urea nitrogen, creatinine, electrolytes (with calculated anion gap), osmolality, serum and urinary ketones and urinalysis, as well as initial arterial blood gases and a complete blood count [93]. Fonseca, ReaPrevalencia de sobrepeso e obesidade em pacientes com diabetes mellitus do tipo 2 no Brasil: Estudo multicentrico nacional.
Mc Lean, et al.Surgery decreases long-term mortality, morbidity, and health care use in morbidly obese patients.
If laboratory measurement of serum potassium is delayed an ECG should be performed for baseline evaluation of potassium status [94,95]. For main therapy it should be performed to optimise tissue perfusion and to treat underlying conditions [17,136].When there is insufficient carbohydrate availability, starvation ketosis may occur by result of physiologically appropriate lipolysis and ketogenesis to provide fuel substrates. 29 311 new cases of T1DM were diagnosed in children before their 15th birthday during a 15-year period between 1989-2003.
An increased WBC count is response to stress is characteristic of DKA and is not indicative of infection. Recent studies have reported from normal or near normal [101] to elevated [31,3] hepatic glucose production rates.
Blood glucose and arterial pH are found to be usually in normal level and the anion gap is at most mildly elevated. If there is evidence of infection, chest X-ray and urine, sputum, throat or blood cultures should also be obtained [93]. This factor possibly contributes to the wide range of plasma glucose levels in DKA that are independent of the severity of ketoacidosis [96]. Although ketonuria may be apparent in urine analysis, modest ketonemia is typical in blood examination [17,136].Chronical alcohol abuse may be the reason of alcoholic ketosis for ethanol is the predominant caloric source for days or weeks. Insulin therapy Insulin lowers the serum glucose concentration (by decreasing gluconeogenesis and glycogenolysis, increasing tissue glucose uptake) and arrests ketone production (by reducing lipolysis and glucagon secretion). If present trends continue, prevalent cases younger than 15 years will rise by 70% in 2020 [15]. The severity of DKA is classified as mild, moderate, or severe based on the severity of metabolic acidosis (blood pH, bicarbonate, and ketones) and the presence of altered mental status as shown in Table 2. Due to nausea or vomiting caused by a precipitating illness or by worsening ketoacidosis itself, a decrease in caloric intake occurs. Patients are usually present in normoglycemic or hypoglycemic state on submission, although some have rarely mild hyperglycemia [136].Toxic ingestions sometimes need to be differentiated and history of the patients with laboratory studies may help for the differantial diagnosis.
There was major concern about; physiologic or low dose insulin therapy was superior to pharmacologic dose regimen and the administration of regular insulin via continuous intravenous infusion or by frequent subcutaneous or intramuscular injections [10,157-160]. Approximately 115 000 patients admitted to the hospital because of DKA in one year in USA [17].
If patients continue to take sufficient amounts of insulin in this situation may maintain euglycemia.
Salicylate, methanol and ethylene glycol each produce an increased anion gap metabolic acidosis without hyperglycemia or ketosis.
Several randomized controlled studies have shown that physiologic or low dose insulin therapy was superior to pharmacologic dose regimen and low-dose insulin therapy is effective regardless of the route of administration in DKA [118,159,160].
Viana, Glucose homeostasis and weight loss in morbidly obese patients undergoing banded sleeve gastrectomy: a prospective clinical study. 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]. But ketone body formation cannot be stopped, so they present as DKA accompanied with only mild elevations of blood glucose or normoglycemia [103-105]. In clinical practice most patients are treated with low dose, intravenous regular insulin until resolution of DKA [30]. Euglycemic DKA can be associated with other conditions such as; near total glycogen depletion [106,107], accelerated lipolysis [108] and free fatty acid production [109], less effectiveness of insulin suppressing lipolysis and ketogenesis during fasting and when there is sufficient circulating fluid volume to maintain glucose excretion [110]. The administration of continuous intravenous infusion of regular insulin is preferred because of its short half-life and easy titration and the delayed onset of action and prolonged half-life [107,127,160]. In women with diabetes, pregnancy is also a condition that is associated with euglycemic ketoacidosis [111,112] as pregnancy is considered to be a state of accelerated starvation [113] with increased lipolysis and ketone body production in the presence of increased insulin insensitivity [114]. It is characterized by a low serum bicarbonate concentration with subsequent chloride retention. The patients were given a liquid diet on the first postoperative day and were to be discharged on the third postoperative day. At presentation leukocytosis with cell counts in the 10,000 –15,000 mm3 range is commonly seen in DKA and may not be indicative of an infection.
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. But leukocytosis with cell counts 25,000 mm3 may indicate infection and require further evaluation [115]. Carbonic anhydrase inhibitor therapy, rapid dilution of plasma bicarbonate by infused saline may be considered as the other varying reasons [143,144]. If plasma glucose does not decrease by 50–75 mg in the first hour, the insulin infusion should be increased every hour until a steady glucose decline is achieved.
In ketoacidosis, leukocytosis may be correlated to elevated levels of cortisol and norepinephrine which is attributed to stress [116]. DKA can be easily differentiated from this condition by the presence of an increased anion gap and hyperglycemia. On admission serum sodium is usually low because of the osmotic flux of water from the intracellular to the extracellular space as a result of hyperglycemia. In complicated diabetics, especially in diabetic nephropathy, if there is hypoalbunemia, it can affect the apparent anion gap, since albumin is negatively charged protein contibuting 50-60% to the normal anion gap.
Statistical analysisDescriptive analysis was conducted and the results were expressed as means, standard deviations, medians, frequency (%), minimum values and maximum values. Half of all deaths in diabetic patients younger than 24 years of age are caused from DKA [26,27].
An increased or even normal serum sodium concentration in the presence of hyperglycemia indicates severe degree of free water loss. The Mann-Whitney test was applied to assess sample variation and homogeneity between groups. TreatmentSuccessful treatment of DKA requires correction of dehydration, hyperglycemia and electrolyte imbalances, identification of comorbid precipitating events and above all, frequent patient monitoring.
Once hyperglycemia is corrected, 12-24 hours of intravenous insulin treatment is sufficient to clear ketones from the circulation [51].Subcutaneous rapid-acting insulin analogs (lispro and aspart) offer an efficacious and cost-effective alternative to continuous intravenous infusions in the treatment of DKA [162-164]. Fisher’s exact test and chi-square test were employed to compare the results between the two groups. PathogenesisThere 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 failure, 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. Serum potassium concentration may be increased because of an extracellular shift of potassium caused by insulin deficiency, hypertonicity and acidemia [117]. These hormonal changes increase glucose production from glycogenolysis and gluconeogenesis and impair glucose utilization by peripheral tissues, resulting in hyperglycemia, osmotic diuresis, electrolyte loss, dehydration, decreased glomerular filtration (further compounding hyperglycemia) and hyperosmolarity.
There were no differences in length of hospital stay, total amount of insulin needed for resolution of hyperglycemia or ketoacidosis.
ResultsIn the preoperative period, no significant difference in age, BMI or waist circumference was found between patients from the SRSG group and patients from the SRGB group (Table 4).
Fluid therapy The most important initial therapeutic intervention is fluid replacement followed by insulin administration. Patients treated with insulin analogs were managed in the open medical wards which reduced cost of hospitalization by 30% [162-164].


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]. So patients with low normal or low serum potassium concentration should be monitored closely. This approach is not widely used for many reasons, including titration difficulties with longer half-life preparations, requirement for hourly nursing interventions and lack of staff experience compared to that with standard insulin infusions. Uncontrolled hepatic fatty acid oxidation in the liver to ketone bodies (beta-hydroxybutyrate and acetoacetate) results ketonemia and metabolic acidosis [40]. If necessary appropriate potassium replacement should be done [93].Insulin mainly affects glucose metabolism, but also protein and lipid metabolism. Initial fluid therapy is directed toward expansion of the intravascular, interstitial and intracellular volume (all of which are reduced in hyperglycemic crises), to establish tissue perfusion for insulin to reach cells [148] and restoration of renal perfusion. However, until these studies are confirmed outside the research arena, patients with severe DKA, hypotension, anasarca or associated severe critical illness should be managed with intravenous regular insulin in the intensive care unit [93].
The pathogenesis causing to hyperglycemia and ketoacidosis are schematized in Figure 1 [30].A number of clinical studies showed that the hyperglycemia in patients with hyperglycemic crises is associated with a severe inflammatory state characterized by an elevation of proinflammatory cytokines tumor necrosis factor alpha (TNF-?) and interleukin-6, and -8 (IL-6,8), C-reactive 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 infection or cardiovascular pathology.
In the literature there are many cases of DKA presented with severe hyperlipidemia [118,119].
The goal of fluid resuscitation is to replace half of the estimated water deficit over the first 12-24 hours and adding for the ongoing losses (eg: vomiting) [51]. Insulin therapy and hydration recover these parameters to near-normal values within 24 hours [41]. In patients with newly diagnosed T1DM presenting with DKA there is an absolute insulin deficiency that causes increased lipolysis and free fatty acid accumulation to the liver, decreased in utilization and excretion which results with hyperlipidemia.
Replacement fluids may decrease the blood glucose by up to 23% because of increased renal perfusion and loss of glucose in urine [149] Hyperglycemia can reduce serum sodium by causing an osmotically driven shift of water from intracellular to extracellular compartments. In addition to this, patients with fever or infections and higher metabolic requirements may need 15% to 20% more insulin than the usual dose [165].In rare cases of patients with allergy to human insulin presenting with hyperglycemic crisis, desensitization to human insulin may be performed before treatment with human insulin.
Recent studies focused on the role of interleukin-1 beta (IL-1?), interleukin-12 (IL-12) and interferon-gamma (IFN-?). As demonstrated in vitro, these cytokines can directly influence beta cell function and viability [42].
As it is related with increased morbidity and mortality, clinicians must be aware of this complication.
PotassiumDespite a total body potassium deficit resulting from the glycosuric osmotic diuresis, mild-to-moderate hyperkalemia is common in patients with hyperglycemic crises upon initial presentation because of proteolysis, acidosis, and insulin deficiency [10,167]. Subsequent choice for fluid replacement depends on hemodynamics, the state of hydration, serum electrolyte levels and urinary output. Insulin therapy, correction of acidosis and volume expansion decrease serum potassium concentration [10]. Therefore, these should be monitored for hyperlipidemia and if there is clinical evidence, for pancreatitis [120-123]. Fluid resuscitation should be individualized according to the patient’s degree of dehydration, mental status and underlying diseases such as congestive heart failure or renal failure [51].
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]. Pseudonormoglycemia [124] and pseudohyponatremia [125] may occur in DKA in the presence of severe chylomicronemia. Glucose, an osmotic diuretic, may produce a high urine output even in severely dehydrated patients. 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-? 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]. On the admission in patients with DKA, serum phosphate level is usually elevated because of an extracellular shift of phosphate caused by insulin deficiency, hypertonicity and increased catabolism.
But the potential role of IL-18 in the acute complications of diabetes mellitus such as DKA is controversial.
As a result, urine output should not be considered a reliable predictor of volume status in hyperglycemic states [152]. Bicarbonate therapyThe hepatic metabolism of free fatty acids generates ketoanions, such as beta-hydroxybutyrate and acetoacetate [171,172].
Impaired tissue perfusion due to volume contraction and the adrenergic response to the often severe underlying precipitating illness result in lactate production [173]. Acute kidney injury leads to accumulation of other unmeasured anions, such as sulphate, urate and phosphate [174]. All these, together with hyperchloremia which predominates during the recovery phase of DKA [175], contribute to the development of acidemia, which often is severe [176,177].Metabolic acidemia can impair myocardial contractility, reduce cardiac output, affect oxyhemoglobin dissociation and tissue oxygen delivery, inhibit intracellular enzymes, such as phosphofructokinase, alter cellular metabolism, and result in vital organ dysfunction [178-181]. But based on currently available evidence, several deleterious effects of bicarbonate therapy have been reported, such as increased risk of hypokalemia, decreased tissue oxygen uptake, cerebral edema and development of paradoxical central nervous system acidosis [182].
Serum IL-18 levels was significantly higher 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 elevated and correlated with C-peptide levels and ICA in patients with T1DM, with marked increase in T1DM with DKA.
Clinicans should be aware of the risk of DKA in diabetic patients with high serum IL-18 [47].
In addition, by placing a Silastic® ring around the stomach in all patients of our sample, both procedures became identical at the portion located above the ring.Gastric bypass is the most used procedure in bariatric surgery and is considered by many the gold standard. The procoagulant and inflammatory states may be due to nonspecific phenomena of stress and may partially explain the association of hyperglycemic crises with a hypercoagulable state [48]. These findings are in accordance with those of some studies,(12,15,17) but in disagreement with those of other studies(13,14) that have regarded SG as the first stage of a definitive surgery.
Precipitating factorsA careful search for precipitating factors should be made, as correction of these contributes to improved outcomes and less frequent recurrences.The most common precipitating factor in the development of DKA is infection [37,49,50] including viral syndromes, urinary tract infections, pelvic inflammatory disease, pneumonia, mucormycosis, malignant otitis externa (with pseudomonas aeruginosa), periodontal abscess and dental infection [51]. The good results of the present study are probably due to the judicious selection of the sample, which excluded BMI greater than 45 and patients with prior stomach or bowel surgery. New-onset T1DM or discontinuation of insulin in T1DM frequently leads to the development of DKA. Other factors that might have contributed to the results of the present study include the calibration of the remaining stomach using a 32-Fr tube and the placement of a Silastic® ring. In young patients with T1DM, psychological problems complicated by eating disorders may be a contributing factor in 20% of recurrent ketoacidosis. Randomized studies showed that phosphate replacement have no any additional benefit on the clinical outcome [126,183] and in contrast, phosphate replacement may trigger hypocalcemia and hypomagnesemia [183,184]. Hypophosphatemia can cause hemolysis, refractory acidosis, reduced cardiac output, respiratory muscle weakness, rhabdomyolysis, central nervous system depression, seizures, coma or acute renal failure. The reduction in blood glucose levels was also similar for both groups, a surprising result that has been reported in another study.(17). Additional prospective studies are needed to document reduction of DKA incidence with the use of continuous subcutaneous insulin infusion devices [54]. Drugs that affect carbohydrate metabolism, such as corticosteroids, thiazides, sympathomimetic agents and pentamidine may precipitate the development of DKA [10]. The association between antipsychotic drugs, especially with atypical antipsychotics and hyperglycemia and even DKA have been reported in some cases [55,56]. Transition to subcutaneous insulinWhen DKA has resolved, patients who are appropriate for oral intake can be started on a multiple dose insulin regimen with a long acting insulin (e.g. There are reports of hyperglycemia, convulsions and glycosuria in overdosage of nalidixic acid [58-61]. To ensure adequate plasma insulin levels and to avoid hyperglycemia and ketonemia intravenous insulin infusion should be continued for 1–2 hours after the subcutaneous insulin is given. Interferon-alpha (IFN-?), a natural protein with anti-viral, anti-proliferative and immunomodulatory effects is routinely administered in chronic hepatitis C (CHC). Patients who are inappropriate for oral intake the treatment should be continued with an infusion of intravenous fluids and insulin [10,17,49,93,187].
Classical IFN-? has been correlated with the development of a variety of autoimmune disorders including Hashimoto thyroiditis, immune-mediated thrombocytopenia, hemolytic anemia, psoriasis, rheumatoid arthritis, systemic lupus erythematosus, primary biliary cirrhosis and sarcoidosis.
A multiple-dose subcutaneous combination regimen is preferred, as it is related with less hypoglycemia and provides a better physiologic pattern of control than other regimens. Patients with known diabetes, whose blood glucose monitoring are in the normal ranges before DKA, may start with dose of insulin they are receiving [160].In the past human insulin (NPH and regular) were usually given in two or three doses per day. With the development of new analogue insulins, basal-bolus regimens with basal (glargine and detemir) and rapid-acting (lispro, aspart, or glulisine) insulin treatments became a major concern in the treatment of DKA. A prospective randomized trial compared with a split mixed regimen of NPH plus regular insulin twice daily treatment and a basal-bolus regimen, including glargine once daily and glulisine before meals following the resolution of DKA. Glycemic control were similar between the two groups but the study showed that treatment with basal-bolus insulin regimen was associated with a lower rate of hypoglycemic events (15%) than the rate in those treated with NPH and regular insulin (41%). High titers of glutamic acid decarboxylase, antinuclear and thyroid (thyroid peroxidase and thyroglobulin) antibodies were detected [65].
Somatostatin therapy in the management of resistant diabetic ketoacidosisAs a inhibiting hormone for counterregulatory hormones, somatostatin may be used in the treatment of DKA. Until 2005, 35 cases of IFN-? related T1DM had been reported in the medical literature [64,66-69]. Somatostatin analogues have been successfully used in the treatment of diabetes associated autonomic neuropathy and they have also been shown to decrease the requirements for insulin [188,189]. DKA was reported in a few classical IFN-? related cases [70-73], in three pegylated IFN-? related cases [65,74,75]. Continuous subcutaneous octreotide infusion suppresses counterregulatory hormones, increases insulin-mediated glucose metabolism by enhancing glucose storage and reduces energy expenditure [189]. The development of DKA and the permanent insulin dependency may be related with a rapidly developing T helper-1-mediated pathogenic mechanism [72]. The incidence of diabetes is less frequent among the patients of nephrotic syndrome in comparison to organ transplant recipients.
Octreotide led to a marked suppression of beta-hydroxybutyrate, acetoacetate and glucagon levels and an associated diminution of bicarbonate consumption and the fall in pH [190]. Cytomegalovirus infection [78,79], protease inhibitor treatment [80,81] and highly active antiretroviral therapy (via immune restoration) may precipitate DKA in HIV-infected patients [82].5. In conclusion, for patients who do not respond to conventional DKA treatment, somatostatin could be added to therapy. History and physical examinationThe acute DKA episode in T1DM evoluation should be done rapidly. MonitoringSuccessful management and early intervention for complications require close monitoring. 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, the entire symptomatic presentation may evolve or develop more acutely and the patient may present with DKA with no prior clues or symptoms. The clinicians should be made a flow chart to obtain all relevant incidents regarding the patient’s condition and clinical outcome [192].
For DKA, the typical clinical findings includes a history of polyuria, polydipsia, weight loss, vomiting, dehydration, weakness and mental status change. Physical examination may include poor skin turgor, Kussmaul respirations, tachycardia and hypotension. For example, patients with initially low potassium, more frequent (hourly) K measurements should be made with ECG monitoring [194,195] or if patient’s neurological status is unstable and has a high risk of cerebral edema, more frequent neurologic and vital sign checks (20-30 minutes) should be made [192].
Close monitoring of arterial blood gases and serum or urine ketones should not be used as predictor of clinical improvement. Despite of successfull treatment by arresting ketogenesis, ketone levels may be considered unchanged or high, as beta-hydroxybutyrate converts to acetoacetate and conventional (nitroprusside) testing detects only acetoacetate and acetone [135]. For avoid this problem laboratory measurement or the use of a bedside fingerstick sample monitor for beta-hydroxybutyrate can be made. It is reasonable to reduce laboratory monitoring frequency when acidosis resolves, the anion gap falls to near normal limits while response to glycemic therapy becomes noticeable [135]. Complications of diabetic ketoacidosis or it’s treatmentMost of the diabetes-related morbidity and mortality in T1DM can be attributed to complications of DKA. As ketoacidosis is corrected, a rapid decline in plasma glucose levels can be occur and this may cause the blood glucose drop to hypoglycemia levels. Hypoglycemia leads to the release of counter-regulatory hormones and this results with rebound ketosis which can lengthen the duration of treatment. In addition to this, severe hypoglycemia can cause cardiac arrhythmias, seizure or loss of consciousness, brain injury including coma or death. Rhabdomyolysis and renal failureAcute renal failure (ARF) is an uncommon complication of DKA and rarely requires renal replacement therapy and it may be severe and potentially life threatening [196,197]. Prolonged profound ketoacidosis and insulin infusions can lead to severe hypophosphatemia, mainly as a result of intracelluar phosphate shifting [198-201].
Peripheral venous thrombosisIn DKA treatment, patients may require central vascular access for intensive fluid replacement. However, this route of vascular access causes many complications [206] like venous thromboembolism (VTE) [207]. Children with thrombophilia, malignancy, congenital cardiac disease, acute infection, trauma and surgery have a high risk for complications of central venous catheter (CVC) related VTE [206].
In the medical literature there have been few reported cases CVC related VTE in DKA children without known risk factors. Thus, DKA and its treatment may promote a prothrombotic state and activation of vascular endothelium, predisposing to thrombosis. Whilst, DKA has not been identified as an isolated risk factor for CVC-related VTE in adults [211].
PancreatitisAcute pancreatitis is a well known complication of DKA in adults [212] but is unusual in childhood. Although hypertriglyceridemia is a known cause of acute pancreatitis and elevated triglyceride concentrations are frequent during DKA, an association between elevated triglyceride concentrations in DKA and pancreatic enzyme elevation or pancreatitis have not be showned in the previous studies [213,215].
The mechanism responsible for pancreatic enzyme elevation in DKA has thus remained unclear.



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