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Abbas E Kitabchi

Publications and source records attributed to Abbas E Kitabchi.

At least 19 recordsLinked to original sources
PubMed2006

Palmitic acid-induced activation of human T-lymphocytes and aortic endothelial cells with production of insulin receptors, reactive oxygen species, cytokines, and lipid peroxidation.

Diabetic conditions are associated with hyperglycemia and hyperlipidemia, but the role of saturated fatty acids (SFA) vs. unsaturated fatty acids (UFA) in activation of T-lymphocytes and human aortic endothelial cells (HAEC) is not known. We investigated in vitro effects of various concentrations of SFA (palmitate) and UFA (oleic, linoleic, linolenic, and arachidonic) acids in activation of these cells. These cells in presence of palmitate, but not UFA, exhibited time, and concentration-dependent emergence of insulin receptors, GLUT 4 expression, generation of ROS, cytokines, lipid peroxidation, and IRS-1. We conclude that both T-lymphocytes and HAEC share common characteristics in exhibiting activation of these cells to palmitate, but not to UFA, by developing insulin receptors and becoming insulin responsive tissues, a hitherto unknown response to palmitate. We hypothesize that these events may serve as protective defense mechanisms against acute effects of glucotoxicity and lipotoxicity in these cells.

Aorta↗
PubMed2006

Narrative review: ketosis-prone type 2 diabetes mellitus.

Several investigators have reported that more than half of African-American persons with new diagnoses of diabetic ketoacidosis have clinical, metabolic, and immunologic features of type 2 diabetes during follow-up. These patients are usually obese, have a strong family history of diabetes, have a low prevalence of autoimmune markers, and lack a genetic association with HLA. Their initial presentation is acute, with a few days to weeks of polyuria, polydipsia, and weight loss and lack of a precipitating cause of metabolic decompensation. At presentation, they have markedly impaired insulin secretion and insulin action, but intensified diabetic management results in significant improvement in beta-cell function and insulin sensitivity sufficient to allow discontinuation of insulin therapy within a few months of follow-up. On discontinuation of insulin therapy, the period of near-normoglycemic remission may last for a few months to several years. The absence of autoimmune markers and the presence of measurable insulin secretion have proven useful in predicting near-normoglycemic remission and long-term insulin dependence in adult patients with a history of diabetic ketoacidosis. This clinical presentation is commonly reported in African and African-American persons but is also observed in Hispanic persons and those from other minority ethnic groups. The underlying mechanisms for beta-cell dysfunction in ketosis-prone type 2 diabetes are not known; however, preliminary evidence suggests an increased susceptibility to glucose desensitization.

Adult↗
PubMed2006

Hyperglycemic crises in diabetes mellitus: diabetic ketoacidosis and hyperglycemic hyperosmolar state.

Diabetic ketoacidosis (DKA) and hyperglycemic hyperosmolar state (HHS) potentially are fatal but largely preventable acute metabolic conditions of uncontrolled diabetes, the incidence of which continues to increase. Mortality from DKA has declined remarkably over the years because of better understanding of its pathophysiology and treatment. The mortality rate of HHS remains alarmingly high, however, owing to older age and mode of presentation of patients and associated comorbid conditions. DKA and HHS also are economically burdensome; therefore, any resources invested in their prevention would be rewarding.

Bicarbonates↗
PubMed2005

De novo emergence of insulin-stimulated glucose uptake in human aortic endothelial cells incubated with high glucose.

Elevated glucose concentrations have profound effects on cell function. We hypothesized that incubation of human aortic endothelial cells (HAEC) with high glucose increases insulin signaling and develops the appearance of insulin-stimulated glucose uptake by the cells. Compared with 5 mM glucose, incubation of HAEC with 30 mM glucose for up to 48 h increased in a time-dependent manner expression of insulin receptor, insulin receptor substrate (IRS)-1, IRS-2, and GLUT1 proteins. High glucose also increased the specific binding of (125)I-labeled insulin in HAEC accompanied by accelerated production of interleukin (IL)-6 and IL-8. Short-term stimulation by 50 microU/ml insulin did not activate [(14)C]glucose uptake by HAEC incubated in 5 mM glucose. However, an addition of insulin to high glucose-exposed endothelial cells led to a significant increase in [(14)C]glucose uptake in a glucose concentration- and time-dependent fashion, reaching a plateau at 48 h of incubation. Furthermore, incubation of HAEC with 30 mM glucose resulted in a new insulin-stimulated extracellular signal-regulated kinase-1/2 mitogen-activated protein kinase phosphorylation and increased lipid peroxidation and production of reactive oxygen species. These studies show for the first time that high glucose increases expression of insulin receptors and downstream elements of the insulin-signaling pathway and transforms "insulin-resistant" aortic endothelial cells into "insulin-sensitive" tissue regarding glucose uptake.

Aorta↗
PubMed2005

Hyperglycemia-induced activation of human T-lymphocytes with de novo emergence of insulin receptors and generation of reactive oxygen species.

Upon activation by phytohemagglutine (PHA), T-lymphocytes (T-cells) express receptors for growth factors, insulin, IGF-1 and IL2 and become insulin sensitive. Diabetic ketoacidosis (DKA) is associated with in vivo emergence of these growth factor receptors without incubation with PHA. As DKA consists of multiple metabolic alterations, in addition to hyperglycemia, we investigated the in vitro effect of different concentrations of glucose (5, 15, and 30 mM) in isolated CD4 of human T-cells at various time intervals (0, 24, 48, and 72 h). Hyperglycemia, but not euglycemia, resulted in de novo emergence of growth factor receptors in a dose- and time-dependent fashion. The activation was also associated with incremental changes in GLUT 4, IRS-1, proinflammatory cytokines, and oxidative stress components. We propose that activation of T-cells with development of insulin receptors in hyperglycemic conditions may serve as a mechanism for control of glucose entry into these cells, thus, protecting them against glucose toxicity.

CD4-Positive T-Lymphocytes↗
PubMed2005

Admission hyperglycemia and other risk factors as predictors of hospital mortality in a medical ICU population.

BACKGROUND: Tight glycemic control is recommended for patients in the ICU, as hyperglycemia is associated with increased morbidity and mortality. DESIGN: Observational cohort of patients admitted to a 12-bed, inner-city, medical ICU (MICU). SUBJECTS: A total of 1,185 of 1,506 patients from July 1, 1999, to December 31, 2002, selected based on a diagnosis other than diabetic ketoacidosis or glycemia > 280 mg/dL or < 80 mg/dL. PURPOSES: To determine if the highest serum glucose level within 24 h after ICU admission is associated with increased hospital mortality when adjusted for confounders. MEASUREMENTS: Age, gender, race, worst values within 24 h after ICU admission to construct the acute physiology and chronic health evaluation (APACHE) II score, and highest glucose within 24 h after ICU admission. Hospital mortality was the primary outcome. Admitting diagnosis, MICU length of stay (LOS), and hospital LOS were obtained. Glucose, albumin (n = 867), and lactic acid (n = 319) were stratified for analysis. ANALYSIS: Univariate analysis identified factors included in the multivariate model. RESULTS: Patients were predominantly African-American (79%) and men (56%; mean age, 49.2 years). The mean ICU admission highest glucose level was 139 +/- 43.7 mg/dL (+/- SD). MICU LOS and hospital LOS were 6.2 days and 12.9 days, respectively, and 50% of patients received mechanical ventilation. MICU and hospital mortality were 18% and 20%, respectively; standardized mortality ratio was 66%. On univariate analysis, survivors (n = 945) and nonsurvivors (n = 240) showed APACHE II score, mechanical ventilation, hypoalbuminemia, lactic acidemia, and logistic organ dysfunction system score to be hospital mortality predictors; however, the highest admission serum glucose level was not. Logistic regression estimated APACHE II score/per point (odds ratio, 1.06; 95% confidence interval, 1.02 to 1.11), mechanical ventilation (odds ratio, 3.06; 95% confidence interval, 1.34 to 6.96), severe hypoalbuminemia (< 2 g/dL) [odds ratio, 2.98; 95% confidence interval, 1.3 to 7.02], and severe lactic acidemia (> or = 8 mmol/L) [odds ratio, 7.3; 95% confidence interval, 2.14 to 24.9], but not ICU admission hyperglycemia, to be associated with hospital mortality. CONCLUSIONS: Conventional factors of disease severity, but not highest glucose value during the first 24 h after ICU admission, predict hospital mortality in an inner-city MICU.

APACHE↗
PubMed2005

Role of insulin secretion and sensitivity in the evolution of type 2 diabetes in the diabetes prevention program: effects of lifestyle intervention and metformin.

Insulin resistance and beta-cell dysfunction, two factors central to the pathogenesis of type 2 diabetes, were studied in relation to the development of diabetes in a group of participants with impaired glucose tolerance in the Diabetes Prevention Program (DPP) at baseline and after specific interventions designed to prevent diabetes. Participants were randomly assigned to placebo (n = 1,082), metformin (850 mg twice a day) (n = 1,073), or intensive lifestyle intervention (n = 1,079). The diabetes hazard rate was negatively associated with baseline insulin sensitivity (hazard rate ratio = 0.62-0.94 per SD difference, depending on treatment group and measure of sensitivity) and with baseline insulin secretion (hazard rate ratio = 0.57-0.76 per SD). Improvements in insulin secretion and insulin sensitivity were associated with lower hazard rates in all treatment arms (hazard rate ratio = 0.46-0.95 per SD increase and 0.29-0.79 per SD increase, respectively). In multivariate models that included the three metabolic variables (changes in body weight, insulin sensitivity, and insulin secretion) each significantly and independently predicted progression to diabetes when adjusted for the other two variables. The intensive lifestyle intervention, which elicited the greatest reduction in diabetes incidence, produced the greatest improvement in insulin sensitivity and the best preservation of beta-cell function after 1 year, whereas the placebo group, which had the highest diabetes incidence, had no significant change in insulin sensitivity and beta-cell function after 1 year. In the metformin group, diabetes risk, insulin sensitivity, and beta-cell function at 1 year were intermediate between those in the intensive lifestyle and placebo groups. In conclusion, higher insulin secretion and sensitivity at baseline and improvements in response to treatment were associated with lower diabetes risk in the DPP. The better preventive effectiveness of intensive lifestyle may be due to improved insulin sensitivity concomitant with preservation of beta-cell function.

Adult↗
PubMed2004

Transcriptome and proteome expression in activated human CD4 and CD8 T-lymphocytes.

T-lymphocytes (T-cells) are unique in that unlike monocytes, they have no insulin receptors, and are insulin insensitive, but upon activation with antigens develop insulin, IGF-1, and IL-2 receptors, and become insulin sensitive tissues. In vivo activation of these cells has now been demonstrated in patients with diabetic ketoacidosis. We analyzed the genomics and proteomics of activated and non-activated CD4+ and CD8+ T-cells of normal subjects using Affymetrix microarray gene chips and proteomes by SELDI-TOF mass spectrometry analysis. Genes for IL-2, insulin, and IGF-1 receptors were increased at least 2-fold in activated vs non-activated T-cells. Using an expression array containing the entire human genome of 39,500 genes, we evaluated approximately 27,000 genes relevant in physiologic and cellular ontologies. Of these, approximately 10,500 genes were increased in activated cells, compared to about 7,000, which were decreased, and approximately 9500, which were unchanged. Among activated ontologies were signal transduction pathways such as IRS-1, IRS-2, Akt, and glycolytic pathways. To our knowledge this is the first report of an hitherto unreported event. Possible implications of these processes are discussed in the light of their physiological significance.

Adult↗
PubMed2004

Efficacy of subcutaneous insulin lispro versus continuous intravenous regular insulin for the treatment of patients with diabetic ketoacidosis.

PURPOSE: To compare the efficacy and safety of subcutaneous insulin lispro with that of a standard low-dose intravenous infusion protocol of regular insulin in patients with uncomplicated diabetic ketoacidosis. METHODS: In this prospective, randomized open trial, 20 patients treated with subcutaneous insulin lispro were managed in regular medicine wards (n=10) or an intermediate care unit (n=10), while 20 patients treated with the intravenous protocol were managed in the intensive care unit. Patients treated with subcutaneous lispro received an initial injection of 0.3 unit/kg followed by 0.1 unit/kg/h until correction of hyperglycemia (blood glucose levels <250 mg/dL), followed by 0.05 to 0.1 unit/kg/h until resolution of diabetic ketoacidosis (pH > or =7.3, bicarbonate > or =18 mEq/L). Patients treated with intravenous regular insulin received an initial bolus of 0.1 unit/kg, followed by an infusion of 0.1 unit/kg/h until correction of hyperglycemia, then 0.05 to 0.1 unit/kg/h until resolution of diabetic ketoacidosis. RESULTS: Mean (+/- SD) admission biochemical parameters in patients treated with subcutaneous lispro (glucose: 674 +/- 154 mg/dL; bicarbonate: 9.2 +/- 4 mEq/L; pH: 7.17 +/- 0.10) were similar to values in patients treated with intravenous insulin (glucose: 611 +/- 264 mg/dL; bicarbonate: 10.6 +/- 4 mEq/L; pH: 7.19 +/- 0.08). The duration of treatment until correction of hyperglycemia (7 +/- 3 hours vs. 7 +/- 2 hours) and resolution of ketoacidosis (10 +/- 3 hours vs. 11 +/- 4 hours) in patients treated with subcutaneous lispro was not different than in patients treated with intravenous regular insulin. There were no deaths in either group, and there were no differences in the length of hospital stay, amount of insulin until resolution of diabetic ketoacidosis, or in the rate of hypoglycemia between treatment groups. Treatment of diabetic ketoacidosis in the intensive care unit was associated with 39% higher hospitalization charges than was treatment with subcutaneous lispro in a non-intensive care setting ($14,429 +/- $5243 vs. $8801 +/- $5549, P <0.01). CONCLUSION: Treatment of adult patients who have uncomplicated diabetic ketoacidosis with subcutaneous lispro every hour in a non-intensive care setting may be safe and more cost-effective than treatment with intravenous regular insulin in the intensive care unit.

3-Hydroxybutyric Acid↗
PubMed2004

Diabetic ketoacidosis induces in vivo activation of human T-lymphocytes.

Diabetic ketoacidosis (DKA) is an inflammatory state associated with immune responses in polymorphonuclear cells (PMN). Activation of subgroup of T-lymphocytes in PMN of DKA patients, however, is not known. We studied in vivo activation of CD4 and CD8 lymphocytes by measuring de novo growth factor receptor for insulin, IGF-1, and IL-2 in eight patients on admission and at resolution of DKA, and compared them with matched controls. The presence of these receptors was demonstrated in all patients' lymphocytes on admission, but not in control subjects. This event was associated with increased levels of thiobarbituric acid-reacting material and dichlorofluorescien, as markers of oxidative stress. Based on these new findings and works in the literature, we hypothesize that hyperglycemia/ketosis results in increased reactive oxygen species, leading to increased levels of cytokines and emergence of growth factor receptors. We propose DKA changes the T-lymphocytes to insulin sensitive tissues as a compensatory mechanism.

CD4-Positive T-Lymphocytes↗
PubMed2004

De novo emergence of growth factor receptors in activated human CD4+ and CD8+ T lymphocytes.

Using phytohemagglutinin (PHA)-activated human T lymphocytes, we have demonstrated de novo emergence of growth factor receptors (insulin, insulin-like growth factor-1 [IGF-1], and interleukin-2 [IL-2]) in the CD4(+) and CD8(+) subsets determined by flow cytometry. This activation was also associated with development of insulin-degrading activity (IDA) in a time-dependent fashion. These events, which are actinomycin- and cycloheximide-sensitive, occur only in activated, but not nonactivated, CD4(+) and CD8(+) lymphocytes. The emergence of these receptors, as well as IDA, which is preceded by CD69 emergence, reaches a plateau by 72 hours and is comparable in both subsets. The IDA is localized in the cytosol, and insulin binding is limited to the cell membrane. T-lymphocyte activation also initiates expression of the IL-2 gene with the transcription of IL-2 mRNA, the level of which is further enhanced by 38% with the addition of insulin. In these activated lymphocytes, insulin binding to its receptor also caused an 83% upregulation of phosphorylated insulin receptor substrate-1 (IRS-1). In situ development of these growth factor receptors and signal transduction mechanisms in T lymphocytes upon activation, such as by proinflammatory cytokines or oxidative stress, could be an important defense mechanism in various disease states in man.

CD4-Positive T-Lymphocytes↗
PubMed2004

Proinflammatory cytokines, markers of cardiovascular risks, oxidative stress, and lipid peroxidation in patients with hyperglycemic crises.

Acute and chronic hyperglycemia are proinflammatory states, but the status of proinflammatory cytokines and markers of oxidative stress and cardiovascular risks is not known in hyperglycemic crises of diabetic ketoacidosis (DKA) and nonketotic hyperglycemia (NKH). We studied 20 lean and 28 obese patients with DKA, 10 patients with NKH, and 12 lean and 12 obese nondiabetic control subjects. We measured 1) proinflammatory cytokines (tumor necrosis factor-alpha, interleukin [IL]-6, IL1-beta, and IL-8), 2) markers of cardiovascular risk (C-reactive protein [CRP], homocysteine, and plasminogen activator inhibitor-1 [PAI-1]), 3) products of reactive oxygen species (ROS; thiobarbituric acid [TBA]-reacting material, and dichlorofluorescein [DCF]), and 4) cortisol, growth hormone (GH), and free fatty acids (FFAs) on admission (before insulin therapy) and after insulin therapy and resolution of hyperglycemia and/or ketoacidosis. Results were compared with lean and obese control subjects. Circulating levels of cytokines, TBA, DCF, PAI-1, FFAs, cortisol, and GH on admission were significantly increased two- to fourfold in patients with hyperglycemic crises compared with control subjects, and they returned to normal levels after insulin treatment and resolution of hyperglycemic crises. Changes in CRP and homocysteine in response to insulin therapy did not reach control levels after resolution of hyperglycemia. We conclude that DKA and NKH are associated with elevation of proinflammatory cytokines, ROS, and cardiovascular risk factors in the absence of obvious infection or cardiovascular pathology. Return of these values to normal levels with insulin therapy demonstrates a robust anti-inflammatory effect of insulin.

Adult↗
PubMed2004

Treatment of diabetic ketoacidosis with subcutaneous insulin aspart.

OBJECTIVE: In this prospective, randomized, open trial, we compared the efficacy and safety of aspart insulin given subcutaneously at different time intervals to a standard low-dose intravenous (IV) infusion protocol of regular insulin in patients with uncomplicated diabetic ketoacidosis (DKA). RESEARCH DESIGN AND METHODS: A total of 45 consecutive patients admitted with DKA were randomly assigned to receive subcutaneous (SC) aspart insulin every hour (SC-1h, n = 15) or every 2 h (SC-2h, n = 15) or to receive IV infusion of regular insulin (n = 15). Response to medical therapy was evaluated by assessing the duration of treatment until resolution of hyperglycemia and ketoacidosis. Additional end points included total length of hospitalization, amount of insulin administration until resolution of hyperglycemia and ketoacidosis, and number of hypoglycemic events. RESULTS: Admission biochemical parameters in patients treated with SC-1h (glucose: 44 +/- 21 mmol/l [means +/- SD], bicarbonate: 7.1 +/- 3 mmol/l, pH: 7.14 +/- 0.09) were similar to those treated with SC-2h (glucose: 42 +/- 21 mmol/l, bicarbonate: 7.6 +/- 4 mmol/l, pH: 7.15 +/- 0.12) and IV regular insulin (glucose: 40 +/- 13 mmol/l, bicarbonate 7.1 +/- 4 mmol/l, pH: 7.11 +/- 0.17). There were no statistical differences in the mean duration of treatment until correction of hyperglycemia (6.9 +/- 4, 6.1 +/- 4, and 7.1 +/- 5 h) or until resolution of ketoacidosis (10 +/- 3, 10.7 +/- 3, and 11 +/- 3 h) among patients treated with SC-1h and SC-2h or with IV insulin, respectively (NS). There was no mortality and no differences in the length of hospital stay, total amount of insulin administration until resolution of hyperglycemia or ketoacidosis, or the number of hypoglycemic events among treatment groups. CONCLUSIONS: Our results indicate that the use of subcutaneous insulin aspart every 1 or 2 h represents a safe and effective alternative to the use of intravenous regular insulin in the management of patients with uncomplicated DKA.

Adult↗
PubMed2003

Changes in serum leptin in lean and obese subjects with acute hyperglycemic crises.

We aimed to determine the effect of insulin replacement on serum leptin concentration in lean and obese patients with diabetic ketoacidosis (DKA). We compared serial leptin levels in 52 patients with DKA, 14 obese subjects with hyperglycemia, and 52 nondiabetic control subjects. Leptin levels on admission were significantly decreased in lean and obese patients with DKA and/or hyperglycemia compared with weight- and gender-matched controls. Insulin therapy resulted in a significant increase in leptin levels within 4 h, with peak stimulation at 12 h. Leptin levels on admission and at resolution of hyperglycemia were higher in obese DKA (9.7 +/- 2 ng/ml and 26.5 +/- 5 ng/ml, respectively; P < 0.001) and obese hyperglycemia subjects (11.9 +/- 4 ng/ml vs. 24.4 +/- 2 ng/ml; P < 0.001) than in lean DKA subjects (5.3 +/- 0.3 ng/ml and 10.1 +/- 2 ng/ml; P < 0.001). We conclude that insulin treatment in patients with acute hyperglycemic crises is followed by rapid and significant increase in leptin concentration, and this increase is more discernible in obese subjects. The low serum leptin level on admission in subjects with hyperglycemic crises may be the result of impaired adipocyte glucose utilization due to insulin deficiency and/or to increased catecholamine levels.

Acute Disease↗