William H Hoffman

Publications (34)63.76 Total impact

• Article: Autophagy in the brains of young patients with poorly controlled T1DM and fatal diabetic ketoacidosis.

  William H Hoffman, John J Shacka, Anuska V Andjelkovic
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  ABSTRACT: Semi-quantitative neuroradiologic studies, quantitative neuron density studies and immunocytochemistry markers of oxidative stress and neuroinflammation indicate neuronal injury and deficits in young patients with chronic poorly controlled type 1 diabetes mellitus (T1DM). Present data suggest that pathogenesis of the neuronal deficits in young patients, who die as the result of diabetic ketoacidosis (DKA) and brain edema (BE), does not involve apoptosis, a prominent form of regulated cell death in many disease states. To further address this we studied mediators of macroautophagy, endoplasmic reticulum (ER) stress and apoptosis. In all areas studied we demonstrated increased levels of macroautophagy-associated proteins including light chain-3 (LC3) and autophagy related protein-4 (Atg4), as well as increased levels of the ER-associated glucose-regulated protein78/binding immunoglobulin protein (GRP78/BiP) in T1DM. In contrast, cleaved caspase-3 was rarely detected in any T1DM brain regions. These results suggest that chronic metabolic instability and oxidative stress may cause alterations in the autophagy-lysosomal pathway but not apoptosis, and macroautophagy-associated molecules may serve as useful candidates for further study in the pathogenesis of early neuronal deficits in T1DM.
  Experimental and Molecular Pathology 11/2011; 93(2):273-80. · 2.42 Impact Factor
• Article: Oxidative damage is present in the fatal brain edema of diabetic ketoacidosis.

  William H Hoffman, Sandra L Siedlak, Yang Wang, Rudy J Castellani, Mark A Smith
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  ABSTRACT: Oxidative stress is implicated as a pathogenic factor in a spectrum of chronic diseases, notably, neurodegenerative disease. Noteworthy in this regard is that type 1 diabetes mellitus (T1DM) results in oxidative stress, leading to systemic complications of T1DM. We hypothesized that oxidative stress associated with diabetic ketoacidosis (DKA) of T1DM might have measurable brain sequelae. Consistent with this hypothesis are neurohistology and neuroradiologic studies of T1DM that suggest oxidative insults are involved in the chronic complications of diabetic encephalopathy. To further address the role of oxidative stress in an acute setting, specifically in fatal brain edema (BE) associated with DKA, we studied neuronal localization and levels of oxidative stress markers reported to be increased in other neurodegenerative conditions. We demonstrated increased levels of 8-hydroxyguanosine (8OHG), 4-hydroxynonenal (HNE), and heme oxygenase-1 (HO-1) in the pyramidal neurons of the hippocampus of DKA BE in comparison to controls. However, in the cerebellum, only 8OHG was increased in the Purkinje cells and other cells of the molecular layer. These results indicate a role for oxidative stress in the pathogenesis of T1DM encephalopathy.
  Brain research 10/2010; 1369:194-202. · 2.46 Impact Factor
• Source

  Available from: Monica V Talor

  Article: Autoantibody heritability in thyroiditis: IgG subclass contributions.

  Ingrid M Outschoorn, Monica V Talor, William H Hoffman, Merrill J Rowley, Ian R Mackay, Noel R Rose, C Lynne Burek
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  ABSTRACT: Using a simple screening technique called regression of offspring on mid-parent (ROMP) to examine the role of IgG subclasses in affected and unaffected siblings of children and adolescents with autoimmune thyroid disease and their parents, both total-restricted and subclass-restricted autoantibodies to thyroglobulin (Tg) were assayed quantitatively for each of the IgG subclasses. There was a significant correlation of anti-Tg titer of probands with parental titers in thyrotoxicosis (TT), (R(2) = 0.569, p = 0.001), but not in chronic lymphocytic thyroiditis. The most striking correlation was in TT patients of African-American ancestry, (R(2) = 0.9863, p = 0.0007). Additional insight is provided by examining the contributions of the IgG subclasses individually, particularly those whose concentrations appear not to have direct influence on the total IgG titers. Thus, using small numbers of patients, and assaying the IgG subclass distributions, as well as any other immunoglobulin isotypes that are significantly altered in autoantibody assays, ROMP can be performed rapidly to ascertain which quantifiable parameters may be usefully extended to predict disease onset and progression.
  Autoimmunity 10/2010; 44(3):195-200. · 2.47 Impact Factor
• Article: Insulin and IGF-1 receptors, nitrotyrosin and cerebral neuronal deficits in two young patients with diabetic ketoacidosis and fatal brain edema.

  William H Hoffman, Anuska V Andjelkovic, Weixian Zhang, Gregory G Passmore, Anders A F Sima
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  ABSTRACT: Gray and white matter structural deficits may accompany type 1 diabetes. Earlier experimental studies have demonstrated neuronal deficits associated with impaired neurotrophic support, inflammation and oxidative stress. In this study we demonstrate in two patients with histories of poorly controlled type 1 diabetes and fatal brain edema of ketoacidosis neuronal deficits associated with a decreased presence of insulin and IGF-1 receptors and accumulation of nitrotyrosin in neurons of affected areas and the choroid plexus. The findings add support to the suggested genesis of T1DM encephalopathy due to compromised neurotrophic protection, oxidative stress, inflammation and neuronal deficits, as demonstrated in T1DM encephalopathy in the BB/Wor-rat.
  Brain research 07/2010; 1343:168-77. · 2.46 Impact Factor
• Article: Inflammation in Diabetic Encephalopathy is Prevented by C-Peptide.

  Anders A F Sima, Weixian Zhang, Christian W Kreipke, José A Rafols, William H Hoffman
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  ABSTRACT: Encephalopathy is an increasingly recognized complication of type 1 diabetes. The underlying mechanisms are not well understood, although insulin deficiency has been implicated. The spontaneously diabetic BB/Wor-rat develops neuro-behavioral deficits and neuronal cell death in hippocampus and frontal cortex, which can be prevented by insulinomimetic C-peptide. Here we examined whether contributing factors such as activation of innate immune mediators are responsive to C-peptide replacement. Seven-month diabetic BB/Wor-rats and those treated with full C-peptide replacement were compared to age-matched control rats. Hippocampi of diabetic rats showed upregulation of RAGE and NF-kappaB, the former being localized to proliferating astrocytes. These changes were associated with increased expression of TNF-alpha, IL-1beta, IL-2 and IL-6 in hippocampi of diabetic rats. Full C-peptide replacement, which did not induce hyperglycemia, resulted in significant prevention of upregulation of RAGE expression, activation of NF-kappaB and activation of pro-inflammatory factors. In conclusion, impaired insulin activity is associated with upregulation of RAGE and pro-inflammatory factors, and these are likely to contribute to previously described oxidative and apoptotic neuronal cell death. Replacement of insulinomimetic C-peptide significantly prevents this cascade of events.
  The Review of Diabetic Studies 02/2009; 6(1):37-42.
• Article: Sequential abnormalities in type 1 diabetic encephalopathy and the effects of C-Peptide.

  Anders A F Sima, Weixian Zhang, Otto Muzik, Christian W Kreipke, José A Rafols, William H Hoffman
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  ABSTRACT: Diabetic encephalopathy is a recently recognized complication in type 1 diabetes. In this review, we summarize a series of experimental results obtained longitudinally in the spontaneously type 1 diabetic BB/Wor-rat, and bringing out the beneficial effects of C-peptide replacement. It is increasingly clear that lack of insulin and C-peptide, and perturbations of their signaling cascades in type 1 diabetes are detrimental to the regulation of neurotrophic factors and their receptors. Other consequences of such deficits and perturbations are innate inflammatory responses with effects on synaptogenesis, neurite degeneration, and early behavioral abnormalities. Replacement of C-peptide, which does not effect hyperglycemia, has beneficial effects on a variety of pro-apoptotic stressors, oxidative stressors, and finally on apoptosis. Eventually, this cascade of events leads to neuronal loss and decreased densities of white matter myelinating cells, with more profound deficits in behavioral and cognitive function. Such changes are likely to underlie gray and white matter atrophy in type 1 diabetes, and are significantly prevented by full C-peptide replacement. Present data demonstrate that C-peptide replacement has beneficial effects on numerous sequential and partly interrelated pathogenetic mechanisms, resulting in prevention of neuronal and oligodendroglial cell loss, with significant prevention of neurobehavioral and cognitive functions.
  The Review of Diabetic Studies 01/2009; 6(3):211-22.
• Article: Inflammatory mediators and blood brain barrier disruption in fatal brain edema of diabetic ketoacidosis.

  William H Hoffman, Svetlana M Stamatovic, Anuska V Andjelkovic
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  ABSTRACT: Brain edema (BE) is an uncommon but life-threatening complication of severe diabetic ketoacidosis (DKA) and its treatment. Despite advances in treatment of DKA, the pathogenesis of both initiation and progression of the associated BE is unclear. In the present study we examined the blood brain barrier (BBB) integrity and the potential involvement of the inflammatory mediators in BBB breakdown in two cases of fatal BE associated with DKA. In both cases there were typical signs of disruption of the BBB manifested by the absence of tight junction proteins (occludin, claudin-5, ZO-1 and JAM-1) in the parenchymal blood vessels, as well as albumin extravasation in examined brain areas. The neuroinflammatory markers chemokine CCL2, NF-kappaB and nitrotyrosine were localized in the perivascular areas of the disrupted BBB and diffusely distributed in the brain parenchyma. Our data indicate that neuroinflammation plays a role in the BBB disruption of the fatal BE of DKA.
  Brain research 01/2009; 1254:138-48. · 2.46 Impact Factor
• Article: Receptor for advanced glycation end products and neuronal deficit in the fatal brain edema of diabetic ketoacidosis.

  William H Hoffman, Carol M Artlett, Weixian Zhang, Christian W Kreipke, Gregory G Passmore, Jose A Rafols, Anders A F Sima
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  ABSTRACT: Radiologic and neuropsychologic studies suggest that diabetes mellitus causes structural changes in the brain and adversely effects cognitive development. Experimental animal models of type 1 diabetes mellitus (T1DM) have advanced these findings by demonstrating duration-related neuronal and cognitive deficits in T1DM BB/Wor rats. We studied the expression of receptor for advanced glycation end products (RAGE) and neuronal densities in the brains of two patients who died as the result of clinical brain edema(BE)that developed during the treatment of severe diabetic ketoacidosis (DKA). RAGE was markedly and diffusely expressed in blood vessels, neurons, and the choroid plexus and co-localized with glial fibrillary acidic protein (GFAP) in astrocytes. Significant neuronal loss was seen in the hippocampus and frontal cortex. Astrocytosis was present and white matter was atrophied in both cases when compared to age-matched controls. Our data supports that a neuroinflammatory response occurs in the BE associated with DKA, and that even after a relatively short duration of poorly controlled T1DM, the pathogenesis of primary diabetic encephalopathy can be initiated.
  Brain research 09/2008; 1238:154-62. · 2.46 Impact Factor
• Article: Matrix extracellular phosphoglycoprotein (MEPE) correlates with serum phosphorus prior to and during octreotide treatment and following excisional surgery in hypophosphatemic linear sebaceous nevus syndrome.

  William H Hoffman, Alka Jain, Harold Chen, Neal S Fedarko
  American Journal of Medical Genetics Part A 08/2008; 146A(16):2164-8. · 2.39 Impact Factor
• Article: Neuroinflammatory response of the choroid plexus epithelium in fatal diabetic ketoacidosis.

  William H Hoffman, Manuel F Casanova, Cornelia D Cudrici, Ekaterina Zakranskaia, Roopa Venugopalan, Sukriti Nag, Michael J Oglesbee, Horea Rus
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  ABSTRACT: A systemic inflammatory response (SIR) occurs prior to and during the treatment of severe diabetic ketoacidosis (DKA). IL-1beta, TNF-alpha and C5b-9 are components of SIR and have been speculated to be involved in the clinical brain edema (BE) of DKA. We studied IL-1beta, TNF-alpha, C5b-9, inducible nitric oxide (iNOS), ICAM-1, IL-10 and Hsp70 expression in the brains of two patients who died as the result of clinical BE during the treatment of DKA. IL-1beta was strongly expressed in the choroid plexus epithelium (CPE) and ependyma, and to a lesser extent in the hippocampus, caudate, white matter radiation of the pons, molecular layer of the cerebellum and neurons of the cortical gray matter. TNF-alpha was expressed to a lesser extent than IL-1beta, and only in the CP. C5b-9, previously shown to be deposited on neurons and oligodendrocytes, was found on CPE and ependymal cells. iNOS and ICAM-1 had increased expression in the CPE and ependyma. Hsp70 and IL-10 were also expressed in the CPE of the case with the shorter duration of treatment. Our data demonstrate the presence of a multifaceted neuroinflammatory cytotoxic insult of the CPE, which may play a role in the pathophysiology of the fatal brain edema of DKA.
  Experimental and Molecular Pathology 09/2007; 83(1):65-72. · 2.42 Impact Factor
• Article: Heritability of levels of autoantibodies to thyroid antigens using the method of plotting regression of offspring on midparent (ROMP).

  Ingrid M Outschoorn, William H Hoffman, Noel R Rose, C Lynne Burek
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  ABSTRACT: Only a few methods can be applied in a simple manner to estimate the genetic control of autoimmunity in humans. Here we examined the heritability of autoantibodies to two thyroid antigens; thyroglobulin (Tg) and thyroperoxidase (TPO, formerly known as thyroid microsomal antigen), using methods of regression of offspring on mid-parental values (ROMP). With the data sets available, affected and unaffected siblings were compared by this rapid screening method using results determined by hemagglutination (HA). The presence of both types of autoantibodies showed positive heritability in patients with Graves' thyrotoxicosis (TT), but it was not observed in chronic lymphocytic or Hashimoto's thyroiditis (CLT) patients. Since these assays have been extensively used over the years by most diagnostic and research laboratories, they should provide some insight as to which quantifiable parameters may be usefully accumulated to help select groups of patients and their families for further genetic study. ROMP may also be useful to determine the sequential appearance of different types of antibody in predicting disease onset in other family members, and in distinguishing maternal and paternal effects on imprinting. The method may be extended to study epitope spreading and other measures of disease progression.
  Autoimmunity 08/2007; 40(5):366-71. · 2.47 Impact Factor
• Article: Complement activation in diabetic ketoacidosis brains.

  William H Hoffman, Cornelia D Cudrici, Ekaterina Zafranskaia, Horea Rus
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  ABSTRACT: The metabolic crisis of diabetic ketoacidosis (DKA) and its treatment can result in the life-threatening complication of clinical brain edema. However, there is limited information available regarding either the pathophysiology or histology of this acute complication. It has been reported that DKA and its treatment are associated with a systemic inflammatory response involving the activation of the complement cascade with increases of SC5b-9 serum level. We studied the brains of two patients, both of whom died as the result of DKA-related brain edema, for the presence of C5b-9, C1q and the expression of the CD59. Apoptosis was also evaluated by the TUNEL method. All regions of the brain demonstrated varying degrees of C5b-9 deposits on neurons, oligodendrocytes and blood vessels. C5b-9 was co-localized with C1q, suggesting the activation of classical pathway. No expression of CD59 was found on neurons, oligodendrocytes or blood vessels in DKA brain, but this complement inhibitor was present on these cells in the normal brain. Rarely, C5b-9 was co-localized with apoptotic neurons and OLG. Our data demonstrate that the metabolic crisis of DKA results in a loss of CD59 expression and assembly of C5b-9 on neurons and oligodendrocytes, suggesting that complement activation and C5b-9 may play a role in the pathophysiology of the brain edema of DKA.
  Experimental and Molecular Pathology 07/2006; 80(3):283-8. · 2.42 Impact Factor
• Source

  Available from: Cheryl A Howe

  Article: Tanner staging of secondary sexual characteristics and body composition, blood pressure, and insulin in black girls.

  William H Hoffman, Paule Barbeau, Mark S Litaker, Maribeth H Johnson, Cheryl A Howe, Bernard Gutin
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  ABSTRACT: To assess Tanner staging (breast and pubic hair development) and its relationship to measures of body composition, blood pressure, and fasting insulin and glucose in young black girls. Subjects were 138 black girls, 8 to 12 years of age, recruited from elementary schools in low socioeconomic status neighborhoods. Exclusion criteria included the presence of any acute/chronic medical conditions. Pubertal stages were assessed by one of two pediatricians and analyzed individually, as well as with a composite index (prepubertal, pubertal/premenarcheal, or pubertal/menarcheal). Glucose and insulin were measured after a 12-hour fast. Measures of body composition included height, weight, BMI, waist and hip circumferences, fat mass, fat-free soft tissue, bone mineral density (DXA), and visceral adipose tissue (magnetic resonance imaging). Resting systolic and diastolic blood pressure were measured by Dinamap. With age in the model, breast development explained significant proportions of the variance in height, weight, fat-free soft tissue, bone mineral density, and insulin. Adding pubic hair development or menarche to those models did not significantly increase the proportion of variance that was explained by breast development. Furthermore, using a composite index of pubertal staging explained a smaller proportion of the variance compared with breast development alone. Combined with age, breast development was a better predictor of body composition and fasting insulin than was pubic hair development or a composite index of pubertal staging.
  Obesity research 01/2006; 13(12):2195-201. · 4.95 Impact Factor
• Article: Diabetic ketoacidosis increases extracellular levels of the major inducible 70-kDa heat shock protein.

  Michael J Oglesbee, Anne V Herdman, Gregory G Passmore, William H Hoffman
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  ABSTRACT: Diabetic ketoacidosis (DKA) represents a metabolic stress whose treatment induces a systemic proinflammatory cytokine profile and accentuates life-threatening acute complications. The present study determined whether serum levels of the major inducible 70-kDa heat shock protein (Hsp72), a modulator of cytokine expression, were influenced by DKA and its treatment. Serum levels of Hsp72 and glucose were measured in five adolescents with type 1 diabetes mellitus (T1DM) prior to, during and following correction of severe DKA. Samples from nine relatively euglycemic T1DM patients served as controls. DKA pre-treatment samples showed significant elevation in Hsp72 (40.8 +/- 6.9 ng/ml) relative to euglycemic T1DM controls (33.6 +/- 3.2 ng/ml) (P < 0.05). Treatment resulted in a decline in Hsp72 to control levels within 24 h, with Hsp72 and glucose levels being tightly correlated (r = 0.9258). Extracellular Hsp72 is increased by DKA, paralleling changes in serum glucose levels.
  Clinical Biochemistry 11/2005; 38(10):900-4. · 2.08 Impact Factor
• Article: Complement activation in diabetic ketoacidosis and its treatment.

  Rita S Jerath, C Lynne Burek, William H Hoffman, Gregory G Passmore
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  ABSTRACT: Recent studies support the presence of an inflammatory response during the treatment of diabetic ketoacidosis (DKA). The objectives of this study were to monitor the complement activation products C3a, C4a, Bb, and C5b-9 prior to, during, and after correction of DKA. All patients had increased levels of C3a at 6-8 h and 24 h (P<0.05). C4a was increased in only one patient. Bb showed an upward trend at 6-8 h, and was significantly elevated at 24 h (P<0.05); sC5b-9 was elevated in all patients prior to treatment or in the first 6-8 h of treatment. Results indicate that the alternative pathway may be the primary pathway of activation. These results extend the observation that both DKA and its treatment produce varying degrees of immunologic stress during the time when acute complications are most likely to occur.
  Clinical Immunology 07/2005; 116(1):11-7. · 4.05 Impact Factor
• Article: Elevated fibroblast growth factor-23 in hypophosphatemic linear nevus sebaceous syndrome.

  William H Hoffman, Harald W Jueppner, Barry R Deyoung, M Sue O'dorisio, Keena S Given
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  ABSTRACT: We report on an adolescent who experienced the onset of linear nevus sebaceous syndrome (LNSS) prior to 1 year of age. At 7 years of age he was diagnosed to have hypophosphatemic rickets. He was suboptimally controlled with phosphate and calcitriol treatment and sustained numerous insufficiency fractures ipsilateral to the linear sebaceous nevus. Fibroblast growth factor-23 (FGF-23), the phosphaturic peptide, was elevated in the plasma. Treamtent with the somatostatin agonist, octreotide, and excision of the nevus were followed by normalization of FGF-23 and clinical improvement. The patient also had hyperimmunoglobulinemia E, which responded to octreotide and surgery. We speculate that in some patients with LNSS there may be more than one mediator of hypophosphatemia and that FGF-23 is the mediator of hyperphosphaturia in this and other hypophosphatemic syndromes.
  American Journal of Medical Genetics Part A 05/2005; 134(3):233-6. · 2.39 Impact Factor
• Article: Study of subclinical cerebral edema in diabetic ketoacidosis by magnetic resonance imaging T2 relaxometry and apparent diffusion coefficient maps.

  Ramon E Figueroa, William H Hoffman, Zahir Momin, Ajay Pancholy, Gregory G Passmore, Jerry Allison
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  ABSTRACT: Cerebral edema is the most significant complication in children with diabetic ketoacidosis (DKA). Our goal was to study whether subclinical cerebral edema was preferentially vasogenic or cytotoxic. Magnetic resonance imaging (MRI)--diffusion-weighted imaging (DWI) and T2 relaxometry (T2R)--were obtained in pediatric patients presenting with severe diabetic ketoacidosis (DKA) 6-12 hours after initial DKA treatment and stabilization and 96 hours after correction of DKA. T2 relaxometry was significantly increased during treatment in both white and gray matter, in comparison to the absolute T2R values 96 hours after correction of DKA (p = .034). Classic intracellular cytotoxic edema could not be detected, based on the lack of a statistically significant decrease in ADC values. ADC values were instead elevated, implying a large component of cell membrane water diffusion, correlating with the elevated white and gray matter T2R We discuss the findings in relation to cerebral blood volume, cerebral vasoregulatory dysfunction, and cerebral hyperemia.
  Endocrine Research 02/2005; 31(4):345-55. · 0.97 Impact Factor
• Article: Relations of fatness and fitness to fasting insulin in black and white adolescents.

  Bernard Gutin, Zenong Yin, Matthew C Humphries, William H Hoffman, Barbara Gower, Paule Barbeau
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  ABSTRACT: To determine in black and white youths the degree to which fatness and cardiovascular fitness (CVF) explained independent proportions of the variance in fasting insulin concentrations. Youths 14 to 18 years of age (n = 278) were studied. Insulin was measured after a 12-hour fast. Percent body fat (%BF) was measured with dual-energy x-ray absorptiometry. CVF was determined with a multistage treadmill test. Girls had higher %BF and lower CVF than boys. Whites were higher in CVF than blacks. There was a race by sex interaction for fasting insulin concentration, such that black girls had the highest and white girls had the lowest concentrations. When %BF and CVF was controlled statistically, this interaction was no longer significant. Multiple regression models that controlled for race, sex, and their interaction showed that (1) both higher %BF and lower CVF were significantly associated with higher insulin concentrations; (2) there were significant interactions with sex, such that the deleterious effects of low CVF and high %BF were greater in boys than in girls; (3) there was a significant CVF-%BF interaction, such that youths who were both fit and lean had especially low insulin concentrations; and (4) sex-specific regressions showed that both %BF and CVF explained significant independent proportion of the insulin variance for the boys but that only %BF did so for the girls. Interventions to prevent hyperinsulinemia in youths should be designed both to minimize fatness and maximize CVF.
  Journal of Pediatrics 01/2005; 145(6):737-43. · 4.11 Impact Factor
• Article: Cerebral vasoreactivity in children and adolescents with type 1 diabetes mellitus.

  William H Hoffman, Mark S Litaker, Ryszard M Pluta, Mark L Camens
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  ABSTRACT: It is well established in clinical and experimental settings that diabetes mellitus, especially if long lasting, impairs autoregulation of cerebral blood flow (CBF). However, the onset and the course of development of this dysfunction remain unknown. We hypothesized that assessment of autoregulatory functions of cerebral arteries in children with relatively short duration of type 1 diabetes mellitus may provide an insight into the pathophysiology of the development of impaired autoregulation of CBF. Such a dysfunction of vasodilation of cerebral arteries can be assessed by transcranial Doppler. Therefore, to examine whether and when autoregulation of CBF becomes affected by diabetes, we used transcranial Doppler and a pCO2 challenge in 17 males between the ages of 12-20 years with type 1 diabetes mellitus of 0.2-16 years duration and with varying degrees of glucose control. The results were compared with age-matched, healthy, nondiabetic controls. The CO2 challenge increased cerebral blood-flow velocities and decreased the pulsatility index. These changes were not influenced by the presence or duration of diabetes, insulin dose, or degree of diabetic control.
  Endocrine Research 09/2004; 30(3):315-25. · 0.97 Impact Factor
• Article: Cytokine response to diabetic ketoacidosis and its treatment.

  William H Hoffman, C Lynne Burek, Jennifer L Waller, Lyle E Fisher, Mahmood Khichi, Larry B Mellick
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  ABSTRACT: The objectives of this study were to monitor plasma cytokines as markers of cellular activation and as potential markers for the progression of the acute complications of diabetic ketoacidosis (DKA). Blood samples were obtained prior to, during and after treatment of severe DKA (pH < 7.2) in six children and adolescents. Plasma IL-10, IL-1beta, TNF-alpha, IL-6, IL-8 and IL-2 cytokine levels were assayed by ELISA at each of the time points. Prior to treatment, elevations of multiple cytokines were found, the highest being IL-10. Treatment of DKA resulted in a significant decrease of IL-10 at 6-8 h (p = 0.0062), and further increases in the inflammatory cytokines at 6-8 h and/or 24 h vs 120 h (baseline): IL-1beta (p =.0048); TNF-alpha (p =.0188) and IL-8 (p =.0048). This study strengthens the hypothesis that the metabolic crisis of DKA, and its treatment, have differential effects on cellular activation and cytokine release. The time frame for the increase in inflammatory cytokines correlates with the reported progression of subclinical brain edema, interstitial pulmonary edema and the development of clinical brain edema.
  Clinical Immunology 09/2003; 108(3):175-81. · 4.05 Impact Factor