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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.

Proinflammatory Cytokines, Markers of Cardiovascular Risks, Oxidative Stress, and Lipid Peroxidation in Patients With Hyperglycemic Crises Frankie B. Stentz , Guillermo E. Umpierrez , Ruben Cuervo and Abbas E. Kitabchi From the Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, University of Tennessee Health Science Center, Memphis, Tennessee Address correspondence and reprint requests to Frankie B. Stentz, PhD, Assistant Professor, Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, University of Tennessee Health Science Center, 951 Court Ave., Room 340M, Memphis, TN 38163. E-mail: fstentz{at}utmem.edu Abstract 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-α, interleukin [IL]-6, IL1-β, 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. AGE, advanced glycation end product CRP, C-reactive protein DCF, dichlorofluorescein DKA, diabetic ketoacidosis FFA, free fatty acid GH, growth hormone IL, interleukin NKH, nonketotic hyperglycemia PAI-1, plasminogen activator inhibitor-1 ROS, reactive oxygen species TBA, thiobarbituric acid TNF-α, tumor necrosis factor-α UTHSC, University of Tennessee Health Science Center Footnotes G.E.U. is currently affiliated with the Division of Endocrinology, Department of Medicine, Emory University School of Medicine, Atlanta, Georgia. Accepted May 12, 2004. Received February 11, 2004. DIABETES

When caloric intake exceeds caloric expenditure, the positive caloric balance and storage of energy in adipose tissue often causes adipocyte hypertrophy and visceral adipose tissue accumulation. These pathogenic anatomic abnormalities may incite metabolic and immune responses that promote Type 2 diabetes mellitus, hypertension and dyslipidemia. These are the most common metabolic diseases managed by clinicians and are all major cardiovascular disease risk factors. 'Disease' is traditionally characterized as anatomic and physiologic abnormalities of an organ or organ system that contributes to adverse health consequences. Using this definition, pathogenic adipose tissue is no less a disease than diseases of other body organs. This review describes the consequences of pathogenic fat cell hypertrophy and visceral adiposity, emphasizing the mechanistic contributions of genetic and environmental predispositions, adipogenesis, fat storage, free fatty acid metabolism, adipocyte factors and inflammation. Appreciating the full pathogenic potential of adipose tissue requires an integrated perspective, recognizing the importance of 'cross-talk' and interactions between adipose tissue and other body systems. Thus, the adverse metabolic consequences that accompany fat cell hypertrophy and visceral adiposity are best viewed as a pathologic partnership between the pathogenic potential adipose tissue and the inherited or acquired limitations and/or impairments of other body organs. A better understanding of the physiological and pathological interplay of pathogenic adipose tissue with other organs and organ systems may assist in developing better strategies in treating metabolic disease and reducing cardiovascular disease risk.

OBJECTIVE:--The purpose of this study was to assess the efficacy of an insulin priming dose with a continuous insulin infusion versus two continuous infusions without a priming dose. RESEARCH DESIGN AND METHODS--This prospective randomized protocol used three insulin therapy methods: 1) load group using a priming dose of 0.07 units of regular insulin per kg body weight followed by a dose of 0.07 unit · kg⁻¹ · h⁻¹ i.v. in 12 patients with diabetic ketoacidosis (DKA); 2) no load group using an infusion of regular insulin of 0.07 unit · kg body weight⁻¹ · h⁻¹ without a loading dose in 12 patients with DKA, and 3) twice no load group using an infusion of regular insulin of 0.14 · kg⁻¹ · h⁻¹ without a loading dose in 13 patients with DKA. Outcome was based on the effects of insulin therapy on biochemical and hormonal changes during treatment and recovery of DKA. RESULTS:--The load group reached a peak in free insulin value (460 μU/ml) within 5 min and plateaued at 88 μU/ml in 60 min. The twice no load group reached a peak (200 μU/ml) at 45 min. The no load group reached a peak (60 μU/ml) in 60-120 min. Five patients in the no load group required supplemental insulin doses to decrease initial glucose levels by 10%; patients in the twice no load and load groups did not. Except for these differences, times to reach glucose [less-than or equal to]250 mg/dl, pH greater-than-or-equal7.3, and HCO₃⁻ greater-than-or-equal15 mEq/l did not differ significantly among the three groups. CONCLUSIONS:--A priming dose in low-dose insulin therapy in patients with DKA is unnecessary if an adequate dose of regular insulin of 0.14 unit · kg body weight⁻¹ · h⁻¹ (about 10 units/h in a 70-kg patient) is given.

[...] the long-term impact of uncontrolled diabetes and its economic burden could be more significant because it can contribute to various complications. Because most cases occur in patients with known diabetes and with previous DKA, resources need to be redirected toward prevention by funding better access to care and educational programs tailored to individual needs, including ethnic and personal health care beliefs.

Treatment of Diabetic Ketoacidosis With Subcutaneous Insulin Aspart Guillermo E. Umpierrez , MD, FACP, FACE 1 , Ruben Cuervo , MD 2 , Ana Karabell , MD 2 , Kashif Latif , MD 2 , Amado X. Freire , MD, MPH 2 and Abbas E. Kitabchi , PHD, MD 2 1 Department of Medicine, Emory University School of Medicine, Atlanta, Georgia 2 University of Tennessee Health Sciences Center, Memphis, Tennessee Address correspondence and reprint requests to Guillermo Umpierrez, MD, FACP, FACE, Associate Professor of Medicine, Emory University School of Medicine, 69 Jesse Hill Jr. Dr., Atlanta, GA 30303. E-mail: geumpie{at}emory.edu Abstract 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. DKA, diabetic ketoacidosis ICU, intensive care unit IM, intramuscular IV, intravenous SC, subcutaneous SC-1h, subcutaneous aspart insulin every hour SC-2h, subcutaneous aspart insulin every 2 h Footnotes A table elsewhere in this issue shows conventional and Système International (SI) units and conversion factors for many substances. Accepted May 9, 2004. Received February 3, 2004. DIABETES CARE

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. Purpose: 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 (≥ 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.

This study examined whether pioglitazone can reduce the risk of type 2 diabetes mellitus in adults with impaired glucose tolerance. As compared with placebo, pioglitazone reduced the conversion of IGT to diabetes by 72% but was associated with significant weight gain and edema. Type 2 diabetes mellitus affects 21 million Americans, 1 and its prevalence is increasing. 2 Microvascular and macrovascular complications are common in type 2 diabetes mellitus and are related to both the severity and the duration of hyperglycemia. 3 The natural history of type 2 diabetes mellitus has been well defined, 4 starting with a genetic predisposition and progression from normal glucose tolerance with insulin resistance to impaired glucose tolerance and eventually type 2 diabetes mellitus with the superimposition of beta-cell failure. Because hyperglycemia plays a central role in the microvascular and macrovascular complications of diabetes, 3 , 5 , 6 it is possible that interventions that . . .

The combination of insulin deficiency and increased counterregulatory hormones in DKA also leads to the release of free fatty acids into the circulation from adipose tissue (lipolysis) and to unrestrained hepatic fatty acid oxidation to ketone bodies β-hydroxybutyrate ([β-OHB] and acetoacetate), with resulting ketonemia and metabolic acidosis (18). A recent study (19) has shown elevated levels of proinflammatory cytokines and lipid peroxidation markers, as well as cardiovascular risk factors (plasminogen activator inhibitor-1) and C-reactive protein, which return to normal levels with insulin therapy and remission of hyperglycemia.

OBJECTIVE: Rates of severe obesity (BMI ≥40 kg/m2) are on the rise, and effective treatment options are needed. We examined the effect of an intensive lifestyle intervention (ILI) on weight loss, cardiovascular disease (CVD) risk, and program adherence in participants with type 2 diabetes who were severely obese compared with overweight (BMI 25 to <30 kg/m2), class I (BMI 30 to <35 kg/m2), and class II (BMI 35 to <40 kg/m2) obese participants. RESEARCH DESIGN AND METHODS: Participants in the Action for Health in Diabetes (Look AHEAD) trial were randomly assigned to ILI or diabetes support and education (DSE). DSE participants received a less intense educational intervention, whereas ILI participants received an intensive behavioral treatment to increase physical activity (PA) and reduce caloric intake. This article focuses on the 2,503 ILI participants (age 58.6 ± 6.8 years). RESULTS: At 1 year, severely obese participants in the ILI group lost –9.04 ± 7.6% of initial body weight, which was significantly greater (P < 0.05) than ILI participants who were overweight (–7.43 ± 5.6%) and comparable to class I (–8.72 ± 6.4%) and class II obese (–8.64 ± 7.4%) participants. All BMI groups had comparable improvements in fitness, PA, LDL cholesterol, triglycerides, blood pressure, fasting glucose, and HbA1c at 1 year. ILI treatment session attendance was excellent and did not differ among weight categories (severe obese 80% vs. others 83%; P = 0.43). CONCLUSIONS: Severely obese participants in the ILI group had similar adherence, percentage of weight loss, and improvement in CVD risk compared with less obese participants. Behavioral weight loss programs should be considered an effective option for this population.