A-beta-subtype of ketosis-prone diabetes is not predominantly a monogenic diabetic syndrome.

OBJECTIVE: Ketosis-prone diabetes (KPD) is an emerging syndrome that encompasses several distinct phenotypic subgroups that share a predisposition to diabetic ketoacidosis. We investigated whether the A-beta- subgroup of KPD, characterized by complete insulin dependence, absent beta-cell functional reserve, lack of islet cell autoantibodies, and strong family history of type 2 diabetes, represents a monogenic form of diabetes. RESEARCH DESIGN AND METHODS: Over 8 years, 37 patients with an A-beta- phenotype were identified in our longitudinally followed cohort of KPD patients. Seven genes, including hepatocyte nuclear factor 4A (HNF4A), glucokinase (GCK), HNF1A, pancreas duodenal homeobox 1 (PDX1), HNF1B, neurogenic differentiation 1 (NEUROD1), and PAX4, were directly sequenced in all patients. Selected gene regions were also sequenced in healthy, unrelated ethnically matched control subjects, consisting of 84 African American, 96 Caucasian, and 95 Hispanic subjects. RESULTS: The majority (70%) of the A-beta- KPD patients had no significant causal polymorphisms in either the proximal promoter or coding regions of the seven genes. The combination of six potentially significant low-frequency, heterozygous sequence variants in HNF-1 alpha (A174V or G574S), PDX1 (putative 5'-untranslated region CCAAT box, P33T, or P239Q), or PAX4 (R133W) were found in 27% (10/37) of patients, with one additional patient revealing two variants, PDX1 P33T and PAX4 R133W. The A174V variant has not been previously reported. CONCLUSIONS: Despite its well-circumscribed, robust, and distinctive phenotype of severe, nonautoimmune-mediated beta-cell dysfunction, A-beta- KPD is most likely not a predominantly monogenic diabetic syndrome. Several A-beta- KPD patients have low-frequency variants in HNF1A, PDX1, or PAX4 genes, which may be of functional significance in their pathophysiology.

Association of amino-terminal-specific antiglutamate decarboxylase (GAD65) autoantibodies with beta-cell functional reserve and a milder clinical phenotype in patients with GAD65 antibodies and ketosis-prone diabetes mellitus.

CONTEXT: We previously characterized patients presenting with diabetic ketoacidosis prospectively into four subgroups of ketosis-prone diabetes mellitus (KPDM), based on the presence or absence of beta-cell autoimmunity (A+ or A-) and beta-cell functional reserve (B+ or B-). The A+B- KPDM subgroup comprises patients with classic, autoimmune type 1 diabetes, whereas the A+B+ KPDM subgroup has only partial beta-cell loss and a distinct clinical phenotype. OBJECTIVE: We hypothesized that epitope specificity of autoantibodies directed against the 65-kDa isoform of glutamate decarboxylase (GAD65) reflects differences in beta-cell destruction. DESIGN: Sera of sequential GAD65Ab-positive KPDM patients admitted for diabetic ketoacidosis (n = 36) were analyzed for their epitope recognition using five GAD65-specific recombinant Fab and their ability to inhibit GAD65 enzymatic activity. All patients were followed longitudinally to assess beta-cell functional reserve and insulin dependence. RESULTS: Binding to an amino-terminal epitope defined by monoclonal antibody DPD correlated positively with fasting serum C-peptide levels at baseline (P = 0.0008) and after 1 yr (P = 0.007). Binding to the DPD-defined epitope also correlated positively with area under the curve for C-peptide after glucagon stimulation (P = 0.007) and with homeostasis model assessment percent B at 1 yr (P = 0.03). Binding to the DPD-defined epitope was significantly stronger in A+B+ than in A+B- patients (P = 0.001). Sera of 16 patients (44%) significantly inhibited GAD65 enzymatic activity, but this did not correlate with beta-cell function. CONCLUSION: DPD-defined epitope specificity is correlated directly with preserved beta-cell functional reserve in GAD65Ab-positive patients and is associated with the milder clinical phenotype of A+B+ KPDM.

Accuracy and predictive value of classification schemes for ketosis-prone diabetes.

OBJECTIVE: Ketosis-prone diabetes (KPD) is an emerging, heterogeneous syndrome. A sound classification scheme for KPD is essential to guide clinical practice and pathophysiologic studies. Four schemes have been used and are based on immunologic criteria, immunologic criteria and insulin requirement, BMI, and immunologic criteria and beta-cell function (Abeta classification). The aim of the present study is to compare the four schemes for accuracy and predictive value in determining whether KPD patients have absent or preserved beta-cell function, which is a strong determinant of long-term insulin dependence and clinical phenotype. RESEARCH DESIGN AND METHODS: Consecutive patients (n = 294) presenting with diabetic ketoacidosis and followed for 12-60 months were classified according to all four schemes. They were evaluated longitudinally for beta-cell autoimmunity, clinical and biochemical features, beta-cell function, and insulin dependence. beta-Cell function was defined by peak plasma C-peptide response to glucagon >or=1.5 ng/ml. The accuracy of each scheme to predict absent or preserved beta-cell function after 12 months of follow-up was tested using multiple statistical analyses. RESULTS: The "Abeta" classification scheme was the most accurate overall, with a sensitivity and specificity of 99.4 and 95.9%, respectively, positive and negative likelihood ratios of 24.55 and 0.01, respectively, and an area under the receiver operator characteristic curve of 0.972. CONCLUSIONS: The Abeta scheme has the highest accuracy and predictive value in classifying KPD patients with regard to clinical outcomes and pathophysiologic subtypes.

Effect of metabolic syndrome on heart attack and mortality in Mexican-American elderly persons: findings of 7-year follow-up from the Hispanic established population for the epidemiological study of the elderly.

PURPOSE: We aim to examine the effect of Metabolic syndrome (MetS) on heart attack and overall mortality in Mexican-American elderly persons over 7-year follow-up. METHODS: We studied 3050 Mexican Americans aged 65 or older from the Hispanic Established Population for the Epidemiological Study of the Elderly conducted in five Southwestern states of the United States. Participants were categorized into two groups: those with or without MetS. A total of 333 (11%) respondents at baseline had met the criteria of MetS (at least three of five characteristics--hyperinsulinemia or fasting plasma glucose > or =110 mg/dl, abdominal obesity, and hypertension--as defined by the World Health Organization). RESULTS: Of 333 participants with MetS, the mean age was 71.1 years and 68% were females (compared with 73.2 years and 56% in those without MetS). Eighty percent of participants with MetS rated their health as fair or poor, compared to 55% of those participants without MetS. Fifty-four percent and 65% of patients with MetS had arthritis and at least one impairment in instrumental activities of daily living (IADL), compared to 39% and 55% of those participants without MetS. MetS was significantly associated with increased incidence of heart attack (odds ratio: 2.75, 95% confidence interval: 1.67-4.54) and was a significant predictor for overall mortality (hazard ratio: 1.46, 95% confidence interval: 1.16-1.84) over a 7-year period after adjusting for other demographic and clinical variables. CONCLUSIONS: Among Mexican-American elderly participants, those with MetS had poorer self-rated health. MetS was significantly associated with increased incidence of heart attack and higher mortality over a 7-year period.

Characteristics of ketosis-prone diabetes in a multiethnic indigent community.

OBJECTIVE: To compare demographic and clinical characteristics among 3 ethnic groups of indigent patients exhibiting diabetic ketoacidosis (DKA), in Houston, Texas. METHODS: Over a span of 3.5 years, 321 patients were interviewed at the time of admission for DKA. Demographic, clinical, and biochemical data and measures of pancreatic beta-cell function were obtained at baseline and during follow up. Pearson's chi-square test, or one-way ANOVA, were used, as appropriate, to evaluate group differences. RESULTS: Of the 321 subjects, 44% were African-American, 40% were Hispanic, and 16% were Caucasian. A significantly higher proportion of Hispanics had preserved beta-cell function, compared to African Americans and Caucasians (51% vs 32% and 32%, respectively; P = .002). This difference, present at the time of the admission, was maintained through follow up. In a multivariate analysis, Hispanic ethnicity (OR 3.61; 95% CI 1.48-9.29) was a significant predictor of preserved beta-cell function. In addition, Hispanics were less likely to develop DKA as a result of treatment non-compliance, and more likely to have DKA precipitated by an acute illness. CONCLUSIONS: Our findings indicated that ethnicity is associated with significant differences in the pathophysiologic and clinical characteristics of indigent, ketosis-prone patients. Hispanic ethnicity was found to be associated with greater beta-cell functional reserve, and less dependence on chronic insulin therapy.

Improved outcomes in indigent patients with ketosis-prone diabetes: effect of a dedicated diabetes treatment unit.

OBJECTIVE: To investigate whether a specialized intervention program could improve diabetes-related health outcomes in indigent patients with type 1 diabetes who were prone to occurrence of diabetic ketoacidosis (DKA). METHODS: Patients with type 1 diabetes mellitus admitted because of DKA during a 24-month period were invited to receive outpatient care in a diabetes treatment unit (DTU). We compared DKA-related readmission rates, change in hemoglobin A1c (HbA1c) values, and diabetes-related medical costs in patients who participated in the DTU program (+DTU) and in those who did not (-DTU). RESULTS: During the study period, 115 patients underwent assessment. Of this overall group, 57 patients (49.6%) consented to participate in the DTU program, and 58 (50.4%) did not. After the follow-up period (median duration, 657 days), the following significant improvements were observed in the +DTU group (in comparison with the -DTU group): lower frequency of readmission for DKA (16% versus 43%; P = 0.001), lower number of readmissions for DKA per patient (0.22 +/- 0.6 versus 1.17 +/- 2.2 [mean +/- standard deviation]; P = 0.003), lower HbA1c level (10.4 +/- 2.3% versus 13.5 +/- 2.3%; P<0.0001), and lower cost of diabetes-related medical care (3,427.20 US dollars +/- 6,275.60 versus 10,119.10 US dollars +/- 19,688.10; P = 0.01). Multivariate analysis revealed that participation in the DTU program was the only factor associated with a significantly decreased risk of DKA-related readmission. CONCLUSION: Low-cost intervention by a dedicated outpatient DTU resulted in significant decreases in DKA-associated readmissions, in HbA1c values, and in costs of diabetes care in a multiethnic, indigent, ketosis-prone patient population.

Economic impact of diabetic ketoacidosis in a multiethnic indigent population: analysis of costs based on the precipitating cause.

OBJECTIVE: Diabetic ketoacidosis (DKA) is a common complication of diabetes. We analyzed the inpatient costs of treating DKA in a multiethnic, indigent population in Houston, Texas. RESEARCH DESIGN AND METHODS: We measured the cost of resources utilized for all patients admitted to our hospital with DKA from 1 January to 31 December 1998. We also analyzed their medical records to determine the factors that precipitated the episode of DKA and then grouped them into three categories: acute illnesses, noncompliance with diabetes treatment, and new-onset diabetes. The data were analyzed by one-way ANOVA. The Tukey-Kramer procedure was used for post hoc multiple comparisons. RESULTS: There were 167 admissions for DKA. The mean age was 40 +/- 13 years. The ethnic distribution was 49% African American, 32% Hispanic American, and 18% white. The total inhospital cost of treating DKA was $1,816,255. The mean cost per hospitalization was $10, 876 +/- 11,024. The frequency distribution by category of DKA-precipitating factor was 18% acute illness, 59% noncompliance, and 23% new onset. There were differences in mean cost of DKA associated with the three categories: $20,864 +/- 17,910 for acute illness, $11,863 +/- 8,701 for new onset, and $7,470 +/- 6,300 for noncompliance (P < 0.0001). The total cost for each category was $671,375 for acute illness, $694,082 for noncompliance, and $450,798 for new onset. CONCLUSIONS: DKA is an expensive complication among indigent, multiethnic diabetic patients. Although the mean cost per admission was lowest for DKA precipitated by noncompliance, this causal category was responsible in sum for the greatest portion of the economic burden.