Diabetes Care
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α-Hydroxybutyric Acid Is a Selective Metabolite Biomarker of Impaired Glucose Tolerance
OBJECTIVE
Plasma metabolites that distinguish isolated impaired glucose tolerance (iIGT) from isolated impaired fasting glucose (iIFG) may be useful biomarkers to predict IGT, a high-risk state for the development of type 2 diabetes.
RESEARCH DESIGN AND METHODS
Targeted metabolomics with 23 metabolites previously associated with dysglycemia was performed with fasting plasma samples from subjects without diabetes at time 0 of an oral glucose tolerance test (OGTT) in two observational cohorts: RISC (Relationship Between Insulin Sensitivity and Cardiovascular Disease) and DMVhi (Diabetes Mellitus and Vascular Health Initiative). Odds ratios (ORs) for a one-SD change in the metabolite level were calculated using multiple logistic regression models controlling for age, sex, and BMI to test for associations with iIGT or iIFG versus normal. Selective biomarkers of iIGT were further validated in the Botnia study.
RESULTS
α-Hydroxybutyric acid (α-HB) was most strongly associated with iIGT in RISC (OR 2.54 [95% CI 1.86–3.48], P value 5E-9) and DMVhi (2.75 [1.81–4.19], 4E-5) while having no significant association with iIFG. In Botnia, α-HB was selectively associated with iIGT (2.03 [1.65–2.49], 3E-11) and had no significant association with iIFG. Linoleoyl-glycerophosphocholine (L-GPC) and oleic acid were also found to be selective biomarkers of iIGT. In multivariate IGT prediction models, addition of α-HB, L-GPC, and oleic acid to age, sex, BMI, and fasting glucose significantly improved area under the curve in all three cohorts.
CONCLUSIONS
α-HB, L-GPC, and oleic acid were shown to be selective biomarkers of iIGT, independent of age, sex, BMI, and fasting glucose, in 4,053 subjects without diabetes from three European cohorts. These biomarkers can be used in predictive models to identify subjects with IGT without performing an OGTT.
Diabetes Care - Tập 39 Số 6 - Trang 988-995 - 2016
Clinical, Autoimmune, and Genetic Characteristics of Adult-Onset Diabetic Patients With GAD Autoantibodies in Japan (Ehime Study) OBJECTIVE—To characterize the clinical, autoimmune, and genetic features in Japanese adult-onset diabetic patients with GAD autoantibodies.
RESEARCH DESIGN AND METHODS—GAD autoantibodies (GADab) were screened in 4,980 diabetic patients with age of onset >20 years in the hospital-based Ehime Study, and the GADab-positive (GADab+) patients were then divided into two groups according to their insulin secretion and compared with nondiabetic subjects. The insulin-deficient state was defined as <0.33 nmol/l serum C-peptide (CPR) at 2 h postprandial or 6 min after a 1-mg glucagon load.
RESULTS—GADab was detected in 188 (3.8%) of the 4,980 diabetic patients tested. Of these patients, 72 (38.3%) were classified as insulin deficient, 97 (51.6%) were classified as non–insulin deficient, and 19 (10.1%) were unclassified. The GADab+ insulin-deficient patients were characterized by young age at onset of diabetes, low BMI, low maximum BMI, and high levels of HbA1c. The prevalence of IA-2 autoantibodies and thyrogastric autoantibodies in the GADab+ insulin-deficient patients were significantly higher than those in the GADab+ non–insulin-deficient patients (P < 0.05). GADab+ patients with insulin deficiency had increased frequencies of HLA DRB1*0405-DQB1*0401, *0802-*0302, and *0901-*0303 haplotypes, whereas the frequency of only HLA DRB1*0405-DQB1*0401 was increased in the case of GADab+ non–insulin-deficient patients. Of note is the fact that the GADab+ non–insulin-deficient group did not differ from healthy control subjects with respect to type 1 diabetes protective haplotype HLA DRB1*1502-DQB1*0601. A total of 13% of the GADab+ patients with diabetes had genotypes comprising the DRB1*1501-DQB1*0602 or *1502-*0601 and were characterized by old age at onset of diabetes, high BMI, resistance to the insulin-deficient state, low titer of GADab, and low frequency of other organ-specific autoantibodies.
CONCLUSIONS—We conclude that GADab+ non–insulin-deficient patients differ from GADab+ patients with insulin deficiency with respect to clinical characteristics, humoral autoimmunity to other organ-specific autoantibodies, as well as HLA class II genes.
Diabetes Care - Tập 25 Số 6 - Trang 995-1001 - 2002
Distinct Genetic and Immunological Features in Patients With Onset of IDDM Before and After Age 40
OBJECTIVE
Young age at onset is a relevant parameter associated with a rapid progression of IDDM. Our major aim was to define differences between IDDM patients with age at diagnosis > 40 years and adult IDDM with onset at a younger age.
RESEARCH DESIGN AND METHODS
The correlation between islet-related antibodies (islet cell antibodies [ICAs] and antibodies [Abs] to GAD and the tyrosine phosphatase IA2), T-cell responses to GAD peptides and HLA class II isotypes was investigated in 23 IDDM patients 12–38 years of age at onset (group 1), 24 patients with IDDM > 40 years of age at onset (group 2), and 12 healthy control subjects. ICAs were measured by indirect immunofluorescence, and GAD-Ab and IA2-Ab were measured by immunoprecipitation tests. T-cell responses against GAD peptides, which had been identified as typical for IDDM, were tested by 5-day proliferation assays. HLA class II alleles were typed by polymerase chain reaction.
RESULTS
ICAs and GAD-Abs were more prevalent in IDDM patients than in control subjects (P < 0.001), but only IDDM group 1 had IA2-Abs (P < 0.001 compared with IDDM group 2 and control subjects). Moreover, antibody combinations differed between IDDM patients of groups 1 and 2. T-cell responses to GAD peptides were seen in 67% of IDDM group 1 and in 71% of IDDM group 2 (P < 0.02 compared with control subjects). IDDM patients of group 1 were more frequently DR4+/DQ8+ and less frequently DR2+/DQ0602+ compared with IDDM patients of group 2 (P < 0.05).
CONCLUSIONS
Our data provide strong evidence for humoral and cellular autoimmunity in adult IDDM patients with onset both before and after 40 years of age. However, late-onset differs from young-onset IDDM with respect to Ab profiles, especially a lack of IA2-Ab, and HLA class II types. These findings have consequences for the diagnostic strategy for identifying slow-onset IDDM in individuals after 40 years of age.
Diabetes Care - Tập 20 Số 4 - Trang 524-529 - 1997
Immunogenetic and Clinical Characterization of Slowly Progressive IDDM
OBJECTIVE
To examine the clinical and immunogenetic heterogeneity of IDDM.
RESEARCH DESIGN AND METHODS
We divided 207 IDDM patients into groups based on the interval from clinical onset to initiation of insulin therapy: group A (<3 mo, acute clinical-onset group, n = 134), group B (3–12 mo, intermediate group, n = 31), and group C (>13 mo, slowly progressive group, n = 42). Immunogenetic and clinical markers were compared between group A and group C.
RESULTS
The mode age of onset was higher in group C (52 yr) than group A (10 yr). Group C had a higher prevalence of islet cell antibodies (42.9%, 18 of 42) than group A (25.4%, 34 of 134, P = 0.05). Serum C-peptide immunoreactivity assayed by radioimmunoassay in response to a 100-g oral glucose tolerance test was significantly higher in group C uhan in group A. Group C patients were also more likely to have a family history of NIDDM (26.1%, 11 of 42) among their first-degree relatives than group A patients (11.2%, 15 of 134, P = 0.039). The prevalences of family history of IDDM and endocrine autoimmune diseases were not different between groups C and A. The frequency of complications of endocrine autoimmune disease was not different between group A (6.7%, 9 of 134) and group C (2.3%, 1 of 42). Significant associations with two class I major histocompatibility complex antigens (HLA-A24 and -Bw54) and one class II antigen (HLA-DR4) were observed in group A. Group A patients were assocciated with three diabetogenic HLA-DQ haplotypes including DQA1*0301-DQB1*0401, DQAl*0301-DQBl*0302, and DQA1 *0301-DQB 1*0303. In contrast, group C lacked the association with class I antigens, although HLA-DR4 and HLA-DQA1* 0301-DQB 1*0401 were more common in this group than in control subjects.
CONCLUSIONS
These results indicate that the clinical subtype with slowly progressive course (slowly progressive IDDM) has distinct findings including late-age onset, high prevalence of islet cell antibodies, preserved β-cell function, and high family history of NIDDM. An additive effect of class I and class II major histocompatibility complex antigens is suggested as an explanation for the acute clinical manifestations and more severe β-cell destruction in group A patients.
Diabetes Care - Tập 16 Số 5 - Trang 780-788 - 1993
Autoantibody Against ICA512 Did Not Improve Test Sensitivity for Slowly Progressive IDDM in Adults
Diabetes Care - Tập 20 Số 4 - Trang 679-680 - 1997
Predictive Value of Autoantibodies to IA-2 for Insulin Requirements in Japanese Subjects With Type 1 Diabetes
Diabetes Care - Tập 26 Số 11 - Trang 3188-3189 - 2003
GAD Antibodies in NIDDM: Ten-year follow-up from the diagnosis
OBJECTIVE
To study the frequency of antibodies to glutamic acid decarboxylase (GAD) and islet cell antibodies (ICAs) and their predictive value with respect to the development of insulin deficiency in 133 newly diagnosed middle-aged patients with non-insulin-dependent diabetes mellitus (NIDDM) and in 126 control subjects and to study the persistence of GAD antibodies in diabetic patients during the follow-up.
RESEARCH DESIGN AND METHODS
The study participants consisted of a well-characterized group of 133 middle-aged newly diagnosed patients with NIDDM and 126 control subjects. The follow-up examinations were performed 5 and 10 years after the baseline. The development of absolute and relative insulin deficiency was based on a stimulated C-peptide level that was undetectable or < 0.70 nmol/l, respectively. GAD antibodies were measured retrospectively from stored samples.
RESULTS
The overall prevalence of GAD antibody and ICA positivity at the time of diagnosis was 9.0 and 3.8% in diabetic patients and 1.6 and 0% in the control population, respectively. During the 10-year follow-up, 3 (2.3%) and 10 (7.5%) of the diabetic patients developed absolute and relative insulin deficiency, respectively. Of these, two (67%) and six (60%) had been GAD antibody-positive at the time of diagnosis. The sensitivity and specificity of the GAD antibody to predict absolute or relative insulin deficiency were 67 vs. 94% and 60 vs. 95%, while corresponding figures for ICA were 33 vs. 97% and 20 vs. 98%, respectively. The negative predictive value of GAD antibody testing was higher than positive predictive value (97 vs. 50%). During the follow-up, low-grade GAD antibody positivity showed an evanescent nature, whereas the high levels were quite persistent.
CONCLUSIONS
In an unselected population of newly diagnosed NIDDM patients, the prevalence of latent autoimmune diabetes in adults was <10%. While GAD antibody and ICA measured at the time of diagnosis of NIDDM are equally specific predictors of subsequent insulin dependency, the GAD antibody may have a higher sensitivity. Therefore, measurements of GAD antibody may aid the clinician in the choice of treatment of these patients.
Diabetes Care - Tập 18 Số 12 - Trang 1557-1565 - 1995
Ethnicity and Sex Affect Diabetes Incidence and Outcomes
OBJECTIVE
Diabetes guidelines recommend aggressive screening for type 2 diabetes in Asian patients because they are considered to have a higher risk of developing diabetes and potentially worse prognosis. We determined incidence of diabetes and risk of death or macrovascular complications by sex among major Asian subgroups, South Asian and Chinese, and white patients with newly diagnosed diabetes.
RESEARCH DESIGN AND METHODS
Using population-based administrative data from British Columbia and Alberta, Canada (1997–1998 to 2006–2007), we identified patients with newly diagnosed diabetes aged ≥35 years and followed them for up to 10 years for death, acute myocardial infarction, stroke, or hospitalization for heart failure. Ethnicity was determined using validated surname algorithms.
RESULTS
There were 15,066 South Asian, 17,754 Chinese, and 244,017 white patients with newly diagnosed diabetes. Chinese women and men had the lowest incidence of diabetes relative to that of white or South Asian patients, who had the highest incidence. Mortality in those with newly diagnosed diabetes was lower in South Asian (hazard ratio 0.69 [95% CI 0.62–0.76], P < 0.001) and Chinese patients (0.69 [0.63–0.74], P < 0.001) then in white patients. Risk of acute myocardial infarction, stroke, or heart failure was similar or lower in the ethnic groups relative to that of white patients and varied by sex.
CONCLUSIONS
The incidence of diagnosed diabetes varies significantly among ethnic groups. Mortality was substantially lower in South Asian and Chinese patients with newly diagnosed diabetes than in white patients.
Diabetes Care - Tập 34 Số 1 - Trang 96-101 - 2011
International Expert Committee Report on the Role of the A1C Assay in the Diagnosis of Diabetes
Diabetes Care - Tập 32 Số 7 - Trang 1327-1334 - 2009
Risk of Lactic Acidosis or Elevated Lactate Concentrations in Metformin Users With Renal Impairment: A Population-Based Cohort Study
OBJECTIVE
The objective of this study was to determine whether treatment with metformin in patients with renal impairment is associated with a higher risk of lactic acidosis or elevated lactate concentrations compared with users of a noninsulin antidiabetic drug (NIAD) who had never used metformin.
RESEARCH DESIGN AND METHODS
A cohort of 223,968 metformin users and 34,571 diabetic patients who had never used metformin were identified from the Clinical Practice Research Datalink (CPRD).The primary outcome was defined as either a CPRD READ code lactic acidosis or a record of a plasma lactate concentration >5 mmol/L. The associations between renal impairment, dose of metformin, and the risk of lactic acidosis or elevated lactate concentrations were determined with time-dependent Cox models and expressed as hazard ratios (HRs).
RESULTS
The crude incidence of lactic acidosis or elevated lactate concentrations in current metformin users was 7.4 per 100,000 person-years (vs. 2.2 per 100,000 person-years in nonusers). Compared with nonusers, risk of lactic acidosis or elevated lactate concentrations in current metformin users was significantly associated with a renal function <60 mL/min/1.73 m2 (adjusted HR 6.37 [95% CI 1.48–27.5]). The increased risk among patients with impaired renal function was further increased in users of ≥730 g of metformin in the preceding year (adjusted HR 11.8 [95% CI 2.27–61.5]) and in users of a recent high daily dose (>2 g) of metformin (adjusted HR 13.0 [95% CI 2.36–72.0]).
CONCLUSIONS
Our study is consistent with current recommendations that the renal function of metformin users should be adequately monitored and that the dose of metformin should be adjusted, if necessary, if renal function falls below 60 mL/min/1.73 m2.
Diabetes Care - Tập 37 Số 8 - Trang 2218-2224 - 2014
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