Introduction
Beta‐cell autoantibodies are established markers of autoimmunity, which we compared between Ghanaian adults with or without diabetes, living in rural and urban Ghana and in three ...European cities.
Methods
In the multicenter cross‐sectional Research on Obesity and Diabetes among African Migrants (RODAM) study (N = 5898), we quantified autoantibodies against glutamic acid decarboxylase (GAD65Ab) by radioligand binding assay (RBA) and established cut‐offs for positivity by displacement analysis. In a subsample, we performed RBA for zinc transporter‐8 autoantibodies (ZnT8Ab). Associations of environmental, sociodemographic, and clinical factors with GAD65Ab were calculated.
Results
In this study population (age: 46.1 ± 11.9 years; female: 62%; Ghana‐rural: 1111; Ghana‐urban: 1455; Europe: 3332), 9.2% had diabetes with adult‐onset. GAD65Ab concentrations were the highest in Ghana‐rural (32.4; 10.8‐71.3 U/mL), followed by Ghana‐urban (26.0; 12.3‐49.1 U/mL) and Europe (11.9; 3.0‐22.8 U/mL) with no differences between European cities. These distributions were similar for ZnT8Ab. Current fever, history of fever, and higher concentrations of liver enzymes marginally explained site‐specific GAD65Ab concentrations. GAD65Ab positivity was as frequent in diabetes as in nondiabetes (5.4% vs 6.1%; P = .25). This was also true for ZnT8Ab positivity.
Conclusion
Geographic location determines the occurrence of GAD65Ab and ZnT8Ab more than the diabetes status. Beta‐cell autoimmunity may not be feasible to differentiate diabetes subgroups in this population.
Among 5898 Ghanaian adults living in rural Ghana, urban Ghana, and three European cities, GAD65Ab was strongly determined by the environment. Thus, GAD65Ab may not differentiate autoimmune subgroups of adult‐onset diabetes.
Highlights • Cardiovascular autonomic nerve function (i.e. E/I ratio) deteriorates over time in type 1 diabetes. • HSP27, MIF and PAI-1 concentrations do not correlate with cardiovascular autonomic ...nerve function. • The change in HbA1c correlates negatively with the change in E/I over time. • Higher HbA1c is associated with worse cardiovascular autonomic nerve function.
Increased Glucose Levels Are Associated With Episodic Memory in Nondiabetic Women
Olov Rolandsson 1 ,
Anna Backeström 1 ,
Sture Eriksson 2 ,
Göran Hallmans 3 and
Lars-Göran Nilsson 4
1 Department of ...Public Health and Clinical Medicine, Family Medicine, Umeå University, Umeå, Sweden
2 Department of Community Medicine and Rehabilitation, Geriatric Medicine, Umeå University, Umeå, Sweden
3 Department of Public Health and Clinical Medicine, Nutritional Research, Umeå University, Umeå, Sweden
4 Department of Psychology, Stockholm University, Stockholm, Sweden
Address correspondence and reprint requests to Dr. Olov Rolandsson, Family Medicine, Department of Public Health and Clinical
Medicine, NUS, S-901 85 Umeå, Sweden. E-mail: olov.rolandsson{at}fammed.umu.se
Abstract
OBJECTIVE —Patients with type 2 diabetes have an increased risk of a reduction in cognitive function. We investigated the hypothesis
that plasma glucose is associated with a reduction in episodic and/or semantic memory already in nondiabetic subjects.
RESEARCH DESIGN AND METHODS —We linked two large population-based datasets in Sweden: the Betula study, in which a random sample from the population aged
35–85 years was investigated for cognitive function, including episodic and semantic memory; and the Västerbotten Intervention
Program, a health survey with subjects aged 40, 50, and 60 years, that includes measuring of fasting and 2-h plasma glucose,
along with other risk factors for diabetes and cardiovascular disease. We identified 411 (179 men and 232 women, mean age
50.6 ± 8.0 years) nondiabetic subjects, free from dementia, who had participated in the two surveys within 6 months.
RESULTS —Women had better episodic (score 7.37 ± 1.42) and semantic memory (score 16.05 ± 2.76) than men (score 6.59 ± 1.29 and 15.15
± 2.92, respectively, P < 0.001 for both). In an adjusted multivariate model, fasting plasma glucose (fPG) and 2-h plasma glucose (2hPG) were significantly
negatively associated with episodic memory (fPG: B −0.198, SE 0.068, β −0.209, P = 0.004; and 2hPG: B −0.061, SE 0.031, β −0.148, P = 0.048, respectively) in women but not in men. The association was not found in relation to semantic memory.
CONCLUSIONS —We conclude that an increase in plasma glucose is associated with impairment in episodic memory in women. This could be explained
by a negative effect on the hippocampus caused by raised plasma glucose levels.
2hPG, 2-hour plasma glucose
CES-D, the Center for Epidemiologic Studies Depression Scale
fPG, fasting plasma glucose
IFG, impaired fasting glucose
IGT, impaired glucose tolerance
MMSE, Mini Mental State Examination
OGTT, oral glucose tolerance test
VIF, variance inflation factor
VIP, Västerbotten Intervention Program
Footnotes
Published ahead of print at http://diabetes.diabetesjournals.org on 31 October 2007. DOI: 10.2337/db07-1215.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore
be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Accepted October 25, 2007.
Received August 30, 2007.
DIABETES
Wolfram syndrome 1 (WFS1) single nucleotide polymorphisms (SNPs) are associated with risk of type 2 diabetes. In this study we aimed to refine this association and investigate the role of ...low-frequency WFS1 variants in type 2 diabetes risk.
For fine-mapping, we sequenced WFS1 exons, splice junctions, and conserved noncoding sequences in samples from 24 type 2 diabetic case and 68 control subjects, selected tagging SNPs, and genotyped these in 959 U.K. type 2 diabetic case and 1,386 control subjects. The same genomic regions were sequenced in samples from 1,235 type 2 diabetic case and 1,668 control subjects to compare the frequency of rarer variants between case and control subjects.
Of 31 tagging SNPs, the strongest associated was the previously untested 3' untranslated region rs1046320 (P = 0.008); odds ratio 0.84 and P = 6.59 x 10(-7) on further replication in 3,753 case and 4,198 control subjects. High correlation between rs1046320 and the original strongest SNP (rs10010131) (r2 = 0.92) meant that we could not differentiate between their effects in our samples. There was no difference in the cumulative frequency of 82 rare (minor allele frequency MAF <0.01) nonsynonymous variants between type 2 diabetic case and control subjects (P = 0.79). Two intermediate frequency (MAF 0.01-0.05) nonsynonymous changes also showed no statistical association with type 2 diabetes.
We identified six highly correlated SNPs that show strong and comparable associations with risk of type 2 diabetes, but further refinement of these associations will require large sample sizes (>100,000) or studies in ethnically diverse populations. Low frequency variants in WFS1 are unlikely to have a large impact on type 2 diabetes risk in white U.K. populations, highlighting the complexities of undertaking association studies with low-frequency variants identified by resequencing.
We hypothesized that individuals with type 2 diabetes and low insulin resistance in combination with impaired beta cell function at diabetes diagnosis have lower mortality compared to those with high ...insulin resistance in combination with preserved beta cell function.
In this prospective cohort study, 864 individuals with type 2 diabetes (median age 60 years) had fasting glucose and fasting C-peptide measured at the time of diabetes diagnosis or up to five years before diagnosis. Insulin resistance was estimated with HOMA-%S and beta cell function with HOMA-%B. Four groups based on the median of HOMA-%S and HOMA-%B were formed: 1) low HOMA-%S and high HOMA-%B, 2) low HOMA-%S and low HOMA-%B, 3) high HOMA-%S and high HOMA-%B, and 4) high HOMA-%S and low HOMA-%B (reference group). Mortality was registered during a median follow up of 15 years after diabetes diagnosis, and the associations between the four groups and mortality was estimated with Cox regression adjusted for gender and age at diabetes diagnosis (model 1) and adjusted for gender, age at diabetes diagnosis, smoking, hypertension, BMI and total cholesterol (model 2).
Group 1 had higher total mortality (model 2: HR 1.58, 95% CI 1.06−2.36) compared to the reference group 4. Group 1 was also associated with higher cardiovascular mortality (model 1: HR 2.24, 95% CI 1.08−4.66), but this difference was no longer significant in model 2.
Insulin resistance in combination with preserved beta cell function at the time of diabetes diagnosis is an independent risk factor for total mortality. Insulin resistance in combination with preserved beta cell function increases the risk for cardiovascular mortality but not independent of conventional risk factors. Thus, treatment of type 2 diabetes should focus not only on normalizing blood glucose levels but also improve insulin resistance.
Disclosure
J. Otten: None. B. Tavelin: None. S. Söderberg: None. O. Rolandsson: None.
Recombinant Fabs of Human Monoclonal Antibodies Specific to the Middle Epitope of GAD65 Inhibit Type 1 Diabetes–Specific GAD65Abs
Carolyn J. Padoa 1 2 ,
J. Paul Banga 3 ,
Anne-Marie Madec 4 ,
Manfred ...Ziegler 5 ,
Michael Schlosser 6 ,
Eva Ortqvist 7 ,
Ingrid Kockum 8 ,
Jerry Palmer 1 ,
Olov Rolandsson 9 ,
Katherine A. Binder 1 ,
Jefferson Foote 10 ,
Dong Luo 1 and
Christiane S. Hampe 1
1 Department of Medicine, University of Washington, Seattle, Washington
2 Department of Chemical Pathology, University of the Witwatersrand & National Health Laboratory Services, Johannesburg, South
Africa
3 Division of Medicine, Guy’s, Kings and St. Thomas’ School of Medicine, London, U.K
4 Institut National de la Santé et de la Recherche Médicale, Laennec Faculty of Medicine, University of Lyon, Lyon, France
5 Institute of Diabetes “Gerhardt Katsch,” Karlsburg, Germany
6 Institute of Pathophysiology, Ernst Moritz Arndt University of Greifswald, Karlsburg, Germany
7 Department of Woman and Child Health, Karolinska Institutet, Stockholm, Sweden
8 Department of Molecular Medicine, Clinical Genetics, Karolinska Institutet, Stockholm, Sweden
9 Department of Public Health and Clinical Medicine, Umeå University, Umeå, Sweden
10 Division of Human Biology, Fred Hutchinson Cancer Research Center, Seattle, Washington
Address correspondence and reprint requests to Dr. Christiane S. Hampe, Department of Medicine, Box 357710, University of
Washington, Seattle, WA 98195. E-mail: champe{at}u.washington.edu
Abstract
Autoantibodies to the 65-kDa isoform of GAD (GAD65Abs) are associated with type 1 diabetes development, but the conformational
nature of the GAD65Ab epitopes complicates the evaluation of disease risk. Six GAD65-specific recombinant Fabs (rFabs) were
cloned from monoclonal antibodies b96.11, DP-C, DP-A, DPD, 144, and 221–442. The binding of GAD65Abs in 61 type 1 diabetic
patients to GAD65 was analyzed by competitive radioimmunoassays with the six rFabs to ascertain disease-specific GAD65Ab binding
specificities. The median binding was reduced significantly by rFab b96.11 (72%) ( P < 0.0001), DP-A (84%) ( P < 0.0001), DP-C (84%) ( P < 0.0001), 221–442 (79%) ( P < 0.0001), and DP-D (80%) ( P < 0.0001). The competition pattern in type 1 diabetic patients differed from that in GAD65Ab-positive late autoimmune diabetes
in adults (LADA) patients ( n = 44), first-degree relatives ( n = 38), and healthy individuals ( n = 14). Whereas 87 and 72% of the type 1 diabetic sera were competed by rFab b96.11 and DP-C, respectively, only 34 and 26%
of LADA patients, 18 and 25% of first-degree relatives, and 7 and 28% of healthy individuals showed competition ( P < 0.0001). These findings support the view that type 1 diabetes is associated with disease- and epitope-specific GAD65Abs
and supports the notion that the middle epitope is disease associated. These GAD65-specific rFabs should prove useful in predicting
type 1 diabetes and in the study of conformational GAD65Ab epitopes.
APS-1, autoimmune polyendocrine syndrome type 1
CDR, complementarity-determining region
GAD65Ab, autoantibody to the 65-kDa isoform of GAD
LADA, late autoimmune diabetes in adults
mAb, monoclonal antibody
rFab, recombinant Fab
RIA, radioimmunoassay
Footnotes
Accepted July 22, 2003.
Received May 8, 2003.
DIABETES
Recent epidemiological data have shown that more than half of all new cases of type 1 diabetes occur in adults. Key genetic, immune, and metabolic differences exist between adult- and childhood-onset ...type 1 diabetes, many of which are not well understood. A substantial risk of misclassification of diabetes type can result. Notably, some adults with type 1 diabetes may not require insulin at diagnosis, their clinical disease can masquerade as type 2 diabetes, and the consequent misclassification may result in inappropriate treatment. In response to this important issue, JDRF convened a workshop of international experts in November 2019. Here, we summarize the current understanding and unanswered questions in the field based on those discussions, highlighting epidemiology and immunogenetic and metabolic characteristics of adult-onset type 1 diabetes as well as disease-associated comorbidities and psychosocial challenges. In adult-onset, as compared with childhood-onset, type 1 diabetes, HLA-associated risk is lower, with more protective genotypes and lower genetic risk scores; multiple diabetes-associated autoantibodies are decreased, though GADA remains dominant. Before diagnosis, those with autoantibodies progress more slowly, and at diagnosis, serum C-peptide is higher in adults than children, with ketoacidosis being less frequent. Tools to distinguish types of diabetes are discussed, including body phenotype, clinical course, family history, autoantibodies, comorbidities, and C-peptide. By providing this perspective, we aim to improve the management of adults presenting with type 1 diabetes.
Wide-scale profiling technologies including metabolomics broaden the possibility of novel discoveries related to the pathogenesis of type 2 diabetes (T2D). By applying non-targeted metabolomics ...approach, we investigated here whether serum metabolite profile predicts T2D in a well-characterized study population with impaired glucose tolerance by examining two groups of individuals who took part in the Finnish Diabetes Prevention Study (DPS); those who either early developed T2D (n = 96) or did not convert to T2D within the 15-year follow-up (n = 104). Several novel metabolites were associated with lower likelihood of developing T2D, including indole and lipid related metabolites. Higher indolepropionic acid was associated with reduced likelihood of T2D in the DPS. Interestingly, in those who remained free of T2D, indolepropionic acid and various lipid species were associated with better insulin secretion and sensitivity, respectively. Furthermore, these metabolites were negatively correlated with low-grade inflammation. We replicated the association between indolepropionic acid and T2D risk in one Finnish and one Swedish population. We suggest that indolepropionic acid, a gut microbiota-produced metabolite, is a potential biomarker for the development of T2D that may mediate its protective effect by preservation of β-cell function. Novel lipid metabolites associated with T2D may exert their effects partly through enhancing insulin sensitivity.
Background and aims: We investigated the separate effects of insulin resistance and beta cell function at the diagnosis of type 2 diabetes on the development of mortality and diabetes complications.
...Materials and methods: This cohort study included 864 individuals with type 2 diabetes (median age 60 years) in whom fasting glucose and fasting C-peptide were measured at diabetes diagnosis. Insulin resistance was estimated by HOMA-%S and beta cell function by HOMA-%B. Four groups were created based on the median HOMA-%S and HOMA-%B values: group 1, high insulin resistance and preserved beta cell function; group 2, high insulin resistance and impaired beta cell function; group 3, low insulin resistance and preserved beta cell function; group 4, low insulin resistance and impaired beta cell function (reference group). Mortality and diabetes complications were registered with a follow-up of 15 years. The associations between the four groups and mortality/complications were estimated by Cox regression adjusted for gender and age at diabetes diagnosis in model 1, and also for smoking, hypertension, BMI, and total cholesterol in model 2. In the figure a Kaplan-Meier plot is displayed not including adjustments for confounding factors.
Results: Total mortality in the four groups is displayed in the figure. Both groups with high insulin resistance had higher total mortality (group 1: HR 1.58, 95% CI 1.06−2.36; group 2: HR 1.85, 95% CI 1.20-2.84) than group 4. Fasting C-peptide, as a continuous variable, was independently associated with total mortality (HR 1.29, 95% CI 1.11−1.49) and cancer mortality (HR 1.42, 95% CI 1.09−1.84).
Conclusion: Insulin resistance was an independent risk factor for total mortality. Thus, treatment of type 2 diabetes should focus not only on normalizing blood glucose levels, but also reducing insulin resistance.
Aims/hypothesis
The aims of the present work were to identify plasma metabolites that predict future type 2 diabetes, to investigate the changes in identified metabolites among individuals who later ...did or did not develop type 2 diabetes over time, and to assess the extent to which inclusion of predictive metabolites could improve risk prediction.
Methods
We established a nested case–control study within the Swedish prospective population-based Västerbotten Intervention Programme cohort. Using untargeted liquid chromatography-MS metabolomics, we analysed plasma samples from 503 case–control pairs at baseline (a median time of 7 years prior to diagnosis) and samples from a subset of 187 case–control pairs at 10 years of follow-up. Discriminative metabolites between cases and controls at baseline were optimally selected using a multivariate data analysis pipeline adapted for large-scale metabolomics. Conditional logistic regression was used to assess associations between discriminative metabolites and future type 2 diabetes, adjusting for several known risk factors. Reproducibility of identified metabolites was estimated by intra-class correlation over the 10 year period among the subset of healthy participants; their systematic changes over time in relation to diagnosis among those who developed type 2 diabetes were investigated using mixed models. Risk prediction performance of models made from different predictors was evaluated using area under the receiver operating characteristic curve, discrimination improvement index and net reclassification index.
Results
We identified 46 predictive plasma metabolites of type 2 diabetes. Among novel findings, phosphatidylcholines (PCs) containing odd-chain fatty acids (C19:1 and C17:0) and 2-hydroxyethanesulfonate were associated with the likelihood of developing type 2 diabetes; we also confirmed previously identified predictive biomarkers. Identified metabolites strongly correlated with insulin resistance and/or beta cell dysfunction. Of 46 identified metabolites, 26 showed intermediate to high reproducibility among healthy individuals. Moreover, PCs with odd-chain fatty acids, branched-chain amino acids, 3-methyl-2-oxovaleric acid and glutamate changed over time along with disease progression among diabetes cases. Importantly, we found that a combination of five of the most robustly predictive metabolites significantly improved risk prediction if added to models with an a priori defined set of traditional risk factors, but only a marginal improvement was achieved when using models based on optimally selected traditional risk factors.
Conclusions/interpretation
Predictive metabolites may improve understanding of the pathophysiology of type 2 diabetes and reflect disease progression, but they provide limited incremental value in risk prediction beyond optimal use of traditional risk factors.
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