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Islet biology, the CDKN2A/B locus and type 2 diabetes risk.

ABSTRACT: Type 2 diabetes, fuelled by the obesity epidemic, is an escalating worldwide cause of personal hardship and public cost. Diabetes incidence increases with age, and many studies link the classic senescence and ageing protein p16(INK4A) to diabetes pathophysiology via pancreatic islet biology. Genome-wide association studies (GWASs) have unequivocally linked the CDKN2A/B locus, which encodes p16 inhibitor of cyclin-dependent kinase (p16(INK4A)) and three other gene products, p14 alternate reading frame (p14(ARF)), p15(INK4B) and antisense non-coding RNA in the INK4 locus (ANRIL), with human diabetes risk. However, the mechanism by which the CDKN2A/B locus influences diabetes risk remains uncertain. Here, we weigh the evidence that CDKN2A/B polymorphisms impact metabolic health via islet biology vs effects in other tissues. Structured in a bedside-to-bench-to-bedside approach, we begin with a summary of the evidence that the CDKN2A/B locus impacts diabetes risk and a brief review of the basic biology of CDKN2A/B gene products. The main emphasis of this work is an in-depth look at the nuanced roles that CDKN2A/B gene products and related proteins play in the regulation of beta cell mass, proliferation and insulin secretory function, as well as roles in other metabolic tissues. We finish with a synthesis of basic biology and clinical observations, incorporating human physiology data. We conclude that it is likely that the CDKN2A/B locus influences diabetes risk through both islet and non-islet mechanisms.

SUBMITTER: Kong Y

PROVIDER: S-EPMC4930689 | biostudies-literature | 2016 Aug

REPOSITORIES: biostudies-literature

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Islet biology, the CDKN2A/B locus and type 2 diabetes risk.

Kong Yahui Y Sharma Rohit B RB Nwosu Benjamin U BU Alonso Laura C LC

Diabetologia 20160507 8

Type 2 diabetes, fuelled by the obesity epidemic, is an escalating worldwide cause of personal hardship and public cost. Diabetes incidence increases with age, and many studies link the classic senescence and ageing protein p16(INK4A) to diabetes pathophysiology via pancreatic islet biology. Genome-wide association studies (GWASs) have unequivocally linked the CDKN2A/B locus, which encodes p16 inhibitor of cyclin-dependent kinase (p16(INK4A)) and three other gene products, p14 alternate reading ...[more]

PMID: 27155872

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Project description:ObjectiveWe tested the ability of a type 1 diabetes (T1D) genetic risk score (GRS) to predict progression of islet autoimmunity and T1D in at-risk individuals.Research design and methodsWe studied the 1,244 TrialNet Pathway to Prevention study participants (T1D patients' relatives without diabetes and with one or more positive autoantibodies) who were genotyped with Illumina ImmunoChip (median [range] age at initial autoantibody determination 11.1 years [1.2-51.8], 48% male, 80.5% non-Hispanic white, median follow-up 5.4 years). Of 291 participants with a single positive autoantibody at screening, 157 converted to multiple autoantibody positivity and 55 developed diabetes. Of 953 participants with multiple positive autoantibodies at screening, 419 developed diabetes. We calculated the T1D GRS from 30 T1D-associated single nucleotide polymorphisms. We used multivariable Cox regression models, time-dependent receiver operating characteristic curves, and area under the curve (AUC) measures to evaluate prognostic utility of T1D GRS, age, sex, Diabetes Prevention Trial-Type 1 (DPT-1) Risk Score, positive autoantibody number or type, HLA DR3/DR4-DQ8 status, and race/ethnicity. We used recursive partitioning analyses to identify cut points in continuous variables.ResultsHigher T1D GRS significantly increased the rate of progression to T1D adjusting for DPT-1 Risk Score, age, number of positive autoantibodies, sex, and ethnicity (hazard ratio [HR] 1.29 for a 0.05 increase, 95% CI 1.06-1.6; P = 0.011). Progression to T1D was best predicted by a combined model with GRS, number of positive autoantibodies, DPT-1 Risk Score, and age (7-year time-integrated AUC = 0.79, 5-year AUC = 0.73). Higher GRS was significantly associated with increased progression rate from single to multiple positive autoantibodies after adjusting for age, autoantibody type, ethnicity, and sex (HR 2.27 for GRS >0.295, 95% CI 1.47-3.51; P = 0.0002).ConclusionsThe T1D GRS independently predicts progression to T1D and improves prediction along T1D stages in autoantibody-positive relatives.

Project description:Aims/hypothesisThe reason for the observed lower rate of islet autoantibody positivity in clinician-diagnosed adult-onset vs childhood-onset type 1 diabetes is not known. We aimed to explore this by assessing the genetic risk of type 1 diabetes in autoantibody-negative and -positive children and adults.MethodsWe analysed GAD autoantibodies, insulinoma-2 antigen autoantibodies and zinc transporter-8 autoantibodies (ZnT8A) and measured type 1 diabetes genetic risk by genotyping 30 type 1 diabetes-associated variants at diagnosis in 1814 individuals with clinician-diagnosed type 1 diabetes (1112 adult-onset, 702 childhood-onset). We compared the overall type 1 diabetes genetic risk score (T1DGRS) and non-HLA and HLA (DR3-DQ2, DR4-DQ8 and DR15-DQ6) components with autoantibody status in those with adult-onset and childhood-onset diabetes. We also measured the T1DGRS in 1924 individuals with type 2 diabetes from the Wellcome Trust Case Control Consortium to represent non-autoimmune diabetes control participants.ResultsThe T1DGRS was similar in autoantibody-negative and autoantibody-positive clinician-diagnosed childhood-onset type 1 diabetes (mean [SD] 0.274 [0.034] vs 0.277 [0.026], p=0.4). In contrast, the T1DGRS in autoantibody-negative adult-onset type 1 diabetes was lower than that in autoantibody-positive adult-onset type 1 diabetes (mean [SD] 0.243 [0.036] vs 0.271 [0.026], p<0.0001) but higher than that in type 2 diabetes (mean [SD] 0.229 [0.034], p<0.0001). Autoantibody-negative adults were more likely to have the more protective HLA DR15-DQ6 genotype (15% vs 3%, p<0.0001), were less likely to have the high-risk HLA DR3-DQ2/DR4-DQ8 genotype (6% vs 19%, p<0.0001) and had a lower non-HLA T1DGRS (p<0.0001) than autoantibody-positive adults. In contrast to children, autoantibody-negative adults were more likely to be male (75% vs 59%), had a higher BMI (27 vs 24 kg/m2) and were less likely to have other autoimmune conditions (2% vs 10%) than autoantibody-positive adults (all p<0.0001). In both adults and children, type 1 diabetes genetic risk was unaffected by the number of autoantibodies (p>0.3). These findings, along with the identification of seven misclassified adults with monogenic diabetes among autoantibody-negative adults and the results of a sensitivity analysis with and without measurement of ZnT8A, suggest that the intermediate type 1 diabetes genetic risk in autoantibody-negative adults is more likely to be explained by the inclusion of misclassified non-autoimmune diabetes (estimated to represent 67% of all antibody-negative adults, 95% CI 61%, 73%) than by the presence of unmeasured autoantibodies or by a discrete form of diabetes. When these estimated individuals with non-autoimmune diabetes were adjusted for, the prevalence of autoantibody positivity in adult-onset type 1 diabetes was similar to that in children (93% vs 91%, p=0.4).Conclusions/interpretationThe inclusion of non-autoimmune diabetes is the most likely explanation for the observed lower rate of autoantibody positivity in clinician-diagnosed adult-onset type 1 diabetes. Our data support the utility of islet autoantibody measurement in clinician-suspected adult-onset type 1 diabetes in routine clinical practice.

Project description:Aims/hypothesisSphingolipids play important roles in beta cell physiology, by regulating proinsulin folding and insulin secretion and in controlling apoptosis, as studied in animal models and cell cultures. Here we investigate whether sphingolipid metabolism may contribute to the pathogenesis of human type 1 diabetes and whether increasing the levels of the sphingolipid sulfatide would prevent models of diabetes in NOD mice.MethodsWe examined the amount and distribution of sulfatide in human pancreatic islets by immunohistochemistry, immunofluorescence and electron microscopy. Transcriptional analysis was used to evaluate expression of sphingolipid-related genes in isolated human islets. Genome-wide association studies (GWAS) and a T cell proliferation assay were used to identify type 1 diabetes related polymorphisms and test how these affect cellular islet autoimmunity. Finally, we treated NOD mice with fenofibrate, a known activator of sulfatide biosynthesis, to evaluate the effect on experimental autoimmune diabetes development.ResultsWe found reduced amounts of sulfatide, 23% of the levels in control participants, in pancreatic islets of individuals with newly diagnosed type 1 diabetes, which were associated with reduced expression of enzymes involved in sphingolipid metabolism. Next, we discovered eight gene polymorphisms (ORMDL3, SPHK2, B4GALNT1, SLC1A5, GALC, PPARD, PPARG and B4GALT1) involved in sphingolipid metabolism that contribute to the genetic predisposition to type 1 diabetes. These gene polymorphisms correlated with the degree of cellular islet autoimmunity in a cohort of individuals with type 1 diabetes. Finally, using fenofibrate, which activates sulfatide biosynthesis, we completely prevented diabetes in NOD mice and even reversed the disease in half of otherwise diabetic animals.Conclusions/interpretationThese results indicate that islet sphingolipid metabolism is abnormal in type 1 diabetes and suggest that modulation may represent a novel therapeutic approach.Data availabilityThe RNA expression data is available online at https://www.dropbox.com/s/93mk5tzl5fdyo6b/Abnormal%20islet%20sphingolipid%20metabolism%20in%20type%201%20diabetes%2C%20RNA%20expression.xlsx?dl=0 . A list of SNPs identified is available at https://www.dropbox.com/s/yfojma9xanpp2ju/Abnormal%20islet%20sphingolipid%20metabolism%20in%20type%201%20diabetes%20SNP.xlsx?dl=0 .

Project description:Aims/hypothesisWe hypothesised that progression of islet autoimmunity and type 1 diabetes mellitus differs among races/ethnicities in at-risk individuals.MethodsIn this study, we analysed the data from the Type 1 Diabetes TrialNet Pathway to Prevention Study. We studied 4873 non-diabetic, autoantibody-positive relatives of individuals with type 1 diabetes followed prospectively (11% Hispanic, 80.9% non-Hispanic white [NHW], 2.9% non-Hispanic black [NHB] and 5.2% non-Hispanic other [NHO]). Primary outcomes were time from single autoantibody positivity confirmation to multiple autoantibody positivity, and time from multiple autoantibody positivity to type 1 diabetes mellitus diagnosis.ResultsConversion from single to multiple autoantibody positivity was less common in Hispanic individuals than in NHW individuals (HR 0.66 [95% CI 0.46, 0.96], p = 0.028) adjusting for autoantibody type, age, sex, Diabetes Prevention Trial Type 1 Risk Score and HLA-DR3-DQ2/DR4-DQ8 genotype. In participants who screened positive for multiple autoantibodies (n = 2834), time to type 1 diabetes did not differ by race/ethnicity overall (p = 0.91). In children who were <12 years old when multiple autoantibody positivity was determined, being overweight/obese had differential effects by ethnicity: type 1 diabetes risk was increased by 36% in NHW children (HR 1.36 [95% CI 1.04, 1.77], p = 0.024) and was nearly quadrupled in Hispanic children (HR 3.8 [95% CI 1.6, 9.1], p = 0.0026). We did not observe this interaction in participants who were ≥12 years old at determination of autoantibody positivity, although this group size was limited. No significant differential risks were observed between individuals of NHB and NHW ethnicity.Conclusions/interpretationThe risk and rate of progression of islet autoimmunity were lower in Hispanic compared with NHW at-risk individuals, while significant differences in the development of type 1 diabetes were limited to children <12 years old and were modified by BMI.

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Islet biology, the CDKN2A/B locus and type 2 diabetes risk.

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Islet biology, the CDKN2A/B locus and type 2 diabetes risk.

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