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  • American Diabetes Association  (33)
  • 1
    Online Resource
    Online Resource
    Intravitreal AAV2.COMP-Ang1 Prevents Neurovascular Degeneration in a Murine Model of Diabetic Retinopathy
    American Diabetes Association ; 2015
    In:  Diabetes Vol. 64, No. 12 ( 2015-12-01), p. 4247-4259
    Details
    In: Diabetes, American Diabetes Association, Vol. 64, No. 12 ( 2015-12-01), p. 4247-4259
    Abstract: Diabetic retinopathy (DR) is the leading cause of blindness in the working-age population in the U.S. The vision-threatening processes of neuroglial and vascular dysfunction in DR occur in concert, driven by hyperglycemia and propelled by a pathway of inflammation, ischemia, vasodegeneration, and breakdown of the blood retinal barrier. Currently, no therapies exist for normalizing the vasculature in DR. Here, we show that a single intravitreal dose of adeno-associated virus serotype 2 encoding a more stable, soluble, and potent form of angiopoietin 1 (AAV2.COMP-Ang1) can ameliorate the structural and functional hallmarks of DR in Ins2Akita mice, with sustained effects observed through six months. In early DR, AAV2.COMP-Ang1 restored leukocyte-endothelial interaction, retinal oxygenation, vascular density, vascular marker expression, vessel permeability, retinal thickness, inner retinal cellularity, and retinal neurophysiological response to levels comparable with nondiabetic controls. In late DR, AAV2.COMP-Ang1 enhanced the therapeutic benefit of intravitreally delivered endothelial colony-forming cells by promoting their integration into the vasculature and thereby stemming further visual decline. AAV2.COMP-Ang1 single-dose gene therapy can prevent neurovascular pathology, support vascular regeneration, and stabilize vision in DR.
    Type of Medium: Online Resource
    ISSN: 0012-1797 , 1939-327X
    URL: Article
    DOI: 10.2337/db14-1030
    Language: English
    Publisher: American Diabetes Association
    Publication Date: 2015
    detail.hit.zdb_id: 1501252-9
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  • 2
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    Membrane Potential-Dependent Inactivation of Voltage-Gated Ion Channels in α-Cells Inhibits Glucagon Secretion From Human Islets
    American Diabetes Association ; 2010
    In:  Diabetes Vol. 59, No. 9 ( 2010-09-01), p. 2198-2208
    Details
    In: Diabetes, American Diabetes Association, Vol. 59, No. 9 ( 2010-09-01), p. 2198-2208
    Abstract: To document the properties of the voltage-gated ion channels in human pancreatic α-cells and their role in glucagon release. RESEARCH DESIGN AND METHODS Glucagon release was measured from intact islets. [Ca2+]i was recorded in cells showing spontaneous activity at 1 mmol/l glucose. Membrane currents and potential were measured by whole-cell patch-clamping in isolated α-cells identified by immunocytochemistry. RESULTS Glucose inhibited glucagon secretion from human islets; maximal inhibition was observed at 6 mmol/l glucose. Glucagon secretion at 1 mmol/l glucose was inhibited by insulin but not by ZnCl2. Glucose remained inhibitory in the presence of ZnCl2 and after blockade of type-2 somatostatin receptors. Human α-cells are electrically active at 1 mmol/l glucose. Inhibition of KATP-channels with tolbutamide depolarized α-cells by 10 mV and reduced the action potential amplitude. Human α-cells contain heteropodatoxin-sensitive A-type K+-channels, stromatoxin-sensitive delayed rectifying K+-channels, tetrodotoxin-sensitive Na+-currents, and low-threshold T-type, isradipine-sensitive L-type, and ω-agatoxin-sensitive P/Q-type Ca2+-channels. Glucagon secretion at 1 mmol/l glucose was inhibited by 40–70% by tetrodotoxin, heteropodatoxin-2, stromatoxin, ω-agatoxin, and isradipine. The [Ca2+]i oscillations depend principally on Ca2+-influx via L-type Ca2+-channels. Capacitance measurements revealed a rapid ( & lt;50 ms) component of exocytosis. Exocytosis was negligible at voltages below −20 mV and peaked at 0 mV. Blocking P/Q-type Ca2+-currents abolished depolarization-evoked exocytosis. CONCLUSIONS Human α-cells are electrically excitable, and blockade of any ion channel involved in action potential depolarization or repolarization results in inhibition of glucagon secretion. We propose that voltage-dependent inactivation of these channels underlies the inhibition of glucagon secretion by tolbutamide and glucose.
    Type of Medium: Online Resource
    ISSN: 0012-1797 , 1939-327X
    URL: Article
    DOI: 10.2337/db09-1505
    Language: English
    Publisher: American Diabetes Association
    Publication Date: 2010
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  • 3
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    γ-Aminobutyric Acid (GABA) Is an Autocrine Excitatory Transmitter in Human Pancreatic β-Cells
    American Diabetes Association ; 2010
    In:  Diabetes Vol. 59, No. 7 ( 2010-07-01), p. 1694-1701
    Details
    In: Diabetes, American Diabetes Association, Vol. 59, No. 7 ( 2010-07-01), p. 1694-1701
    Abstract: Paracrine signaling via γ-aminobutyric acid (GABA) and GABAA receptors (GABAARs) has been documented in rodent islets. Here we have studied the importance of GABAergic signaling in human pancreatic islets. RESEARCH DESIGN AND METHODS Expression of GABAARs in islet cells was investigated by quantitative PCR, immunohistochemistry, and patch-clamp experiments. Hormone release was measured from intact islets. GABA release was monitored by whole-cell patch-clamp measurements after adenoviral expression of α1β1 GABAAR subunits. The subcellular localization of GABA was explored by electron microscopy. The effects of GABA on electrical activity were determined by perforated patch whole-cell recordings. RESULTS PCR analysis detected relatively high levels of the mRNAs encoding GABAAR α2, β3, γ2, and π subunits in human islets. Patch-clamp experiments revealed expression of GABAAR Cl− channels in 52% of β-cells (current density 9 pA/pF), 91% of δ-cells (current density 148 pA/pF), and 6% of α-cells (current density 2 pA/pF). Expression of GABAAR subunits in islet cells was confirmed by immunohistochemistry. β-Cells secreted GABA both by glucose-dependent exocytosis of insulin-containing granules and by a glucose-independent mechanism. The GABAAR antagonist SR95531 inhibited insulin secretion elicited by 6 mmol/l glucose. Application of GABA depolarized β-cells and stimulated action potential firing in β-cells exposed to glucose. CONCLUSIONS Signaling via GABA and GABAAR constitutes an autocrine positive feedback loop in human β-cells. The presence of GABAAR in non–β-cells suggests that GABA may also be involved in the regulation of somatostatin and glucagon secretion.
    Type of Medium: Online Resource
    ISSN: 0012-1797 , 1939-327X
    URL: Article
    DOI: 10.2337/db09-0797
    Language: English
    Publisher: American Diabetes Association
    Publication Date: 2010
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  • 4
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    A Type 1 Diabetes Genetic Risk Score Predicts Progression of Islet Autoimmunity and Development of Type 1 Diabetes in Individuals at Risk
    American Diabetes Association ; 2018
    In:  Diabetes Care Vol. 41, No. 9 ( 2018-09-01), p. 1887-1894
    Details
    In: Diabetes Care, American Diabetes Association, Vol. 41, No. 9 ( 2018-09-01), p. 1887-1894
    Abstract: We 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 METHODS We 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. RESULTS Higher 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 & gt;0.295, 95% CI 1.47–3.51; P = 0.0002). CONCLUSIONS The T1D GRS independently predicts progression to T1D and improves prediction along T1D stages in autoantibody-positive relatives.
    Type of Medium: Online Resource
    ISSN: 0149-5992 , 1935-5548
    URL: Article
    DOI: 10.2337/dc18-0087
    Language: English
    Publisher: American Diabetes Association
    Publication Date: 2018
    detail.hit.zdb_id: 1490520-6
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  • 5
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    Identical and Nonidentical Twins: Risk and Factors Involved in Development of Islet Autoimmunity and Type 1 Diabetes
    American Diabetes Association ; 2019
    In:  Diabetes Care Vol. 42, No. 2 ( 2019-02-01), p. 192-199
    Details
    In: Diabetes Care, American Diabetes Association, Vol. 42, No. 2 ( 2019-02-01), p. 192-199
    Abstract: There are variable reports of risk of concordance for progression to islet autoantibodies and type 1 diabetes in identical twins after one twin is diagnosed. We examined development of positive autoantibodies and type 1 diabetes and the effects of genetic factors and common environment on autoantibody positivity in identical twins, nonidentical twins, and full siblings. RESEARCH DESIGN AND METHODS Subjects from the TrialNet Pathway to Prevention Study (N = 48,026) were screened from 2004 to 2015 for islet autoantibodies (GAD antibody [GADA], insulinoma-associated antigen 2 [IA-2A] , and autoantibodies against insulin [IAA]). Of these subjects, 17,226 (157 identical twins, 283 nonidentical twins, and 16,786 full siblings) were followed for autoantibody positivity or type 1 diabetes for a median of 2.1 years. RESULTS At screening, identical twins were more likely to have positive GADA, IA-2A, and IAA than nonidentical twins or full siblings (all P & lt; 0.0001). Younger age, male sex, and genetic factors were significant factors for expression of IA-2A, IAA, one or more positive autoantibodies, and two or more positive autoantibodies (all P ≤ 0.03). Initially autoantibody-positive identical twins had a 69% risk of diabetes by 3 years compared with 1.5% for initially autoantibody-negative identical twins. In nonidentical twins, type 1 diabetes risk by 3 years was 72% for initially multiple autoantibody–positive, 13% for single autoantibody–positive, and 0% for initially autoantibody-negative nonidentical twins. Full siblings had a 3-year type 1 diabetes risk of 47% for multiple autoantibody–positive, 12% for single autoantibody–positive, and 0.5% for initially autoantibody-negative subjects. CONCLUSIONS Risk of type 1 diabetes at 3 years is high for initially multiple and single autoantibody–positive identical twins and multiple autoantibody–positive nonidentical twins. Genetic predisposition, age, and male sex are significant risk factors for development of positive autoantibodies in twins.
    Type of Medium: Online Resource
    ISSN: 0149-5992 , 1935-5548
    URL: Article
    DOI: 10.2337/dc18-0288
    Language: English
    Publisher: American Diabetes Association
    Publication Date: 2019
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  • 6
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    Identification of Genetic Variation Influencing Metformin Response in a Multiancestry Genome-Wide Association Study in the Diabetes Prevention Program (DPP)
    American Diabetes Association ; 2023
    In:  Diabetes Vol. 72, No. 8 ( 2023-08-01), p. 1161-1172
    Details
    In: Diabetes, American Diabetes Association, Vol. 72, No. 8 ( 2023-08-01), p. 1161-1172
    Abstract: Genome-wide significant loci for metformin response in type 2 diabetes reported elsewhere have not been replicated in the Diabetes Prevention Program (DPP). To assess pharmacogenetic interactions in prediabetes, we conducted a genome-wide association study (GWAS) in the DPP. Cox proportional hazards models tested associations with diabetes incidence in the metformin (MET; n = 876) and placebo (PBO; n = 887) arms. Multiple linear regression assessed association with 1-year change in metformin-related quantitative traits, adjusted for baseline trait, age, sex, and 10 ancestry principal components. We tested for gene-by-treatment interaction. No significant associations emerged for diabetes incidence. We identified four genome-wide significant variants after correcting for correlated traits (P & lt; 9 × 10−9). In the MET arm, rs144322333 near ENOSF1 (minor allele frequency [MAF]AFR = 0.07; MAFEUR = 0.002) was associated with an increase in percentage of glycated hemoglobin (per minor allele, β = 0.39 [95% CI 0.28, 0.50] ; P = 2.8 × 10−12). rs145591055 near OMSR (MAF = 0.10 in American Indians) was associated with weight loss (kilograms) (per G allele, β = −7.55 [95% CI −9.88, −5.22]; P = 3.2 × 10−10) in the MET arm. Neither variant was significant in PBO; gene-by-treatment interaction was significant for both variants [P(G×T) & lt; 1.0 × 10−4]. Replication in individuals with diabetes did not yield significant findings. A GWAS for metformin response in prediabetes revealed novel ethnic-specific associations that require further investigation but may have implications for tailored therapy.
    Type of Medium: Online Resource
    ISSN: 0012-1797
    URL: Article
    DOI: 10.2337/db22-0702
    Language: English
    Publisher: American Diabetes Association
    Publication Date: 2023
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  • 7
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    A Genome-Wide Association Study of Diabetic Kidney Disease in Subjects With Type 2 Diabetes
    American Diabetes Association ; 2018
    In:  Diabetes Vol. 67, No. 7 ( 2018-07-01), p. 1414-1427
    Details
    In: Diabetes, American Diabetes Association, Vol. 67, No. 7 ( 2018-07-01), p. 1414-1427
    Abstract: Identification of sequence variants robustly associated with predisposition to diabetic kidney disease (DKD) has the potential to provide insights into the pathophysiological mechanisms responsible. We conducted a genome-wide association study (GWAS) of DKD in type 2 diabetes (T2D) using eight complementary dichotomous and quantitative DKD phenotypes: the principal dichotomous analysis involved 5,717 T2D subjects, 3,345 with DKD. Promising association signals were evaluated in up to 26,827 subjects with T2D (12,710 with DKD). A combined T1D+T2D GWAS was performed using complementary data available for subjects with T1D, which, with replication samples, involved up to 40,340 subjects with diabetes (18,582 with DKD). Analysis of specific DKD phenotypes identified a novel signal near GABRR1 (rs9942471, P = 4.5 × 10−8) associated with microalbuminuria in European T2D case subjects. However, no replication of this signal was observed in Asian subjects with T2D or in the equivalent T1D analysis. There was only limited support, in this substantially enlarged analysis, for association at previously reported DKD signals, except for those at UMOD and PRKAG2, both associated with estimated glomerular filtration rate. We conclude that, despite challenges in addressing phenotypic heterogeneity, access to increased sample sizes will continue to provide more robust inference regarding risk variant discovery for DKD.
    Type of Medium: Online Resource
    ISSN: 0012-1797 , 1939-327X
    URL: Article
    DOI: 10.2337/db17-0914
    Language: English
    Publisher: American Diabetes Association
    Publication Date: 2018
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  • 8
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    Effect of Metformin and Lifestyle Interventions on Mortality in the Diabetes Prevention Program and Diabetes Prevention Program Outcomes Study
    American Diabetes Association ; 2021
    In:  Diabetes Care Vol. 44, No. 12 ( 2021-12-01), p. 2775-2782
    Details
    In: Diabetes Care, American Diabetes Association, Vol. 44, No. 12 ( 2021-12-01), p. 2775-2782
    Abstract: To determine whether metformin or lifestyle modification can lower rates of all-cause and cause-specific mortality in the Diabetes Prevention Program and Diabetes Prevention Program Outcomes Study. RESEARCH DESIGN AND METHODS From 1996 to 1999, 3,234 adults at high risk for type 2 diabetes were randomized to an intensive lifestyle intervention, masked metformin, or placebo. Placebo and lifestyle interventions stopped in 2001, and a modified lifestyle program was offered to everyone, but unmasked study metformin continued in those originally randomized. Causes of deaths through 31 December 2018 were adjudicated by blinded reviews. All-cause and cause-specific mortality hazard ratios (HRs) were estimated from Cox proportional hazards regression models and Fine-Gray models, respectively. RESULTS Over a median of 21 years (interquartile range 20–21), 453 participants died. Cancer was the leading cause of death (n = 170), followed by cardiovascular disease (n = 131). Compared with placebo, metformin did not influence mortality from all causes (HR 0.99 [95% CI 0.79, 1.25]), cancer (HR 1.04 [95% CI 0.72, 1.52] ), or cardiovascular disease (HR 1.08 [95% CI 0.70, 1.66]). Similarly, lifestyle modification did not impact all-cause (HR 1.02 [95% CI 0.81, 1.28] ), cancer (HR 1.07 [95% CI 0.74, 1.55]), or cardiovascular disease (HR 1.18 [95% CI 0.77, 1.81] ) mortality. Analyses adjusted for diabetes status and duration, BMI, cumulative glycemic exposure, and cardiovascular risks yielded results similar to those for all-cause mortality. CONCLUSIONS Cancer was the leading cause of mortality among adults at high risk for type 2 diabetes. Although metformin and lifestyle modification prevented diabetes, neither strategy reduced all-cause, cancer, or cardiovascular mortality rates.
    Type of Medium: Online Resource
    ISSN: 0149-5992 , 1935-5548
    URL: Article
    DOI: 10.2337/dc21-1046
    Language: English
    Publisher: American Diabetes Association
    Publication Date: 2021
    detail.hit.zdb_id: 1490520-6
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  • 9
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    The Impact of Physical Activity on the Prevention of Type 2 Diabetes: Evidence and Lessons Learned From the Diabetes Prevention Program, a Long-Standing Clinical Trial Incorporating Subjective and Objective Activity Measures
    American Diabetes Association ; 2021
    In:  Diabetes Care Vol. 44, No. 1 ( 2021-01-01), p. 43-49
    Details
    In: Diabetes Care, American Diabetes Association, Vol. 44, No. 1 ( 2021-01-01), p. 43-49
    Abstract: Across the Diabetes Prevention Program (DPP) follow-up, cumulative diabetes incidence remained lower in the lifestyle compared with the placebo and metformin randomized groups and could not be explained by weight. Collection of self-reported physical activity (PA) (yearly) with cross-sectional objective PA (in follow-up) allowed for examination of PA and its long-term impact on diabetes prevention. RESEARCH DESIGN AND METHODS Yearly self-reported PA and diabetes assessment and oral glucose tolerance test results (fasting glucose semiannually) were collected for 3,232 participants with one accelerometry assessment 11–13 years after randomization (n = 1,793). Mixed models determined PA differences across treatment groups. The association between PA and diabetes incidence was examined using Cox proportional hazards models. RESULTS There was a 6% decrease (Cox proportional hazard ratio 0.94 [95% CI 0.92, 0.96]; P & lt; 0.001) in diabetes incidence per 6 MET-h/week increase in time-dependent PA for the entire cohort over an average of 12 years (controlled for age, sex, baseline PA, and weight). The effect of PA was greater (12% decrease) among participants less active at baseline ( & lt;7.5 MET-h/week) (n = 1,338) (0.88 [0.83, 0.93]; P & lt; 0.0001), with stronger findings for lifestyle participants. Lifestyle had higher cumulative PA compared with metformin or placebo (P & lt; 0.0001) and higher accelerometry total minutes per day measured during follow-up (P = 0.001 and 0.047). All associations remained significant with the addition of weight in the models. CONCLUSIONS PA was inversely related to incident diabetes in the entire cohort across the study, with cross-sectional accelerometry results supporting these findings. This highlights the importance of PA within lifestyle intervention efforts designed to prevent diabetes and urges health care providers to consider both PA and weight when counseling high-risk patients.
    Type of Medium: Online Resource
    ISSN: 0149-5992 , 1935-5548
    URL: Article
    DOI: 10.2337/dc20-1129
    Language: English
    Publisher: American Diabetes Association
    Publication Date: 2021
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  • 10
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    The Effect of Interventions to Prevent Type 2 Diabetes on the Development of Diabetic Retinopathy: The DPP/DPPOS Experience
    American Diabetes Association ; 2022
    In:  Diabetes Care Vol. 45, No. 7 ( 2022-07-07), p. 1640-1646
    Details
    In: Diabetes Care, American Diabetes Association, Vol. 45, No. 7 ( 2022-07-07), p. 1640-1646
    Abstract: To determine whether interventions that slow or prevent the development of type 2 diabetes in those at risk reduce the subsequent prevalence of diabetic retinopathy. RESEARCH DESIGN AND METHODS The Diabetes Prevention Program (DPP) randomized subjects at risk for developing type 2 diabetes because of overweight/obesity and dysglycemia to metformin (MET), intensive lifestyle intervention (ILS), or placebo (PLB) to assess the prevention of diabetes. During the DPP and DPP Outcome Study (DPPOS), we performed fundus photography over time on study participants, regardless of their diabetes status. Fundus photographs were graded using the Early Treatment Diabetic Retinopathy Study grading system, with diabetic retinopathy defined as typical lesions of diabetic retinopathy (microaneurysms, exudates, or hemorrhage, or worse) in either eye. RESULTS Despite reduced progression to diabetes in the ILS and MET groups compared with PLB, there was no difference in the prevalence of diabetic retinopathy between treatment groups after 1, 5, 11, or 16 years of follow-up. No treatment group differences in retinopathy were found within prespecified subgroups (baseline age, sex, race/ethnicity, baseline BMI). In addition, there was no difference in the prevalence of diabetic retinopathy between those exposed to metformin and those not exposed to metformin, regardless of treatment group assignment. CONCLUSIONS Interventions that delay or prevent the onset of type 2 diabetes in overweight/obese subjects with dysglycemia who are at risk for diabetes do not reduce the development of diabetic retinopathy for up to 20 years.
    Type of Medium: Online Resource
    ISSN: 0149-5992
    URL: Article
    DOI: 10.2337/dc21-2417
    Language: English
    Publisher: American Diabetes Association
    Publication Date: 2022
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