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1.
BMJ. 2019 Apr 10;365:l1204. doi: 10.1136/bmj.l1204.

Incidence of type 2 diabetes mellitus in men receiving steroid 5α-reductase inhibitors: population based cohort study.

Author information

1
Research Department of Practice and Policy, School of Pharmacy, University College London, London, UK.
2
School of Pharmacy, Institute of Clinical Pharmacy and Pharmaceutical Sciences, College of Medicine, National Cheng Kung University, Tainan City, Taiwan.
3
University/BHF Centre for Cardiovascular Science, Queen's Medical Research Institute, University of Edinburgh, Edinburgh EH16 4TJ, UK.
4
Institute of Genetic Medicine, International Centre for Life, Newcastle University, Newcastle upon Tyne, UK.
5
Medicines Monitoring Unit, Ninewells Hospital and Medical School, Dundee, UK.
6
University/BHF Centre for Cardiovascular Science, Queen's Medical Research Institute, University of Edinburgh, Edinburgh EH16 4TJ, UK ruth.andrew@ed.ac.uk.

Abstract

OBJECTIVE:

To investigate the incidence of new onset type 2 diabetes mellitus in men receiving steroid 5α-reductase inhibitors (dutasteride or finasteride) for long term treatment of benign prostatic hyperplasia.

DESIGN:

Population based cohort study.

SETTING:

UK Clinical Practice Research Datalink (CPRD; 2003-14) and Taiwanese National Health Insurance Research Database (NHIRD; 2002-12).

PARTICIPANTS:

Men in the CPRD who received dutasteride (n=8231), finasteride (n=30 774), or tamsulosin (n=16 270) were evaluated. Propensity score matching (2:1; dutasteride to finasteride or tamsulosin) produced cohorts of 2090, 3445, and 4018, respectively. In the NHIRD, initial numbers were 1251 (dutasteride), 4194 (finasteride), and 86 263 (tamsulosin), reducing to 1251, 2445, and 2502, respectively, after propensity score matching.

MAIN OUTCOMES MEASURE:

Incident type 2 diabetes using a Cox proportional hazard model.

RESULTS:

In the CPRD, 2081 new onset type 2 diabetes events (368 dutasteride, 1207 finasteride, and 506 tamsulosin) were recorded during a mean follow-up time of 5.2 years (SD 3.1 years). The event rate per 10 000 person years was 76.2 (95% confidence interval 68.4 to 84.0) for dutasteride, 76.6 (72.3 to 80.9) for finasteride, and 60.3 (55.1 to 65.5) for tamsulosin. There was a modest increased risk of type 2 diabetes for dutasteride (adjusted hazard ratio 1.32, 95% confidence interval 1.08 to 1.61) and finasteride (1.26, 1.10 to 1.45) compared with tamsulosin. Results for the NHIRD were consistent with the findings for the CPRD (adjusted hazard ratio 1.34, 95% confidence interval 1.17 to 1.54 for dutasteride, and 1.49, 1.38 to 1.61 for finasteride compared with tamsulosin). Propensity score matched analyses showed similar results.

CONCLUSIONS:

The risk of developing new onset type 2 diabetes appears to be higher in men with benign prostatic hyperplasia exposed to 5α-reductase inhibitors than in men receiving tamsulosin, but did not differ between men receiving dutasteride and those receiving finasteride. Additional monitoring might be required for men starting these drugs, particularly in those with other risk factors for type 2 diabetes.

PMID:
30971393
DOI:
10.1136/bmj.l1204
[Indexed for MEDLINE]
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Conflict of interest statement

Competing interests: All authors have completed the ICMJE uniform disclosure form at www.icmje.org/coi_disclosure.pdf and declare: no support from any organisation for the submitted work; no financial relationships with any organisations that might have an interest in the submitted work in the previous three years; no other relationships or activities that could appear to have influenced the submitted work.

2.
BMJ. 2019 Apr 9;365:l1328. doi: 10.1136/bmj.l1328.

Efficacy and safety of dual SGLT 1/2 inhibitor sotagliflozin in type 1 diabetes: meta-analysis of randomised controlled trials.

Author information

1
Humanitas University Gradenigo Hospital, 8 Corso Regina Margherita, 10132 Turin, Italy giovanni_musso@yahoo.it.
2
Laboratory of Diabetes and Metabolic Disorders, Department of Medical Sciences, University of Turin, Turin, Italy.
3
Humanitas University Gradenigo Hospital, 8 Corso Regina Margherita, 10132 Turin, Italy.

Abstract

OBJECTIVE:

To assess the efficacy and safety of dual sodium glucose cotransporter (SGLT) 1/2 inhibitor sotagliflozin in type 1 diabetes mellitus.

DESIGN:

Meta-analysis of randomised controlled trials.

DATA SOURCES:

Medline; Cochrane Library; Embase; international meeting abstracts; international and national clinical trial registries; and websites of US, European, and Japanese regulatory authorities, up to 10 January 2019.

ELIGIBILITY CRITERIA FOR SELECTING STUDIES:

Randomised controlled trials evaluating the effect of sotagliflozin versus active comparators or placebo on glycaemic and non-glycaemic outcomes and on adverse events in type 1 diabetes in participants older than 18. Three reviewers extracted data for study characteristics, outcomes of interest, and risk of bias and summarised strength of evidence using the grading of recommendations assessment, development, and evaluation approach. Main outcomes were pooled using random effects models.

RESULTS:

Of 739 records identified, six randomised placebo controlled trials (n=3238, duration 4-52 weeks) were included. Sotagliflozin reduced levels of glycated haemoglobin (HbA1c; weighted mean difference -0.34% (95% confidence interval -0.41% to -0.27%), P<0.001); fasting plasma glucose (-16.98 mg/dL, -22.1 to -11.9; 1 mg/dL=0.0555 mmol/L) and two hour-postprandial plasma glucose (-39.2 mg/dL, -50.4 to -28.1); and daily total, basal, and bolus insulin dose (-8.99%, -10.93% to -7.05%; -8.03%, -10.14% to -5.93%; -9.14%, -12.17% to -6.12%; respectively). Sotagliflozin improved time in range (weighted mean difference 9.73%, 6.66% to 12.81%) and other continuous glucose monitoring parameters, and reduced body weight (-3.54%, -3.98% to -3.09%), systolic blood pressure (-3.85 mm Hg, -4.76 to -2.93), and albuminuria (albumin:creatinine ratio -14.57 mg/g, -26.87 to -2.28). Sotagliflozin reduced hypoglycaemia (weighted mean difference -9.09 events per patient year, -13.82 to -4.36) and severe hypoglycaemia (relative risk 0.69, 0.49 to 0.98). However, the drug increased the risk of ketoacidosis (relative risk 3.93, 1.94 to 7.96), genital tract infections (3.12, 2.14 to 4.54), diarrhoea (1.50, 1.08 to 2.10), and volume depletion events (2.19, 1.10 to 4.36). Initial HbA1c and basal insulin dose adjustment were associated with the risk of diabetic ketoacidosis. A sotagliflozin dose of 400 mg/day was associated with a greater improvement in most glycaemic and non-glycaemic outcomes than the 200 mg/day dose, without increasing the risk of adverse events. The quality of evidence was high to moderate for most outcomes, but low for major adverse cardiovascular events and all cause death. The relatively short duration of trials prevented assessment of long term outcomes.

CONCLUSIONS:

In type 1 diabetes, sotagliflozin improves glycaemic and non-glycaemic outcomes and reduces hypoglycaemia rate and severe hypoglycaemia. The risk of diabetic ketoacidosis could be minimised by appropriate patient selection and down-titration of the basal insulin dose.

PMID:
30967375
DOI:
10.1136/bmj.l1328
[Indexed for MEDLINE]
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3.
Diabet Med. 2019 Apr 10. doi: 10.1111/dme.13963. [Epub ahead of print]

Lipid profile is associated with treatment regimen in a large cohort of children and adolescents with Type 1 diabetes mellitus: a study from the international SWEET database.

Author information

1
Diabetes Centre, Division of Endocrinology, Diabetes and Metabolism, First Department of Paediatrics, National and Kapodistrian University of Athens, Medical School, Aghia Sophia Children's Hospital, Athens, Greece.
2
Institute of Epidemiology and Medical Biometry, ZIBMT, Ulm University, Ulm, Germany.
3
German Centre for Diabetes Research, Munich-Neuherberg, Germany.
4
Centre for Child Health Research, Telethon Kids Institute, University of Western, Australia.
5
J. N. Medical College (KAHER) and the KLE Diabetes Centre, KLES Dr Prabhakar Kore Hospital, Belgaum, India.
6
Hospital de Pediatria Garrahan, Buenos Aires, Argentina.
7
Faculty of Medicine and Health Sciences, Sherbrooke University, Sherbrooke, Canada.

Abstract

AIMS:

To examine the effect of pump vs injection therapy on the lipid profile of children with Type 1 diabetes mellitus.

METHODS:

A cross-sectional analysis of the lipid profile of children aged ≤ 18 years with Type 1 diabetes mellitus from SWEET, an international diabetes registry, was conducted with a focus on the effect of treatment regimen. Dyslipidaemia was defined as LDL cholesterol ≥2.6 mmol/l or non-HDL cholesterol ≥3.1 mmol/l. LDL and non-HDL cholesterol values among 14 290 children (52% boys, 51% receiving pump therapy) from 60 SWEET centres were analysed by linear and logistic regression analysis adjusted for sex, age, diabetes duration, HbA1c and BMI-standard deviation score group, region, and common interactions between age, sex, HbA1c and BMI.

RESULTS:

This study confirmed the established associations of increased lipids with female sex, age, diabetes duration, HbA1c and BMI. LDL and non-HDL cholesterol levels were lower in the pump therapy group compared to the injection therapy group [LDL cholesterol: injection therapy 2.44 mmol/l (95% CI 2.42 to 2.46) vs pump therapy 2.39 mmol/l (95% CI 2.37-2.41), P<0.001; non-HDL cholesterol: injection therapy 2.88 mmol/l (95% CI 2.86 to 2.90) vs pump therapy 2.80 mmol/l (95% CI 2.78-2.82), both P<0.0001]. Similarly, the odds ratios for LDL cholesterol ≥2.6 mmol/l [0.89 (95% CI 0.82-0.97)] and non-HDL cholesterol ≥3.1 mmol/l [0.85 (0.78 to 0.93)] were significantly lower in the pump therapy group, even after all adjustments.

CONCLUSIONS:

Our results indicate that pump therapy is associated with a better lipid profile. This article is protected by copyright. All rights reserved.

PMID:
30972800
DOI:
10.1111/dme.13963
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4.
Diabet Med. 2019 Apr 10. doi: 10.1111/dme.13964. [Epub ahead of print]

Incidence and predictors of recurrent and other new diabetic foot ulcers: a retrospective cohort study.

Author information

1
Steno Diabetes Centre Copenhagen, Gentofte, Denmark.

Abstract

AIMS:

To estimate progression rates, evaluate risk factors for progression, and study rate ratios for progression among people with a healed diabetic foot ulcer according to whether the healed ulcer was neuropathic, neuro-ischaemic or critically ischaemic.

METHODS:

We conducted a retrospective cohort study in all individuals with a healed diabetic foot ulcer treated at the Steno Diabetes Centre Copenhagen foot clinic in the period 2010 to 2016. The outcome of interest was recurrent/other new diabetic foot ulcers.

RESULTS:

A total of 780 people had a healed diabetic foot ulcer in the study period (2010-2016). The participants were followed for 1249 person-years [median (Q1-Q3) 1.04 (0.38-2.46) person-years] in total. One-third (33.1%) developed a recurrent/other new diabetic foot ulcer per year. Male gender, people with Type 2 diabetes and smokers had a statistically significantly higher risk of progression to a recurrent/other new diabetic foot ulcer compared to participants without these risk factors. Participants with neuro-ischaemic or critically ischaemic diabetic foot ulcers had statistically significantly higher progression rates than participants with neuropathic diabetic foot ulcers.

CONCLUSIONS:

Focus should be on preventing future recurrent/other new diabetic foot ulcers especially in people with ischaemia. This article is protected by copyright. All rights reserved.

PMID:
30972797
DOI:
10.1111/dme.13964
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5.
Diabet Med. 2019 Apr 10. doi: 10.1111/dme.13962. [Epub ahead of print]

Risk factors and outcomes for neonatal hypoglycaemia and neonatal hyperbilirubinaemia in pregnancies complicated by gestational diabetes mellitus: a single centre retrospective 3-year review.

Author information

1
School of Medicine, Western Sydney University.
2
Departmentt of Endocrinology, Campbelltown Hospital, Campbelltown, NSW, Australia.

Abstract

AIM:

To determine risk factors associated with neonatal hypoglycaemia and hyperbilirubinaemia, and assess their impact on neonatal outcomes in pregnancies complicated by gestational diabetes mellitus (GDM).

METHODS:

Retrospective review investigating all pregnancies complicated by GDM at Campbelltown Hospital (Sydney, Australia) between 1 January 2013 and 31 December 2015. Main outcomes measured were neonatal hypoglycaemia (capillary glucose levels < 1.8 mmol/l) and hyperbilirubinaemia (total serum bilirubin levels greater than age-appropriate thresholds for phototherapy). Adjusted odds ratios [95% confidence interval (CI)] are shown, calculated by multivariable logistic regression.

RESULTS:

Some 60 (7.8%) infants developed hypoglycaemia, 58 (7.5%) developed hyperbilirubinaemia and 13 (1.7%) developed both. Risk of developing hypoglycaemia increased 1.8-fold (95% CI 1.3-2.6, P < 0.001) per gestational week at GDM diagnosis, 1.1-fold (95% CI 1.0-1.3, P = 0.04) per mmol/l maternal fasting glucose, 6.2-fold (95% CI 2.6-16.2, P < 0.001) with maternal history of macrosomia, 10.8-fold (95% CI 4.1-27.6, P < 0.001) with multiple pregnancy and 1.1-fold (95% CI 1.0-1.3, P = 0.04) per gestational week at birth. Risk of hyperbilirubinaemia increased with multiple pregnancy (26.4; 95% CI 11.7-59.7, P < 0.001), and 1.5-fold (95% CI 1.1-2.1, P = 0.01) per gestational week at GDM diagnosis. Hypoglycaemia was associated with a 2.8-fold (95% CI 1.1-7.1, P = 0.03) increased risk of macrosomia, a 5.4-fold (95% CI 1.1-27.3, P = 0.04) excess risk of shoulder dystocia and a 6.4-fold increased risk of 5-min APGAR ≤ 7 (95% CI 1.2-1.7, P < 0.001). Hyperbilirubinaemia was associated with an excess risk of polycythaemia (packed cell volume > 0.6; 97.1, 95% CI 38.9-241.5, P < 0.001).

CONCLUSIONS:

Neonatal hypoglycaemia and hyperbilirubinaemia largely occur in different pregnancies. Both are associated with earlier GDM diagnosis; however, hypoglycaemia is more associated with maternal glycaemia and its sequelae, and hyperbilirubinaemia is associated with polycythaemia. This article is protected by copyright. All rights reserved.

PMID:
30972790
DOI:
10.1111/dme.13962
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6.
Diabet Med. 2019 Apr 6. doi: 10.1111/dme.13960. [Epub ahead of print]

Persistent C-peptide is associated with reduced hypoglycaemia but not HbA1c in adults with longstanding Type 1 diabetes: evidence for lack of intensive treatment in UK clinical practice?

Author information

1
Institute of Biomedical and Clinical Science, London, UK.
2
NIHR Exeter Clinical Research Facility, University of Exeter Medical School, London, UK.
3
Blood Sciences, Royal Devon and Exeter NHS Foundation Trust, Exeter, London, UK.
4
Department of Immunobiology, School of Immunobiology & Microbial Sciences, Kings College London, London, UK.
5
NIHR Biomedical Research Centre Guys and St Thomas' NHS Foundation Trust and Kings College London, London, UK.
6
Department of Diabetes Immunology, Diabetes& Metabolism Research Institute at the City of Hope National Medical Center,, Duarte, CA, USA.
7
Department of Immunohaematology & Blood Transfusion, Leiden University Medical Center, Leiden, The Netherlands.

Abstract

AIMS:

Most people with Type 1 diabetes have low levels of persistent endogenous insulin production. The Diabetes Control and Complications Trial showed that close to diagnosis preserved endogenous insulin was associated with lower HbA1c , hypoglycaemia and complication rates, when intensively treated. We aimed to assess the clinical impact of persistent C-peptide on rate of hypoglycaemia and HbA1c in those with long duration (> 5 years) Type 1 diabetes.

METHODS:

We conducted a cross-sectional case-control study of 221 people (median age 24 years) with Type 1 diabetes. We confirmed ongoing endogenous insulin secretion by measuring C-peptide after a mixed-meal tolerance test. We compared self-reported hypoglycaemia (n = 160), HbA1c , insulin dose and microvascular complications (n = 140) in those with preserved and low C-peptide.

RESULTS:

Stimulated median (IQR) C-peptide was 114 (43, 273) pmol/l and < 3 (< 3, < 3) pmol/l in those with preserved and low C-peptide respectively. Participants with preserved C-peptide had lower reported monthly rates of hypoglycaemia, with 21% fewer symptomatic episodes, 5.9 vs. 7.5 [incidence rate ratio (IRR) 0.79, P = 0.001], and 65% fewer asymptomatic episodes, 1.0 vs. 2.9 (IRR 0.35, P < 0.001). Those with preserved C-peptide had a lower insulin dose (0.68 vs. 0.81 units/kg, P = 0.01) but similar HbA1c (preserved 69 vs. low 67 mmol/mol, P = 0.06).

CONCLUSIONS:

Adults with Type 1 diabetes and preserved endogenous insulin production receiving usual care in the UK have lower daily insulin doses and fewer self-reported hypoglycaemic episodes, but no difference in HbA1c . This is consistent with non-intensive treatment in previous studies, and suggests a need to consider therapy intensification to gain full benefit of preserved endogenous insulin. This article is protected by copyright. All rights reserved.

PMID:
30955221
DOI:
10.1111/dme.13960
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7.
Diabetes. 2019 Apr 9. pii: db190057. doi: 10.2337/db19-0057. [Epub ahead of print]

Low-dose Anti-Thymocyte Globulin Preserves C-Peptide and Reduces A1c in New Onset Type 1 Diabetes: Two Year Clinical Trial Data.

Author information

1
From the University of Florida Diabetes Institute, Gainesville, FL (M.J.H., D.A.S. M.A.A.), Benaroya Research Institute, Seattle, WA (S.A.L, L.B. and C.J.G), Diabetes Research Institute, University of Miami Miller School of Medicine, Miami, FL, (J.S.S., D.B., J.B.M.), University of South Florida, Tampa, FL (J.P.K, B.N.B., S.M.G., M.W., J.L.M., H.R.), University of Pittsburgh, Pittsburgh, PA (D.J.B.), Indiana University, Indianapolis, IN (L.A.D.), University of California San Francisco, San Francisco, CA (S.E.G.), Columbia University, New York, NY (R.G.), University of Colorado Barbara Davis Center for Childhood Diabetes, Aurora, CO, (P.A.G.), Yale University, New Haven, CT (K.C.H.), University of Minnesota, Minneapolis, MN, (A.M.), Vanderbilt University, Nashville, TN (W.E.R.), The National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD (L.M.S.), and Stanford University, Stanford, CA (D.M.W.). hallemj@peds.ufl.edu.
2
From the University of Florida Diabetes Institute, Gainesville, FL (M.J.H., D.A.S. M.A.A.), Benaroya Research Institute, Seattle, WA (S.A.L, L.B. and C.J.G), Diabetes Research Institute, University of Miami Miller School of Medicine, Miami, FL, (J.S.S., D.B., J.B.M.), University of South Florida, Tampa, FL (J.P.K, B.N.B., S.M.G., M.W., J.L.M., H.R.), University of Pittsburgh, Pittsburgh, PA (D.J.B.), Indiana University, Indianapolis, IN (L.A.D.), University of California San Francisco, San Francisco, CA (S.E.G.), Columbia University, New York, NY (R.G.), University of Colorado Barbara Davis Center for Childhood Diabetes, Aurora, CO, (P.A.G.), Yale University, New Haven, CT (K.C.H.), University of Minnesota, Minneapolis, MN, (A.M.), Vanderbilt University, Nashville, TN (W.E.R.), The National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD (L.M.S.), and Stanford University, Stanford, CA (D.M.W.).

Abstract

A three-arm, randomized, double-masked, placebo-controlled phase 2b trial performed by the Type 1 Diabetes TrialNet Study Group previously demonstrated that low-dose anti-thymocyte globulin (ATG, 2.5mg/kg) preserved β-cell function and reduced HbA1c for one year in new-onset type 1 diabetes. Subjects (N=89) were randomized to: 1) ATG and pegylated granulocyte-colony stimulating factor (GCSF); 2) ATG alone; or 3) placebo. Herein, we report two-year AUC C-peptide and HbA1c, pre-specified secondary endpoints, and potential immunologic correlates. The two-year mean mixed-meal tolerance test (MMTT)-stimulated AUC C-peptide, analyzed by ANCOVA adjusting for baseline C-peptide, age, and sex (N=82) with significance defined as one-sided p<0.025, was significantly higher in subjects treated with ATG versus placebo (p=0.00005) but not ATG/GCSF versus placebo (p=0.032). HbA1c was significantly reduced at 2-years in subjects treated with ATG (p=0.011) and ATG/GCSF (p=0.022) versus placebo. Flow-cytometric analyses demonstrated reduced circulating CD4:CD8 ratio, increased regulatory T cell (Treg): conventional CD4 T cell (Tconv) ratios, and increased PD-1+CD4+ T cells following low-dose ATG and ATG/GCSF. Low-dose ATG partially preserved β-cell function and reduced HbA1c two years after therapy in new-onset type 1 diabetes. Future studies should determine whether low-dose ATG might prevent or delay the onset of type 1 diabetes.

PMID:
30967424
DOI:
10.2337/db19-0057
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8.
Diabetes. 2019 Apr 8. pii: db190045. doi: 10.2337/db19-0045. [Epub ahead of print]

Trisomy 21 is a Cause of Permanent Neonatal Diabetes that is Autoimmune but not HLA Associated.

Author information

1
Institute of Biomedical and Clinical Science, University of Exeter Medical School, Exeter, UK.
2
Section of Adult and Pediatric Endocrinology, Diabetes and Metabolism, Kovler Diabetes Center, The University of Chicago, Chicago, IL, USA.
3
Bristol Medical School, University of Bristol, Bristol, U.K.
4
Institute of Biomedical and Clinical Science, University of Exeter Medical School, Exeter, UK A.T.Hattersley@exeter.ac.uk.

Abstract

Identifying new causes of permanent neonatal diabetes (diagnosis <6 months; PNDM) provides important insights into β-cell biology. Patients with Down syndrome (DS) resulting from trisomy 21 are 4 times more likely to have childhood diabetes with an intermediate HLA association. It is not known if DS can cause PNDM. We found trisomy 21 was 7 times more likely in our PNDM cohort than in the population (13/1522 = 85/10,000 observed vs. 12.6/10,000 expected) and none of the 13 DS-PNDM cases had a mutation in the known PNDM genes which explained 82.9% of non-DS PNDM. Islet autoantibodies were present in 4/9 DS-PNDM patients but DS-PNDM was not associated with polygenic susceptibility to type 1 diabetes. We conclude that trisomy 21 is a cause of autoimmune PNDM that is not HLA associated. We propose that autoimmune diabetes in DS is heterogeneous and includes coincidental type 1 diabetes that is HLA associated and diabetes caused by trisomy 21 that is not HLA associated.

PMID:
30962220
DOI:
10.2337/db19-0045
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9.
Diabetes. 2019 Apr 8. pii: db181128. doi: 10.2337/db18-1128. [Epub ahead of print]

Genetic Variation Within the HLA-DRA1 Gene Modulates Susceptibility to Type 1 Diabetes in HLA-DR3 Homozygotes.

Author information

1
Department of Medicine, Divisions of Transfusion Medicine, University of Massachusetts Medical School, Worcester, MA.
2
Children's Hospital Oakland Research Institute, Oakland, CA.
3
Department of Clinical Sciences, Lund University/CRC, Skåne University Hospital, Malmö, Sweden.
4
Department of Microbiology and Immunology, Drexel University College of Medicine, Philadelphia, PA.
5
Department of Medicine and Endocrinology, University of Massachusetts Medical School, Worcester, MA John.Mordes@umassmed.edu.

Abstract

Type 1 diabetes (T1D) involves the interaction of multiple gene variants, environmental factors, and immunoregulatory dysfunction. Major T1D genetic risk loci T1D encode the Human Leukocyte Antigens HLA-DR and DQ. Genetic heterogeneity and linkage disequilibrium in the highly polymorphic HLA region confound attempts to identify additional T1D susceptibility loci. To minimize HLA heterogeneity, T1D patients (N=365) and controls (N=668) homozygous for the HLA-DR3 high-risk haplotype were selected from multiple large T1D studies and examined to identify new T1D susceptibility loci using molecular inversion probe sequencing technology. We report that risk for T1D in HLA-DR3 homozygotes is increased significantly by a previously unreported haplotype of three SNPs within the first intron of HLA-DRA1. The homozygous risk haplotype has an odds ratio of 4.65 relative to the protective homozygous haplotype in our sample. Individually, these SNPs reportedly function as "expression quantitative trait loci," modulating HLA-DR and DQ expression. Analysis of available data concludes that the tri-SNP haplotype within HLA-DRA1 may modulate class II expression, suggesting that increased T1D risk could be attributable to regulated expression of class II genes. These findings could help clarify the role of HLA in T1D susceptibility and improve diabetes risk assessment, particularly in high-risk HLA-DR3 homozygous individuals.

PMID:
30962219
DOI:
10.2337/db18-1128
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10.
Diabetes Care. 2019 Apr 9. pii: dc181796. doi: 10.2337/dc18-1796. [Epub ahead of print]

Diabetes-Related Complications and Mortality in Patients With Young-Onset Latent Autoimmune Diabetes: A 14-Year Analysis of the Prospective Hong Kong Diabetes Register.

Luk AOY1,2,3, Lau ESH4, Lim C5, Kong APS5,2,3, Chow E5, Ma RCW5,2,3, Chan JCN5,2,3.

Author information

1
Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong Special Administrative Region, People's Republic of China andrealuk@cuhk.edu.hk.
2
Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong Special Administrative Region, People's Republic of China.
3
Hong Kong Institute of Diabetes and Obesity, The Chinese University of Hong Kong, Hong Kong Special Administrative Region, People's Republic of China.
4
Asia Diabetes Foundation, Hong Kong Special Administrative Region, People's Republic of China.
5
Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong Special Administrative Region, People's Republic of China.

Abstract

OBJECTIVE:

Young-onset diabetes is heterogeneous in etiology and disease progression. We compared the incidence of diabetes-related complications and mortality in patients with young-onset type 2 diabetes with or without anti-GAD antibodies and patients with type 1 diabetes. We determined changes in glycemic control before and after commencement of insulin therapy stratified by antibody status.

RESEARCH DESIGN AND METHODS:

Between 1994 and 2012, 1,504 consecutively enrolled patients with type 2 diabetes who had received a diagnosis at <40 years of age and had available anti-GAD antibody status, and 251 patients with type 1 diabetes from the Hong Kong Diabetes Register were followed for incident cardiovascular disease (CVD), end-stage renal disease (ESRD), severe hypoglycemia, and all-cause mortality until June 2015. Information on insulin use and HbA1c levels during follow-up was obtained.

RESULTS:

Anti-GAD antibodies were positive in 8.1% of patients with type 2 diabetes (GAD+). Using multivariate Cox regression, patients with GAD+ had a lower hazard of CVD (hazard ratio [HR] 0.43, P = 0.048), a higher hazard of severe hypoglycemia (HR 1.63, P = 0.032), and a similar hazard of ESRD and mortality compared with counterparts without anti-GAD antibodies (GAD-). Compared with patients with type 1 diabetes, ESRD were more likely to develop (HR 2.91, P = 0.043) in patients with GAD+, but no differences were detected in the hazards of severe hypoglycemia, CVD, and mortality. Among new insulin users (n = 304), patients with GAD+ had larger reductions in HbA1c than patients with GAD-after 12 months of insulin use (-2.30 ± 3.80% [25 ± 42 mmol/mol] vs -0.72 ± 1.86% [8 ± 20 mmol/mol], P = 0.05).

CONCLUSIONS:

Anti-GAD positivity identifies a group of patients with a different prognosis compared with patients without antibodies and those with type 1 diabetes. Patients with GAD+ responded differently to insulin compared with patients with GAD-.

PMID:
30967437
DOI:
10.2337/dc18-1796
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11.
Diabetes Care. 2019 Apr 9. pii: dc182591. doi: 10.2337/dc18-2591. [Epub ahead of print]

Efficacy of Fish Oil and/or Probiotic Intervention on the Incidence of Gestational Diabetes Mellitus in an At-Risk Group of Overweight and Obese Women: A Randomized, Placebo-Controlled, Double-Blind Clinical Trial.

Author information

1
Department of Obstetrics and Gynecology, University of Turku and Turku University Hospital, Turku, Finland outi.pellonpera@utu.fi.
2
Institute of Biomedicine, Integrative Physiology, and Pharmacology, University of Turku, Turku, Finland.
3
Institute of Clinical Medicine, Biostatistics, University of Turku, Turku, Finland.
4
Department of Obstetrics and Gynecology, University of Turku and Turku University Hospital, Turku, Finland.
5
Department of Medicine, University of Turku and Turku University Hospital, Turku, Finland.

Abstract

OBJECTIVE:

To assess whether the risk of gestational diabetes mellitus (GDM) may be lowered and glucose metabolism improved by daily administration of fish oil and/or probiotic supplements in overweight and obese pregnant women.

RESEARCH DESIGN AND METHODS:

We randomized in a double-blind manner 439 women (mean 13.9 ± 2.1 gestational weeks [gw]) into four intervention groups: fish oil + placebo, probiotics + placebo, fish oil + probiotics, and placebo + placebo. Fish oil (1.9 g docosahexaenoic acid and 0.22 g eicosapentaenoic acid) and probiotic supplements (Lactobacillus rhamnosus HN001 and Bifidobacterium animalis ssp. lactis 420, 1010 colony-forming units each) were provided for daily consumption from randomization beyond delivery. Primary outcomes were the incidence of GDM diagnosed with oral glucose tolerance test targeted at 24-28 gw and the change in fasting glucose between randomization and late pregnancy (mean 35.2 ± 0.9 gw). Insulin concentration, insulin resistance HOMA2-IR index, and pregnancy outcomes were determined, as were adverse effects related to the intervention. Analyses were by intent to treat.

RESULTS:

No differences were found among the intervention groups in the maternal and neonatal pregnancy outcomes or side effects related to the intervention (P > 0.05). The proportion of women with GDM (94 of 377; fish oil + placebo, 23 of 96, 24.0%; probiotics + placebo, 25 of 99, 25.3%; fish oil + probiotics, 26 of 91, 28.6%; and placebo + placebo, 20 of 91, 22.0%) or the change in glucose, insulin, or HOMA2-IR (n = 364) did not differ among the intervention groups (P > 0.11 for all comparisons).

CONCLUSIONS:

An intervention with fish oil and/or probiotics during pregnancy seemed to be both safe and well tolerated but conferred no benefits in lowering the risk of GDM or improving glucose metabolism in overweight and obese women.

PMID:
30967436
DOI:
10.2337/dc18-2591
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12.
Diabetes Care. 2019 Apr 9. pii: dc182147. doi: 10.2337/dc18-2147. [Epub ahead of print]

Elevated Serum Uric Acid Is Associated With Greater Risk for Hypertension and Diabetic Kidney Diseases in Obese Adolescents With Type 2 Diabetes: An Observational Analysis From the Treatment Options for Type 2 Diabetes in Adolescents and Youth (TODAY) Study.

Author information

1
University of Colorado Anschutz Medical Campus and Children's Hospital Colorado, Aurora, CO.
2
Joslin Diabetes Center, Boston, MA.
3
The University of Texas Health Science Center at San Antonio, San Antonio, TX.
4
George Washington University Biostatistics Center, Rockville, MD elghorml@bsc.gwu.edu.
5
Department of Medicine, State University of New York Upstate Medical University, Syracuse, NY.
6
Department of Pediatrics, Saint Louis University Health Sciences Center, St. Louis, MO.

Abstract

OBJECTIVE:

Elevated serum uric acid (SUA) is increasingly recognized as a risk factor for kidney disease in adults with diabetes, but data in youth are limited. We hypothesized that elevated SUA predicts development of elevated urinary albumin excretion (UAE) and hypertension over time in teens with type 2 diabetes (T2D).

RESEARCH DESIGN AND METHODS:

Serum creatinine, cystatin C, SUA, and the urine albumin-to-creatinine ratio (UACR) were assessed in 539 obese youth, ages 12-17 years, with T2D duration <2 years at baseline in the Treatment Options for Type 2 Diabetes in Adolescents and Youth (TODAY) study. Estimated glomerular filtration rate (eGFR) was calculated using creatinine and cystatin C. Hypertension was defined as systolic or diastolic blood pressure ≥130/80 mmHg and elevated urine albumin excretion (UAE) as UACR ≥30 mg/g. Cox proportional hazard models evaluated the relationship between SUA and outcome variables longitudinally over an average follow-up of 5.7 years, adjusting for age, sex, race/ethnicity, BMI, HbA1c, eGFR, ACE inhibitor/angiotensin receptor blocker use, and TODAY treatment group assignment.

RESULTS:

At baseline, hyperuricemia (≥6.8 mg/dL) was present in 25.6% of participants, hypertension in 18.7%, and elevated UAE in 6.1%. During follow-up of up to 7 years, hypertension developed in 37.4% and UAE in 18.0%. Higher baseline SUA increased the risk of incident hypertension (hazard ratio [HR] 1.19, 95% CI 1.03-1.38, per 1 mg/dL increase in SUA) and elevated UAE (HR 1.24, 95% CI 1.03-1.48) in adjusted models.

CONCLUSIONS:

Hyperuricemia was common in youth with T2D. Higher baseline SUA independently increased the risk for onset of hypertension and elevated UAE. Research is needed to determine whether SUA-lowering therapies can impede development of diabetic kidney disease and hypertension in T2D youth.

PMID:
30967435
DOI:
10.2337/dc18-2147
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13.
Diabetes Care. 2019 Apr 9. pii: dc181983. doi: 10.2337/dc18-1983. [Epub ahead of print]

Glucose Variables in Type 1 Diabetes Studies With Dapagliflozin: Pooled Analysis of Continuous Glucose Monitoring Data From DEPICT-1 and -2.

Author information

1
Clinical and Experimental Endocrinology, University of Leuven, Leuven, Belgium chantal.mathieu@uzleuven.be.
2
Department of Medicine, State University of New York at Buffalo, Buffalo, NY.
3
Institute for Endocrinology & Diabetes, Schneider Children's Medical Centre of Israel, Petah Tikva, Israel.
4
Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel.
5
Institute of Medicine, University of Gothenburg, Gothenburg, Sweden.
6
Department of Medicine, NU Hospital Group, Uddevalla, Sweden.
7
MedImmune, Gaithersburg, MD.
8
AstraZeneca, Mölndal, Sweden.
9
AstraZeneca, Gaithersburg, MD.

Abstract

OBJECTIVE:

This pooled analysis assessed continuous glucose monitoring (CGM) in patients with inadequately controlled type 1 diabetes (HbA1c ≥7.7 to ≤11.0% [≥61 to ≤97 mmol/mol]) who received dapagliflozin as an adjunct to adjustable insulin.

RESEARCH DESIGN AND METHODS:

CGM data were pooled from two 24-week, double-blind, randomized, phase 3 studies: Dapagliflozin Evaluation in Patients with Inadequately Controlled Type 1 diabetes (DEPICT-1 and DEPICT-2). These studies comprised 1,591 patients receiving dapagliflozin 5 mg (n = 530), dapagliflozin 10 mg (n = 529), or placebo (n = 532).

RESULTS:

Baseline characteristics were balanced between treatment groups. Patients receiving dapagliflozin 5 mg or 10 mg both spent more time with HbA1c in the range of >3.9 to ≤10.0 mmol/L (>70 to ≤180 mg/dL) over 24 h than those receiving the placebo. The adjusted mean (SE) change from baseline at week 24 was 6.48% (0.60) with dapagliflozin 5 mg, 8.08% (0.60) with dapagliflozin 10 mg, and -2.59% (0.61) with placebo. At week 24, the mean amplitude of glucose excursion over 24 h, mean 24-h glucose values, and postprandial glucose values were also improved in patients receiving dapagliflozin over those receiving placebo. No marked differences were found at week 24 between dapagliflozin 5 or 10 mg and placebo with regard to the percentage of glucose values ≤3.9 mmol/L (≤70 mg/dL) or ≤3.0 mmol/L (≤54 mg/dL) over 24 h, or to nocturnal (0000-0559 h) glucose values ≤3.9 mmol/L (≤70 mg/dL).

CONCLUSIONS:

In patients with type 1 diabetes, treatment with dapagliflozin over 24 weeks improved time in range, mean glucose, and glycemic variability without increasing the time spent in the range indicating hypoglycemia.

PMID:
30967434
DOI:
10.2337/dc18-1983
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14.
Diabetes Care. 2019 Apr 9. pii: dc182282. doi: 10.2337/dc18-2282. [Epub ahead of print]

Predicting Islet Cell Autoimmunity and Type 1 Diabetes: An 8-Year TEDDY Study Progress Report.

Collaborators (225)

Rewers M, Bautista K, Baxter J, Felipe-Morales D, Driscoll K, Frohnert BI, Gallant M, Gesualdo P, Hoffman M, Karban R, Liu E, Norris J, Steck A, Waugh K, Toppari J, Simell OG, Adamsson A, Ahonen S, Hekkala MÅA, Holappa H, Hyöty H, Ikonen A, Ilonen J, Jäminki S, Jokipuu S, Karlsson L, Kähönen M, Knip M, Koivikko ML, Koreasalo M, Kurppa K, Kytölä J, Latva-Aho T, Lindfors K, Lönnrot M, Mäntymäki E, Mattila M, Multasuo K, Mykkänen T, Niininen T, Niinistö S, Nyblom M, Oikarinen S, Ollikainen P, Pohjola S, Rajala P, Rautanen J, Riikonen A, Romo M, Ruohonen S, Simell S, Sjöberg M, Stenius A, Tossavainen P, Vähä-Mäkilä M, Vainionpää S, Varjonen E, Veijola R, Viinikangas I, Virtanen SM, She JX, Schatz D, Hopkins D, Steed L, Bryant J, Silvis K, Haller M, Gardiner M, McIndoe R, Sharma A, Anderson SW, Jacobsen L, Marks J, Towe PD, Ziegler AG, Bonifacio E, D'Angelo M, Gavrisan A, Gezginci C, Heublein A, Hoffmann V, Hummel S, Keimer A, Knopff A, Koch C, Koletzko S, Ramminger C, Roth R, Scholz M, Stock J, Warncke K, Wendel L, Winkler C, Lernmark Å, Agardh D, Aronsson CA, Ask M, Bremer J, Cilio C, Ericson-Hallström E, Fors A, Fransson L, Gard T, Bennet R, Hansen M, Hyberg S, Jisser H, Johansen F, Jonsdottir B, Jovic S, Larsson HE, Lindström M, Lundgren M, Månsson-Martinez M, Markan M, Melin J, Mestan Z, Nilsson C, Ottosson K, Rahmati K, Ramelius A, Salami F, Sjöberg A, Sjöberg B, Törn C, Wallin A, Wimar Å, Åberg S, Hagopian WA, Killian M, Crouch CC, Skidmore J, Akramoff A, Chavoshi M, Dunson K, Hervey R, Lyons R, Meyer A, Mulenga D, Radtke J, Romancik M, Schmitt D, Schwabe J, Zink S, Becker D, Franciscus M, Smith MD, Daftary A, Klein MB, Yates C, Krischer JP, Austin-Gonzalez S, Avendano M, Baethke S, Brown R, Burkhardt B, Butterworth M, Clasen J, Cuthbertson D, Eberhard C, Fiske S, Garmeson J, Gowda V, Heyman K, Hsiao B, Karges C, Laras FP, Lee HS, Li Q, Liu S, Liu X, Lynch K, Maguire C, Malloy J, McCarthy C, Merrell A, Meulemans S, Parikh H, Quigley R, Remedios C, Shaffer C, Smith L, Smith S, Sulman N, Tamura R, Tewey D, Toth M, Uusitalo U, Vehik K, Vijayakandipan P, Wood K, Yang J, Yu L, Miao D, Bingley P, Williams A, Chandler K, Ball O, Kelland I, Grace S, Gillard B, Hagopian W, Chavoshi M, Radtke J, Schwabe J, Erlich H, Mack SJ, Fear AL, Ke S, Mulholland N, Rich SS, Chen WM, Onengut-Gumuscu S, Farber E, Pickin RR, Davis J, Davis J, Gallo D, Bonnie J, Campolieto P, Akolkar B, Bourcier K, Briese T, Johnson SB, Triplett E.

Abstract

OBJECTIVE:

Assessment of the predictive power of TEDDY-identified risk factors for islet autoimmunity (IA), the type of autoantibody appearing first, and type 1 diabetes (T1D).

RESEARCH DESIGN AND METHODS:

A total of 7,777 children were followed from birth to a median of 9.1 years of age for the development of islet autoantibodies and progression to T1D. Time-dependent sensitivity, specificity, and receiver operating characteristic (ROC) curves were calculated to provide estimates of their individual and collective ability to predict IA and T1D.

RESULTS:

HLA genotype (DR3/4 vs. others) was the best predictor for IA (Youden's index J = 0.117) and single nucleotide polymorphism rs2476601, in PTPN22, was the best predictor for insulin autoantibodies (IAA) appearing first (IAA-first) (J = 0.123). For GAD autoantibodies (GADA)-first, weight at 1 year was the best predictor (J = 0.114). In a multivariate model, the area under the ROC curve (AUC) was 0.678 (95% CI 0.655, 0.701), 0.707 (95% CI 0.676, 0.739), and 0.686 (95% CI 0.651, 0.722) for IA, IAA-first, and GADA-first, respectively, at 6 years. The AUC of the prediction model for T1D at 3 years after the appearance of multiple autoantibodies reached 0.706 (95% CI 0.649, 0.762).

CONCLUSIONS:

Prediction modeling statistics are valuable tools, when applied in a time-until-event setting, to evaluate the ability of risk factors to discriminate between those who will and those who will not get disease. Although significantly associated with IA and T1D, the TEDDY risk factors individually contribute little to prediction. However, in combination, these factors increased IA and T1D prediction substantially.

PMID:
30967432
DOI:
10.2337/dc18-2282
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15.
J Clin Endocrinol Metab. 2019 Apr 12. pii: jc.2018-02507. doi: 10.1210/jc.2018-02507. [Epub ahead of print]

Endothelial function, adipokine serum levels and white matter hyperintesities in subjects with diabetic foot syndrome.

Author information

1
Department of Promoting Health, Maternal-Infant. Excellence and Internal and Specialized Medicine G. D'Alessandro, University of Palermo ( Italy).
2
Department of Surgical, Oncological and Oral Sciences (Di.Chir.On.S.).
3
Internal Medicine and Stroke Care Ward, Department of Promoting Health, Maternal-Infant. Excellence and Internal and Specialized Medicine G. D'Alessandro, University of Palermo ( Italy).
4
Section of Clinical Biochemistry and Molecular Biology, Department of Biopathology and Medical Biotechnologies (Di.Bi.Med.), University of Palermo.
5
Triolo Zancla Home Care, Palermo.

Abstract

CONTEXT:

No study analysed the prevalence of white matter hyperintesities (WMHs) in subjects with diabetic foot syndrome (DFS) and their relationship with adipokine serum levels and indexes of endothelial and cognitive performance.

OBJECTIVE:

To evaluate omentin and vaspin serum levels and WMHs prevalence in subjects with DFS and to analyse their relationship with other endothelial, arterial stiffness and cognitive function.

RESEARCH DESIGN AND METHODS:

Case-control study enrolling 40 subjects with DFS, 40 diabetic subjects without foot complications, 40 controls with foot lesions without diabetes and 40 patients without diabetes mellitus.

MAIN OUTCOME MEASURE:

Pulse wave velocity (PWV), augmentation index (Aix), Reactive hyperemia index (RHI), serum vaspin and omentin levels, Fazekas Score, MMSE.

RESULTS:

Subjects with DFS showed higher mean PWV values if compared with diabetic controls, lower RHI values if compared with controls. They also showed a lower mean MMSE score, significantly lower omentin serum levels, a higher prevalence of grade 2 severity of periventricular hyperintensities (PVH). We observed a significant positive correlation between PWV and PVH, between Fazekas Score and PWV among diabetic subjects, whereas among subjects with diabetic foot we observed a significant negative correlation between PVH and RHI.

CONCLUSIONS:

Diabetes seems to be more associated with endothelial function disturbance in comparison with patients with diabetic foot that exhibit a more strict association with microvascular brain damage as indicated by our significant finding of an association with periventricular hyperintensities.

16.
J Clin Endocrinol Metab. 2019 Apr 12. pii: jc.2018-02397. doi: 10.1210/jc.2018-02397. [Epub ahead of print]

Identifying Pathogenic Variants of Monogenic Diabetes Using Targeted Panel Sequencing in an East Asian Population.

Park SS1, Jang SS2, Ahn CH1, Kim JH1, Jung HS1, Cho YM1,3, Lee YA4, Shin CH4,5, Chae JH4,5, Kim JH6, Choi SH3,7, Jang HC3,7, Bae JC8, Won JC9, Kim SH10,11, Kim JI2,12,13, Kwak SH1, Park KS1,3,14.

Author information

1
Department of Internal Medicine, Seoul National University Hospital, Seoul, Republic of Korea.
2
Department of Biomedical Sciences, Seoul National University Graduate School, Seoul, Republic of Korea.
3
Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Republic of Korea.
4
Department of Pediatrics, Seoul National University Hospital, Seoul, Republic of Korea.
5
Department of Pediatrics, Seoul National University College of Medicine, Seoul, Republic of Korea.
6
Department of Pediatrics, Seoul National University Bundang Hospital, Seongnam, Republic of Korea.
7
Department of Internal Medicine, Seoul National University Bundang Hospital.
8
Department of Internal Medicine, Samsung Changwon Hospital, Changwon, Republic of Korea.
9
Department of Internal Medicine, Sanggye Paik Hospital, Seoul, Republic of Korea.
10
Department of Internal Medicine, Cheil General Hospital & Women's Healthcare Center, Seoul, Republic of Korea.
11
Department of Internal Medicine, Dankook University College of Medicine, Seoul, Republic of Korea.
12
Department of Biochemistry and Molecular Biology, Seoul National University College of Medicine, Seoul, Republic of Korea.
13
Genomic Medicine Institute, Medical Research Center, Seoul National University, Seoul, Republic of Korea.
14
Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology, Seoul National University, Seoul, Republic of Korea.

Abstract

PURPOSE:

Monogenic diabetes is a specific type of diabetes in which precision medicine could be applied. In this study, we used targeted panel sequencing to investigate pathogenic variants in Korean patients clinically suspected to have monogenic diabetes.

METHODS:

The eligibility criteria for inclusion were non-type 1 diabetes patients with an age of onset ≤ 30 years and a BMI (body mass index) ≤ 30 kg/m2. Among the 2,090 non-type 1 diabetes patients, 109 were suspected to have monogenic diabetes and subjected to genetic testing. We analyzed 30 monogenic diabetes genes using targeted panel sequencing. The pathogenicity of the genetic variants was evaluated according to the American College of Medical Genetics and Genomics and the Association for Molecular Pathology guidelines.

RESULTS:

Among the 109 suspected monogenic diabetes patients, 23 (21.1%) patients harbored pathogenic/likely pathogenic variants. A total of 14 pathogenic/likely pathogenic variants of common maturity onset diabetes of the young (MODY) genes were identified in GCK, HNF1A, HNF4A, and HNF1B. Other pathogenic/likely pathogenic variants were identified in WFS1, INS, ABCC8 and FOXP3. The mitochondrial DNA 3243 A>G variant was identified in five participants. Patients with pathogenic/likely pathogenic variants had a significantly higher MODY probability, a lower BMI, and a lower C-peptide level than those without pathogenic/likely pathogenic variants (P=0.007, P=0.001, and P=0.012, respectively).

CONCLUSIONS:

Using targeted panel sequencing followed by pathogenicity evaluation, we were able to make molecular genetic diagnoses for 23 (21.1%) suspected monogenic diabetes patients. Lower BMI, higher MODY probability, and lower C-peptide levels were characteristics of these participants.

17.
J Clin Endocrinol Metab. 2019 Apr 8. pii: jc.2019-00087. doi: 10.1210/jc.2019-00087. [Epub ahead of print]

Effect of the GLP-1 receptor agonist exenatide on impaired awareness of hypoglycemia in type 1 diabetes; a randomized controlled trial.

Author information

1
Department of Internal Medicine, Radboud university medical center, Nijmegen, the Netherlands.

Abstract

CONTEXT:

Impaired awareness of hypoglycemia (IAH), resulting from habituation to recurrent hypoglycemia, can be reversed by strict avoidance of hypoglycemia. Adjunctive treatment with glucagon-like peptide-1 (GLP-1) receptor agonists may reduce glucose variability, hence lower the risk of hypoglycemia and improve awareness. The aim of our study was to investigate the effect of exenatide on awareness of hypoglycemia in people with type 1 diabetes and IAH.

METHODS:

This was a randomized double-blind, placebo-controlled cross-over trial. Ten patients with type 1 diabetes and IAH were included (age 38.5±4.4 years, 40% males, HbA1c 7.2±0.4 % (55.2±4.8 mmol/mol)). Patients were treated with exenatide 5µg twice daily (first 2 weeks), followed by 10µg twice daily (remaining 4 weeks) or matching placebo, with a 4-week washout period. Patients wore blinded glucose sensors in the final weeks and modified hyperinsulinemic normoglycemic-hypoglycemic glucose clamps (nadir 2.5 mmol/l) were performed at the end of each treatment period.

RESULTS:

Treatment with exenatide caused body weight to fall as compared to placebo (-3.9±0.9 vs. 0.6±1.2 kg, p=0.047). Exenatide did not change mean 24-hour glucose levels (8.3±0.4 vs. 8.5±0.3 mmol/l, exenatide vs. placebo, p=0.64), median (interquartile range) percentage of time spent in hypoglycemia (15.5 [4.5, 25.5] vs. 7.8 [4.4, 17.1]%, p=0.11) and frequency of hypoglycemia (15.8±3.7 vs. 12.1±3.5, p=0.19). Symptom scores in response to clamped hypoglycemia were similar between exenatide (median change 1.0 [-1.5, 7.0]) and placebo (4.5 [1.5, 5.8], p=0.08).

CONCLUSIONS:

Six weeks treatment with exenatide did not improve awareness of hypoglycemia in patients with type 1 diabetes and IAH.

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