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1.
BMJ. 2019 Mar 5;364:l995. doi: 10.1136/bmj.l995.

Questions over future of global diabetes group as founding members resign.

PMID:
30837211
DOI:
10.1136/bmj.l995
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Conflict of interest statement

Competing interests: I have read and understood BMJ policy on declaration of interests and have no relevant interests to declare.

2.
Diabet Med. 2019 Apr;36(4):397-398. doi: 10.1111/dme.13938.

Predicting the future: Diabetes and Brexit.

Author information

1
University of Southampton.
PMID:
30848534
DOI:
10.1111/dme.13938
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3.
Diabet Med. 2019 Mar 8. doi: 10.1111/dme.13945. [Epub ahead of print]

Impact of glycaemic control on fracture risk in 5368 people with newly diagnosed Type 1 diabetes: a time-dependent analysis.

Author information

1
Institute of Applied Health Research, University of Birmingham, Birmingham, UK.
2
Department of Diabetes, University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK.
3
Institute of Immunology and Immunotherapy, Birmingham, UK.
4
NIHR Birmingham Biomedical Research Centre, University Hospitals Birmingham NHS Foundation Trust and University of Birmingham, Birmingham, UK.
5
Centre for Endocrinology, Diabetes and Metabolism, University of Birmingham, Birmingham, UK.
6
Health Data Research UK Midlands, Birmingham, UK.

Abstract

AIMS:

To assess whether glycaemic control is associated with a lifelong increased risk of fracture in people with newly diagnosed Type 1 diabetes.

METHODS:

People with newly diagnosed Type 1 diabetes between 1 January 1995 and 10 May 2016 were identified in The Health Improvement Network database. Longitudinal HbA1c measurements from diagnosis to fracture or study end or loss to follow-up were collected. A Cox proportional hazards model with HbA1c included as a time-dependent variable was fitted to these data.

RESULTS:

Some 5368 people with newly diagnosed Type 1 diabetes were included. The estimated adjusted hazard ratio (aHR) for HbA1c was statistically significant [aHR 1.007; 95% confidence interval (CI) 1.002-1.011 (mmol/mol) and aHR 1.07; 95% CI 1.03-1.12 (%)]. An incremental higher risk of fracture was observed with increasing levels of HbA1c .

CONCLUSIONS:

In people with newly diagnosed Type 1 diabetes, higher HbA1c is associated with an increased risk for fractures.

PMID:
30848519
DOI:
10.1111/dme.13945
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4.
5.
Diabetes. 2019 Mar 4. pii: db180686. doi: 10.2337/db18-0686. [Epub ahead of print]

HLA Class II Antigen Processing and Presentation Pathway Components Demonstrated by Transcriptome and Protein Analyses of islet β-Cells from Donors with Type 1 Diabetes.

Author information

1
Institute of Biomedical & Clinical Science, University of Exeter Medical School, Exeter, Devon, UK.
2
Program in Molecular Medicine, Diabetes Center of Excellence, University of Massachusetts Medical School, Worcester, MA, USA.
3
Department of Medicine, Division of Diabetes, Diabetes Center of Excellence, University of Massachusetts Medical School, Worcester, MA, USA.
4
Math and Science Division, Babson College, Wellesley, MA, USA.
5
Pediatric Department, Oslo University Hospital, Oslo, Norway and Faculty of Medicine, University of Oslo, Oslo, Norway.
6
Institute of Cellular Therapeutics, Allegheny-Singer Research Institute Department of Biological Sciences, Carnegie Mellon University, Pittsburgh, PA, USA.
7
Division of Diabetes, Endocrinology and Metabolism, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA.
8
Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN, USA.
9
Veterans Affairs Tennessee Valley Healthcare System, Nashville, TN, USA.
10
Program in Bioinformatics, University of Massachusetts Medical School Worcester, MA, USA.
11
Department of Medicine, Division of Diabetes, Diabetes Center of Excellence, University of Massachusetts Medical School, Worcester, MA, USA David.Harlan@umassmemorial.org.

Abstract

Type 1 diabetes studies consistently generate data showing islet β-cell dysfunction and T-cell mediated anti-β-cell specific autoimmunity. To explore the pathogenesis, we interrogated the β-cell transcriptomes from donors with and without type 1 diabetes using both bulk-sorted and single β-cells. Consistent with immunohistological studies, β-cells from donors with type 1 diabetes displayed increased Class I transcripts and associated mRNA species. These β-cells also expressed mRNA for Class II and Class II antigen presentation pathway components, but lacked macrophage marker, CD68. Immunohistological study of three independent recent-onset type 1 diabetic donor cohorts showed Class II protein and its transcriptional regulator Class II major histocompatibility complex trans-activator (CIITA) protein expressed by a subset of insulin+ CD68- β-cells, specifically found in islets with lymphocytic infiltrates. β-cell surface expression of HLA Class II was detected on a portion of CD45-insulin+ β-cells from donors with type 1 diabetes by immunofluorescence and flow cytometry. Our data demonstrate that pancreatic β-cells from donors with type 1 diabetes express Class II molecules on selected cells with other key genes in those pathways and inflammation-associated genes. β-cell expression of Class II molecules suggests that β-cells may interact directly with islet-infiltrating CD4+ T-cells, and may play an immunopathogenic role.

PMID:
30833470
DOI:
10.2337/db18-0686
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6.
Diabetes. 2019 Mar 4. pii: db181050. doi: 10.2337/db18-1050. [Epub ahead of print]

Fasting-Induced Transcription Factors Repress Vitamin D Bioactivation, a Mechanism for Vitamin D Deficiency in Diabetes.

Author information

1
Research Unit of Biomedicine, Pharmacology and Toxicology, University of Oulu, Oulu, Finland.
2
Medical Research Center Oulu, Oulu University Hospital and University of Oulu, Oulu, Finland.
3
Admescope Ltd., Typpitie 1, 90620 Oulu, Finland.
4
A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland.
5
Vegetative Physiology, Medical Faculty, University of Köln, Köln, Germany.
6
Institute for Clinical Chemistry and Pathobiochemistry, Department for Diagnostic Laboratory Medicine, University Hospital Tuebingen, 72076 Tuebingen, Germany.
7
German Center for Diabetes Research (DZD e.V.), Neuherberg, Germany.
8
Department of Medicine, Washington University School of Medicine, St. Louis, Missouri, United States of America.
9
Research Unit of Biomedicine, Pharmacology and Toxicology, University of Oulu, Oulu, Finland jukka.hakkola@oulu.fi.

Abstract

Low 25-hydroxyvitamin D levels correlate with the prevalence of diabetes, however, the mechanisms remain uncertain. Here, we show that nutritional deprivation responsive mechanisms regulate vitamin D metabolism. Both fasting and diabetes suppressed hepatic cytochrome P450 (CYP) 2R1, the main vitamin D 25-hydroxylase, responsible for the first bioactivation step. Overexpression of coactivator peroxisome proliferator-activated receptor gamma coactivator 1-α (PGC-1α), induced physiologically by fasting and pathologically in diabetes, resulted in dramatic downregulation of CYP2R1 in mouse hepatocytes in an estrogen-related receptor α (ERRα)-dependent manner. However, PGC-1α knockout did not prevent fasting-induced suppression of CYP2R1 in the liver indicating that additional factors contribute to the CYP2R1 repression. Furthermore, glucocorticoid receptor (GR) activation repressed the liver CYP2R1, suggesting GR involvement in the regulation of CYP2R1. GR antagonist mifepristone partially prevented CYP2R1 repression during fasting suggesting that glucocorticoids and GR contribute to the CYP2R1 repression during fasting. Moreover, fasting upregulated the vitamin D catabolizing CYP24A1 in the kidney through the PGC-1α-ERRα pathway. Our study uncovers a molecular mechanism for vitamin D deficiency in diabetics and reveals a novel negative feedback mechanism controlling cross-talk between energy homeostasis and the vitamin D pathway.

PMID:
30833469
DOI:
10.2337/db18-1050
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7.
Diabetes. 2019 Mar 4. pii: db170821. doi: 10.2337/db17-0821. [Epub ahead of print]

Loss-of-Function Mutation in Thiamine Transporter 1 in a Family with Autosomal Dominant Diabetes.

Author information

1
Department of Medicine, Harvard Medical School, Boston, MA, 02215, USA.
2
Section on Genetics and Epidemiology, Joslin Diabetes Center, Boston, MA, 02215, USA.
3
Division of Molecular Medicine, Research Department, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, 10700, Thailand.
4
Section on Islet Cell and Regenerative Biology, Joslin Diabetes Center, Boston, MA, 02215, USA.
5
Division of Hospital and Ambulatory Medicine, Department of Medicine, Faculty of Medicine, Chulalongkorn University, Bangkok, 10330, Thailand.
6
Division of Nephrology and Hypertension, University of Utah School of Medicine, Salt Lake City, UT, 84105, USA.
7
Department of Medicine, Harvard Medical School, Boston, MA, 02215, USA. alessandro.doria@joslin.harvard.edu.

Abstract

Solute Carrier Family 19 Member 2 (SLC19A2) encodes thiamine transporter 1 (THTR1), which facilitates thiamine transport across the cell membrane. SLC19A2 homozygous mutations have been described as a cause of thiamine-responsive megaloblastic anemia (TRMA), an autosomal recessive syndrome characterized by megaloblastic anemia, diabetes mellitus, and sensorineural deafness. Here we describe a loss-of-function SLC19A2 mutation (c.A1063C: p.Lys355Gln) in a family with early-onset diabetes and mild TRMA traits transmitted in an autosomal dominant fashion. We show that SLC19A2 deficient β-cells are characterized by impaired thiamine uptake, which is not rescued by overexpression of the p.Lys355Gln mutant protein. We further demonstrate that SLC19A2 deficit causes impaired insulin secretion in conjunction with mitochondrial dysfunction, loss of protection against oxidative stress, and cell cycle arrest. These findings link SLC19A2 mutations to autosomal dominant diabetes and suggest a role of SLC19A2 in β-cell function and survival.

PMID:
30833467
DOI:
10.2337/db17-0821
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8.
Diabetes Care. 2019 Mar 4. pii: dc181854. doi: 10.2337/dc18-1854. [Epub ahead of print]

Self-Monitoring of Blood Glucose in Youth-Onset Type 2 Diabetes: Results From the TODAY Study.

Author information

1
State University of New York Upstate Medical University, Syracuse, NY.
2
The Biostatistics Center, George Washington University, Rockville, MD braffett@bsc.gwu.edu.
3
Case Western Reserve University, Rainbow Babies and Children's Hospital, Cleveland, OH.
4
Massachusetts General Hospital Diabetes Center, Harvard Medical School, Boston, MA.
5
The Biostatistics Center, George Washington University, Rockville, MD.
6
University of Colorado School of Medicine, Aurora, CO.
7
Joslin Diabetes Center, Harvard Medical School, Boston, MA.
8
Children's Hospital of Los Angeles, Los Angeles, CA.
9
Children's Hospital of Philadelphia, Philadelphia, PA.
10
University of Texas Health Science Center San Antonio, San Antonio, TX.

Abstract

OBJECTIVE:

To determine whether self-monitoring of blood glucose (SMBG) is associated with lower HbA1c in youth with type 2 diabetes taking oral medications only or after starting insulin for persistently elevated HbA1c.

RESEARCH DESIGN AND METHODS:

TODAY participants (n = 699) taking oral medications were asked to perform SMBG twice daily. After reaching primary outcome (PO) (HbA1c ≥8% [64 mmol/mol]) over 6 months or an inability to wean from temporary insulin because of metabolic decompensation), insulin glargine was started. HbA1c and percent of SMBG (SMBG%) (percent days when the meter was used one or more times) before and after PO were analyzed.

RESULTS:

SMBG declined over time and was inversely related to HbA1c (P < 0.0001). Of 298 youth who reached PO and started insulin, 282 had SMBG data. At PO, mean ± SD age was 15.8 ± 2.3 years, BMI 35.5 ± 7.9 kg/m2, and HbA1c 9.6 ± 2.0% (81 ± 21.9 mmol/mol); 65.3% were female. Median SMBG% was 40% at PO, which increased to 49% after 6 months and fell to 41% after 1 year on insulin. At PO, 22% of youth checked ≥80% of days, which increased to 25% and fell to 19% after 6 and 12 months using insulin, respectively. At PO, compared with those who checked <80%, youth who checked ≥80% were younger and with a lower BMI, HbA1c, and blood pressure. SMBG ≥80% was associated with ≥1% reduction in HbA1c at 6 and 12 months after insulin initiation.

CONCLUSIONS:

Low SMBG adherence was common and associated with higher HbA1c. Optimal SMBG frequency in youth using or not using insulin, and whether less frequent SMBG is a marker for overall worse self-care, require further study.

PMID:
30833375
DOI:
10.2337/dc18-1854
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9.
Diabetes Care. 2019 Mar 4. pii: dc181399. doi: 10.2337/dc18-1399. [Epub ahead of print]

Importance of Treatment Status in Links Between Type 2 Diabetes and Alzheimer Disease.

Author information

1
Department of Psychology, University of Southern California, Los Angeles, CA danation@usc.edu ecmcinto@usc.edu.

Abstract

OBJECTIVE:

To investigate relationships among type 2 diabetes treatment, Alzheimer disease biomarkers, and risk for dementia.

RESEARCH DESIGN AND METHODS:

Participants from the Alzheimer Disease Neuroimaging Initiative (N = 1,289) who were dementia-free at baseline and underwent health assessment, cognitive testing, and MRI. A subset (n = 900) obtained a lumbar puncture to determine cerebrospinal fluid (CSF) phosphorylated tau (p-tau), total tau (t-tau), and β-amyloid 1-42 (Aβ1-42). Participants were grouped by fasting blood glucose and medication history: euglycemia (EU), prediabetes (PD), untreated diabetes (UD), and treated diabetes (TD). Relationships were investigated between treatment status and CSF biomarkers and risk for dementia.

RESULTS:

The UD group displayed greater p-tau, t-tau, and p-tau/Aβ1-42 levels than the EU, PD, and TD groups (P values <0.05) and higher t-tau/Aβ1-42 than the EU and PD groups (P values <0.05). The UD group progressed to dementia at higher rates than the EU group (hazard ratio 1.602 [95% CI 1.057-2.429]; P = 0.026).

CONCLUSIONS:

Treatment status may alter the relationship between type 2 diabetes and both Alzheimer disease biomarker profile and risk for dementia. UD is associated with elevated tau pathology and risk for dementia, whereas TD is not. Although this study is observational and therefore causality cannot be inferred, findings support the potential importance of treatment status in Alzheimer disease risk associated with type 2 diabetes.

PMID:
30833374
DOI:
10.2337/dc18-1399
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10.
Diabetes Care. 2019 Mar 4. pii: dc180575. doi: 10.2337/dc18-0575. [Epub ahead of print]

Long-term Association of Depression Symptoms and Antidepressant Medication Use With Incident Cardiovascular Events in the Look AHEAD (Action for Health in Diabetes) Clinical Trial of Weight Loss in Type 2 Diabetes.

Author information

1
The University of Texas Health Science Center at San Antonio, San Antonio, TX hazuda@uthscsa.edu.
2
Wake Forest School of Medicine, Winston-Salem, NC.
3
The Miriam Hospital/Brown Medical School, Providence, RI.
4
National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD.
5
The University of Tennessee, Memphis, TN.
6
University of Pennsylvania, Philadelphia, PA.
7
Joslin Diabetes Center, Boston, MA.
8
Colorado Center for Behavioral Medicine, Denver, CO.

Abstract

OBJECTIVE:

To examine whether depression symptoms or antidepressant medication (ADM) use predicts the probability of cardiovascular events in overweight/obese individuals with type 2 diabetes.

RESEARCH DESIGN AND METHODS:

Preplanned analyses of depression and incident cardiovascular disease (CVD) were performed in the Look AHEAD (Action for Health in Diabetes) weight loss trial after a median follow-up of 9.6 years. Depression symptoms, assessed with the Beck Depression Inventory (BDI), were analyzed both as a continuous and dichotomized variable (BDI score <10 or ≥10). ADM use was coded from participants' prescription medications. Four composite CVD outcomes were defined in the study protocol. Sex-stratified Cox proportional hazards models were adjusted for a range of baseline covariates.

RESULTS:

Depression symptoms were only significantly associated with a composite secondary outcome comprising CVD death, nonfatal myocardial infarction, nonfatal stroke, hospitalized angina, congestive heart failure, peripheral vascular disease, coronary artery bypass graft, and carotid endarterectomy. Significant sex interactions were observed for BDI score and BDI score ≥10. BDI score was significantly associated with higher probability of this composite outcome in men, but was not associated with the outcome in women. BDI score ≥10 was positively associated with this composite outcome in men but was negatively associated in women. Exploratory analysis identified a significant BDI ≥10 × ADM use interaction for this composite outcome that differed in men versus women. Men with both BDI score ≥10 and ADM use compared with those with neither had 60% higher probability of the outcome, whereas women with both compared with those with neither had 50% lower probability.

CONCLUSIONS:

Sex differences in the association of depression symptoms and ADM use with incident CVD warrant further investigation.

PMID:
30833373
DOI:
10.2337/dc18-0575
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11.
Diabetes Care. 2019 Mar 4. pii: dc181320. doi: 10.2337/dc18-1320. [Epub ahead of print]

Nonproteinuric Versus Proteinuric Phenotypes in Diabetic Kidney Disease: A Propensity Score-Matched Analysis of a Nationwide, Biopsy-Based Cohort Study.

Author information

1
Department of Nephrology and Laboratory Medicine, Faculty of Medicine, Institute of Medical, Pharmaceutical and Health Sciences, Graduate School of Medical Sciences, Kanazawa University, Ishikawa, Japan m.yamanouchi@toranomon.gr.jp twada@m-kanazawa.jp.
2
Nephrology Center, Toranomon Hospital, Tokyo, Japan.
3
Nephrology Center, Toranomon Hospital Kajigaya, Kanagawa, Japan.
4
Okinaka Memorial Institute for Medical Research, Tokyo, Japan.
5
Division of Nephrology, Kanazawa University Hospital, Kanazawa, Japan.
6
Department of Pathology, Toranomon Hospital, Tokyo, Japan.
7
Department of Pathology, Yokohama City University Graduate School of Medicine, Kanagawa, Japan.
8
Department of Nephrology, Fujita Health University School of Medicine, Aichi, Japan.
9
Department of Pathology, Clinical Research Center, National Hospital Organization Chiba-East National Hospital, Chiba, Japan.
10
Health Administration Center, Niigata University, Niigata, Japan.
11
Clinical Pharmacology and Therapeutics, Tohoku University Graduate School of Pharmaceutical Sciences, Miyagi, Japan.
12
Department of Pathology, Faculty of Medicine, Fukuoka University, Fukuoka, Japan.
13
Department of Pathology, Dokkyo Medical University Saitama Medical Center, Saitama, Japan.
14
Division of Nephrology and Kidney Center, Kobe University Graduate School of Medicine, Hyogo, Japan.
15
Department of Nephrology, Kanazawa Medical University School of Medicine, Ishikawa, Japan.
16
Department of Nephrology, Nagasaki University Hospital, Nagasaki, Japan.
17
Department of Nephrology, Nara Medical University, Nara, Japan.
18
Department of Cardiovascular Medicine, Nephrology and Neurology, University of the Ryukyus School of Medicine, Okinawa, Japan.
19
Division of Nephrology, Department of Internal Medicine, St. Marianna University School of Medicine, Kanagawa, Japan.
20
Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan.
21
Division of Nephrology, Department of Internal Medicine, Nagoya University Graduate School of Medicine, Nagoya, Japan.

Abstract

OBJECTIVE:

Clinicopathological characteristics, renal prognosis, and mortality in patients with type 2 diabetes and reduced renal function without overt proteinuria are scarce.

RESEARCH DESIGN AND METHODS:

We retrospectively assessed 526 patients with type 2 diabetes and reduced renal function (estimated glomerular filtration rate [eGFR] <60 mL/min/1.73 m2), who underwent clinical renal biopsy and had follow-up data, from Japan's nationwide multicenter renal biopsy registry. For comparative analyses, we derived one-to-two cohorts of those without proteinuria versus those with proteinuria using propensity score-matching methods addressing the imbalances of age, sex, diabetes duration, and baseline eGFR. The primary end point was progression of chronic kidney disease (CKD) defined as new-onset end-stage renal disease, decrease of eGFR by ≥50%, or doubling of serum creatinine. The secondary end point was all-cause mortality.

RESULTS:

Eighty-two patients with nonproteinuria (urine albumin-to-creatinine ratio [UACR] <300 mg/g) had lower systolic blood pressure and less-severe pathological lesions compared with 164 propensity-matched patients with proteinuria (UACR ≥300 mg/g). After a median follow-up of 1.9 years (interquartile range 0.9-5.0 years) from the date of renal biopsy, the 5-year CKD progression-free survival was 86.6% (95% CI 72.5-93.8%) for the nonproteinuric group and 30.3% (95% CI 22.4-38.6%) for the proteinuric group (log-rank test P < 0.001). The lower renal risk was consistent across all subgroup analyses. The all-cause mortality was also lower in the nonproteinuric group (log-rank test P = 0.005).

CONCLUSIONS:

Patients with nonproteinuric diabetic kidney disease had better-controlled blood pressure and fewer typical morphological changes and were at lower risk of CKD progression and all-cause mortality.

PMID:
30833372
DOI:
10.2337/dc18-1320
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12.
Diabetes Care. 2019 Mar 4. pii: dc182149. doi: 10.2337/dc18-2149. [Epub ahead of print]

Improved Time in Range and Glycemic Variability With Sotagliflozin in Combination With Insulin in Adults With Type 1 Diabetes: A Pooled Analysis of 24-Week Continuous Glucose Monitoring Data From the inTandem Program.

Author information

1
Department of Diabetes, Endocrinology, and Clinical Research, Childrens and Youth Hospital Auf der Bult, Hannover Medical School, Hannover, Germany danne@hka.de.
2
L'institut du thorax, Department of Endocrinology, CIC 1413 INSERM, CHU Nantes, Nantes, France.
3
Department of Medicine, University of North Carolina School of Medicine, Chapel Hill, NC.
4
Department of Medicine and Pediatrics, Barbara Davis Center for Diabetes, University of Colorado Denver, Aurora, CO.
5
Dallas Diabetes Research Center at Medical City, Dallas, TX.
6
Lexicon Pharmaceuticals, Inc., The Woodlands, TX.
7
Department of Pediatrics, Baylor College of Medicine and Texas Children's Hospital, Houston, TX.
8
Department of Internal Medicine, Division of Cardiology, University of Texas Southwestern Medical Center, Dallas, TX.
9
Keck School of Medicine of the University of Southern California, Los Angeles, CA.

Abstract

OBJECTIVE:

To evaluate effects of the dual sodium-glucose cotransporter (SGLT) 1 and SGLT2 inhibitor sotagliflozin in combination with insulin on glucose time in range (TIR) and glucose excursions, postprandial glucose (PPG), and other glycemic metrics in adults with type 1 diabetes using masked continuous glucose monitoring (CGM).

RESEARCH DESIGN AND METHODS:

Data sets from the inTandem1 (clinical trial reg. no. NCT02384941) and inTandem2 (clinical trial reg. no. NCT02421510) double-blind randomized trials evaluating sotagliflozin versus placebo in adults with type 1 diabetes treated with optimized insulin were pooled for analyses of masked CGM data from a subset of participants in each trial. The pooled cohort included patients randomized to receive placebo (n = 93), sotagliflozin 200 mg (n = 89), or sotagliflozin 400 mg (n = 96). The primary outcome was change from baseline to week 24 in glucose TIR (3.9-10.0 mmol/L [70-180 mg/dL]). Secondary end points included time below and above the target range and 2-h PPG level assessed after a standardized mixed meal.

RESULTS:

Mean percentage of glucose TIR/percentage time spent at <3.9 mmol/L (<70 mg/dL) during week 24 was 51.6%/5.9%, 57.8%/5.5%, and 64.2%/5.5%, with placebo, sotagliflozin 200 mg, and sotagliflozin 400 mg, respectively, which corresponded to a placebo-adjusted change from a baseline of +5.4/-0.3% (P = 0.026; +1.3/-0.1 h/day) for sotagliflozin 200 mg and +11.7/-0.1% (P < 0.001; +2.8/-0.02 h/day) for sotagliflozin 400 mg. Placebo-adjusted PPG reductions were 1.9 ± 0.7 mmol/L (35 ± 13 mg/dL; P = 0.004) and 2.8 ± 0.7 mmol/L (50 ± 13 mg/dL; P < 0.001) with sotagliflozin 200 and 400 mg, respectively.

CONCLUSIONS:

Combined with optimized insulin in type 1 diabetes, sotagliflozin significantly increased glucose TIR without increasing time spent at <3.9 mmol/L and reduced PPG, thereby improving glycemic control.

PMID:
30833371
DOI:
10.2337/dc18-2149
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13.
Diabetes Care. 2019 Mar 4. pii: dc182062. doi: 10.2337/dc18-2062. [Epub ahead of print]

Risk Factors for Kidney Disease in Type 1 Diabetes.

Author information

1
Endocrinology and Metabolism, University of Toronto, Toronto, Canada.
2
Biostatistics Center, The George Washington University, Rockville, MD.
3
Division of Nephrology, University of Washington, Seattle, WA.
4
Endocrinology, Metabolism, and Molecular Medicine, Northwestern University, Chicago, IL.
5
Pediatrics and Endocrinology, Yale School of Medicine, New Haven, CT.
6
University of California, San Diego, CA.
7
Internal Medicine/MEND, University of Michigan Medical Center, Ann Arbor, MI.
8
Pediatrics, Washington University, St. Louis, MO.
9
Metabolism, Endocrinology, and Diabetes, University of Michigan, Ann Arbor, MI.
10
Genetics and Genomic Biology, Hospital for Sick Children, Toronto, Canada.
11
Epidemiology, University of Pittsburgh, Pittsburgh, PA.
12
National Institute of Diabetes and Digestive and Kidney Diseases/National Insitutes of Health, Bethesda, MD.
13
Biostatistics Center, The George Washington University, Rockville, MD jml@bsc.gwu.edu.

Abstract

OBJECTIVE:

In type 1 diabetes (T1D), the course of microalbuminuria is unpredictable and timing of glomerular filtration rate (GFR) loss is uncertain. Thus, there is a need to identify the risk factors associated with the development of more advanced stages of kidney disease through large, long-term systematic analysis.

RESEARCH DESIGN AND METHODS:

Multivariable Cox proportional hazards models assessed the association of baseline and time-dependent glycemic and nonglycemic risk factors for incident macroalbuminuria and reduced estimated GFR (eGFR; defined as <60 mL/min/1.73 m2) over a mean of 27 years in the Diabetes Control and Complications Trial (DCCT) cohort.

RESULTS:

Higher mean HbA1c (hazard ratio [HR] 1.969 per 1% higher level [95% CI 1.671-2.319]) and male sex (HR 2.767 [95% CI 1.951-3.923]) were the most significant factors independently associated with incident macroalbuminuria, whereas higher mean triglycerides, higher pulse, higher systolic blood pressure (BP), longer diabetes duration, higher current HbA1c, and lower mean weight had lower magnitude associations. For incident reduced eGFR, higher mean HbA1c (HR 1.952 per 1% higher level [95% CI 1.714-2.223]) followed by higher mean triglycerides, older age, and higher systolic BP were the most significant factors.

CONCLUSIONS:

Although several risk factors associated with macroalbuminuria and reduced eGFR were identified, higher mean glycemic exposure was the strongest determinant of kidney disease among the modifiable risk factors. These findings may inform targeted clinical strategies for the frequency of screening, prevention, and treatment of kidney disease in T1D.

PMID:
30833370
DOI:
10.2337/dc18-2062
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14.
Diabetes Care. 2019 Mar 4. pii: dc182308. doi: 10.2337/dc18-2308. [Epub ahead of print]

Risk Factors for Retinopathy in Type 1 Diabetes: The DCCT/EDIC Study.

Author information

1
Mason Eye Institute, University of Missouri, Columbia, MO.
2
Biostatistics Center, The George Washington University, Washington, DC.
3
Department of Ophthalmology, Joslin Diabetes Center, Boston, MA.
4
Department of Internal Medicine, University of Iowa, Iowa City, IA.
5
Rainbow Babies and Children's Hospital, Cleveland, OH.
6
Diabetes Center, University of South Florida, Tampa, FL.
7
Pediatrics, Washington University, St. Louis, MO.
8
University of Wisconsin, Madison, WI.
9
Department of Medicine, Northwestern University, Evanston, IL.
10
University of New Mexico, Albuquerque, NM.
11
Vanderbilt University Medical Center, Nashville, TN.
12
University of Michigan Kellogg Eye Center, Ann Arbor, MI.
13
Biostatistics Center, The George Washington University, Washington, DC jml@bsc.gwu.edu.

Abstract

OBJECTIVE:

The Diabetes Control and Complications Trial (DCCT) demonstrated that intensive therapy reduced the development and progression of retinopathy in type 1 diabetes (T1D) compared with conventional therapy. The Epidemiology of Diabetes Interventions and Complications (EDIC) study observational follow-up showed persistent benefits. In addition to glycemia, we now examine other potential retinopathy risk factors (modifiable and nonmodifiable) over more than 30 years of follow-up in DCCT/EDIC.

RESEARCH DESIGN AND METHODS:

The retinopathy outcomes were proliferative diabetic retinopathy (PDR), clinically significant macular edema (CSME), and ocular surgery. The survival (event-free) probability was estimated using the Kaplan-Meier method. Cox proportional hazards models assessed the association between risk factors and subsequent risk of retinopathy. Both forward- and backward-selection approaches determined the multivariable models.

RESULTS:

Rate of ocular events per 1,000 person-years was 12 for PDR, 14.5 for CSME, and 7.6 for ocular surgeries. Approximately 65%, 60%, and 70% of participants remained free of PDR, CSME, and ocular surgery, respectively. The greatest risk factors for PDR in descending order were higher mean HbA1c, longer duration of T1D, elevated albumin excretion rate (AER), and higher mean diastolic blood pressure (DBP). For CSME, risk factors, in descending order, were higher mean HbA1c, longer duration of T1D, and greater age and DBP, and for ocular surgeries were higher mean HbA1c, older age, and longer duration of T1D.

CONCLUSIONS:

Mean HbA1c was the strongest risk factor for the progression of retinopathy. Although glycemic control is important, elevated AER and DBP were other modifiable risk factors associated with the progression of retinopathy.

PMID:
30833368
DOI:
10.2337/dc18-2308
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15.
Diabetes Care. 2019 Mar 4. pii: dc181841. doi: 10.2337/dc18-1841. [Epub ahead of print]

Randomized Trial of a Tailored Cognitive Behavioral Intervention in Type 2 Diabetes With Comorbid Depressive and/or Regimen-Related Distress Symptoms: 12-Month Outcomes From COMRADE.

Author information

1
Department of Family Medicine, Brody School of Medicine, East Carolina University, Greenville, NC cummingsd@ecu.edu.
2
Center for Health Disparities, East Carolina University, Greenville, NC.
3
Department of Psychology, University of British Columbia, Kelowna, British Columbia, Canada.
4
School of Social Work, University of South Florida, Tampa, FL.
5
Department of Psychology, East Carolina University, Greenville, NC.
6
Department of Family Medicine, Brody School of Medicine, East Carolina University, Greenville, NC.

Abstract

OBJECTIVE:

This study evaluated the effect of cognitive behavioral therapy (CBT) plus lifestyle counseling in primary care on hemoglobin A1c (HbA1c) in rural adult patients with type 2 diabetes (T2D) and comorbid depressive or regimen-related distress (RRD) symptoms.

RESEARCH DESIGN AND METHODS:

This study was a randomized controlled trial of a 16-session severity-tailored CBT plus lifestyle counseling intervention compared with usual care. Outcomes included changes in HbA1c, RRD, depressive symptoms, self-care behaviors, and medication adherence across 12 months.

RESULTS:

Patients included 139 diverse, rural adults (mean age 52.6 ± 9.5 years; 72% black; BMI 37.0 ± 9.0) with T2D (mean HbA1c = 9.6 [81 mmol/mol] ± 2.0) and comorbid depressive or distress symptoms. Using intent-to-treat analyses, patients in the intervention experienced marginally significant improvements in HbA1c (-0.92 ± 1.81 vs. -0.31 ± 2.04; P = 0.06) compared with usual care. However, intervention patients experienced significantly greater improvements in RRD (-1.12 ± 1.05 vs. -0.31 ± 1.22; P = 0.001), depressive symptoms (-3.39 ± 5.00 vs. -0.90 ± 6.17; P = 0.01), self-care behaviors (+1.10 ± 1.30 vs. +0.58 ± 1.45; P = 0.03), and medication adherence (+1.00 ± 2.0 vs. +0.17 ± 1.0; P = 0.02) versus usual care. Improvement in HbA1c correlated with improvement in RRD (r = 0.3; P = 0.0001) and adherence (r = -0.23; P = 0.007).

CONCLUSIONS:

Tailored CBT with lifestyle counseling improves behavioral outcomes and may improve HbA1c in rural patients with T2D and comorbid depressive and/or RRD symptoms.

PMID:
30833367
DOI:
10.2337/dc18-1841
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16.
J Clin Endocrinol Metab. 2019 Mar 8. pii: jc.2018-02414. doi: 10.1210/jc.2018-02414. [Epub ahead of print]

Plasma Fibroblast Growth Factor 21 is Associated with Severity of Nonalcoholic Steatohepatitis in Patients with Obesity and Type 2 Diabetes.

Author information

1
Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, University of Florida College of Medicine, Gainesville, FL.
2
Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, Malcom Randall Veterans Affairs Medical Center, Gainesville, Florida.

Abstract

CONTEXT:

The relationship between plasma FGF21, insulin resistance and steatohepatitis has not been systematically assessed.

OBJECTIVE:

To determine if higher plasma FGF21 is associated with worse steatohepatitis on liver biopsy in patients with NAFLD.

DESIGN AND SETTING:

Cross-sectional study in a University Hospital.Patients Interventions and Main Outcome MeasuresPatients with BMI>25 (n=187) underwent: (a) euglycemic hyperinsulinemic clamp to assess tissue specific insulin resistance; (b) liver magnetic resonance spectroscopy (1H-MRS) for intrahepatic triglyceride (IHTG) quantification, (c) liver biopsy (if NAFLD present; n=146); and (d) fasting plasma FGF21 levels.

METHODS AND RESULTS:

Patients were divided into three groups: (a) No NAFLD (n=41); (b) No NASH: patients with isolated steatosis or borderline NASH (n=52); and (c) NASH: patients with definite NASH (n=94). Groups were well-matched for age/gender, prevalence of T2DM and A1c.During euglycemic hyperinsulinemic insulin clamp, insulin sensitivity in skeletal muscle and adipose tissue worsened from No NAFLD to NASH (both p<0.001). Plasma FGF21 levels correlated inversely with insulin sensitivity in adipose tissue (r=-0.17, p=0.006) and skeletal muscle (r=-0.23, p=0.007), but not with liver insulin sensitivity. Plasma FGF21 was higher in patients with NASH (453±262 pg/ml) when compared to No NASH (341±198pg/ml, p=0.03) or No NAFLD (325±289 pg/ml, p=0.02). Plasma FGF21 increased with the severity of necroinflammation (p=0.02), and most significantly with worse fibrosis (p<0.001), but not with worsening steatosis (p=0.60).

CONCLUSIONS:

Plasma FGF21 correlates with severity of steatohepatitis, in particular of fibrosis, in patients with NASH. Measurement of FGF21 may help identify patients at the highest risk of disease progression.

17.
J Clin Endocrinol Metab. 2019 Mar 8. pii: jc.2019-00084. doi: 10.1210/jc.2019-00084. [Epub ahead of print]

Skeletal Fragility & Its Clinical Determinants In Children With Type 1 Diabetes.

Author information

1
Developmental Endocrinology Research Group, School of Medicine, Dentistry & Nursing, University of Glasgow, UK.
2
Paediatric Diabetes Service, NHS Greater Glasgow & Clyde, Glasgow, UK.
3
Department of Clinical Biochemistry, Royal Hospital for Children, NHS Greater Glasgow and Clyde, Glasgow UK.
4
Department of Clinical Physics, NHS Greater Glasgow and Clyde, Glasgow UK.

Abstract

CONTEXT:

Type 1 diabetes (T1D) is associated with an increased fracture risk at all ages.

OBJECTIVE:

To understand the determinants of bone health and fractures in children with T1D.

DESIGN:

Case-control study of children with T1D on bone turnover markers, DXA and 3T-MRI of the proximal tibia to assess bone microarchitecture and vertebral marrow adiposity, compared to age and sex-matched healthy children.

RESULTS:

32 children with T1D at a median (range) age of 13.7 years (10.4,16.7) and 26 controls aged 13.8 years (10.2,17.8) were recruited. In children with T1D, serum BAP SDS, CTX SDS, and total body and lumbar spine BMD SDS were lower (all p<0.05). Children with T1D also had lower trabecular volume [0.55 (0.47,0.63) vs 0.59 (0.47,0.63); p=0.024], lower trabecular number [1.67 (1.56,1.93) vs 1.82 (1.56,1.99); p=0.004] and higher trabecular separation [0.27 (0.21,0.32) vs 0.24 (0.20,0.33); p=0.001] than controls. Marrow adiposity was similar in both groups (p=0.25). Bone formation as assessed by BAP was lower in children with poorer glycemic control (p=0.009) and who were acidotic at initial presentation (p=0.017) but higher in children on continuous subcutaneous insulin infusion (p=0.025). Fractures were more likely to be encountered in children with T1D compared to controls [31% vs 19%; p<0.001]. Compared to those without fractures, the T1D children with a fracture history had poorer glycemic control (p=0.007) and lower total body BMD (p<0.001) but no differences in bone microarchitecture.

CONCLUSION:

Children with T1D display a low bone turnover state with reduced bone mineralisation and poorer bone microarchitecture.

18.
J Clin Endocrinol Metab. 2019 Mar 8. pii: jc.2019-00008. doi: 10.1210/jc.2019-00008. [Epub ahead of print]

Separate and Combined Effects of GIP and GLP-1 Infusions on Bone Metabolism in Overweight Men without Diabetes.

Author information

1
Clinical Metabolic Physiology, Steno Diabetes Center Copenhagen, Gentofte Hospital, Hellerup, Denmark.
2
Department of In Vivo Pharmacology, Zealand Pharma A/S, Glostrup, Denmark.
3
Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
4
Department of Medicine, Gentofte Hospital, Hellerup, Denmark.
5
Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
6
Department of Clinical Chemistry, Rigshospitalet, University of Copenhagen, Glostrup, Denmark.
7
OPEN, Odense University Hospital, Odense, Denmark.
8
Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
9
Department of Clinical Pharmacology, Bispebjerg Hospital, Copenhagen, Denmark.

Abstract

CONTEXT:

The gut-derived incretin hormones, glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide 1 (GLP-1), have been suggested to play a role in bone metabolism. Exogenous administration of GIP inhibits bone resorption, while the effect of GLP-1 is less clear. Furthermore, the combined effect of exogenous GIP and GLP-1 on bone metabolism is unknown.

OBJECTIVE:

To investigate the effect of separate and combined infusions of the incretin hormones GIP and GLP-1 on bone resorption and formation.

DESIGN:

Randomized, double-blinded, placebo-controlled, crossover study including five study days.

PARTICIPANTS:

Seventeen overweight/obese men.

INTERVENTIONS:

On the first study day, a 50 g oral glucose tolerance test (OGTT) was performed. On the next four study days, isoglycemic IV glucose infusions (IIGI), mimicking the glucose excursions from the OGTT, were performed with concomitant infusions of GIP (4 pmol/kg/min), GLP-1 (1 pmol/kg/min), GIP+GLP-1 (4 and 1 pmol/kg/min, respectively) or placebo, respectively.

PRIMARY OUTCOMES:

Changes in bone resorption assessed by measurements of carboxy-terminal type I collagen crosslinks (CTX), and in bone formation as assessed by procollagen type 1 N-terminal propeptide (P1NP) concentrations.

RESULTS:

During the OGTT, CTX was significantly lowered by 54±13% from baseline (mean±SD) compared to 28±12% during IIGI+saline (P <0.0001). During IIGI+GLP-1 and IIGI+GIP, respectively, CTX was lowered by 65±16% and 74±9% from baseline, while IGII+GIP+GLP-1 lowered CTX by 84±4% from baseline. P1NP levels were unaffected by the interventions.

CONCLUSIONS:

Our data suggest that GLP-1, like GIP, may be involved in regulation of bone resorption and that GIP and GLP-1 together have partially additive inhibitory effects.

19.
J Clin Endocrinol Metab. 2019 Mar 7. pii: jc.2018-02196. doi: 10.1210/jc.2018-02196. [Epub ahead of print]

Continuous Glucose Monitoring Predicts Progression to Diabetes in Autoantibody Positive Children.

Author information

1
Barbara Davis Center for Childhood Diabetes, University of Colorado School of Medicine, Aurora, Colorado, USA.

Abstract

CONTEXT:

Accurate measures are needed for the prediction and diagnosis of type 1 diabetes (T1D) in at risk subjects.

OBJECTIVE:

The purpose of this study was to explore the value of continuous glucose monitoring (CGM) in predicting T1D onset.

DESIGN AND SETTING:

The Diabetes Autoimmunity Study in the Young (DAISY) prospectively follows children at increased risk for development of islet autoantibodies (Ab+) and T1D.

PARTICIPANTS:

We analyzed 23 Ab+ subjects with available longitudinal CGM data.

MAIN OUTCOME MEASURE:

CGM metrics as glycemic predictors of progression to diabetes.

RESULTS:

Of 23 Ab+ subjects with a baseline CGM, eight progressed to diabetes at a median age of 13.8 years during a median follow-up of 17.7 years (IQR 14.6-22.0 years). Compared to non-progressors, subjects who progressed to diabetes had significantly increased baseline glycemic variability (SD 29 vs 21 mg/dl, p=0.047), daytime sensor average (122 vs 106 mg/dl, p=0.02), and daytime sensor area under the curve (AUC, 470,370 vs 415,465, p=0.047). They spent 24% of time above 140 mg/dl and 12% above 160 mg/dl compared to, respectively, 8% and 3% for non-progressors (both p=0.005). A receiver-operating curve (ROC) analysis showed AUC of 0.85 for %time spent above 140 or 160 mg/dl. The cutoff of 18% time spent above 140 mg/dl had 75% sensitivity, 100% specificity, and 100% PPV for diabetes prediction, although these values could change as some non-progressors may develop diabetes with longer follow-up.

CONCLUSIONS:

In conclusion, >18% CGM time spent above 140 mg/dl predicts progression to diabetes in islet Ab+ children.

20.
J Clin Endocrinol Metab. 2019 Mar 5. pii: jc.2018-02743. doi: 10.1210/jc.2018-02743. [Epub ahead of print]

Gestational diabetes, but not pre-pregnancy overweight predicts cardio-metabolic markers in offspring twenty years later.

Author information

1
National Institute for Health and Welfare, Helsinki and Oulu, Finland.
2
PEDEGO Research Unit (Research Unit for Pediatrics, Dermatology, Clinical Genetics, Obstetrics and Gynecology), Medical Research Center Oulu (MRC Oulu), Oulu University Hospital and University of Oulu, Oulu, Finland.
3
Department of Nursing Science, University of Turku, Turku, Finland.
4
Institute of Health Sciences, University of Oulu, Oulu, Finland.
5
Department of Psychology and Logopedics, University of Helsinki, Helsinki, Finland.
6
Children's Hospital, Pediatric Research Center, Helsinki University Hospital and University of Helsinki, Helsinki, Finland.
7
Department of Psychology, University of Warwick, Warwick, United Kingdom.
8
NordLab Oulu, Oulu University Hospital, Oulu, Finland.
9
Department of Clinical Chemistry, University of Oulu, Oulu, Finland.
10
Department of Epidemiology and Biostatistics, MRC-PHE Centre for Environment & Health, School of Public Health, Imperial College London, London, UK.
11
Center for Life Course Health Research, Faculty of Medicine, University of Oulu, Oulu, Finland.
12
Biocenter Oulu, University of Oulu, Oulu, Finland.
13
Unit of Primary Care, Oulu University Hospital, Oulu, Finland.
14
Department of Life Sciences, College of Health and Life Sciences, Brunel University London, Kingston Lane, Uxbridge, Middlesex UB8 3PH, United Kingdom.
15
Department of General Practice and Primary Health Care, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.
16
Folkhälsan Research Center, Helsinki, Finland.
17
Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology, Trondheim, Norway.

Abstract

CONTEXT:

Maternal gestational diabetes (GDM) and pre-pregnancy overweight/obesity (body mass index, BMI ≥25kg/m2) may adversely affect offspring cardio-metabolic health.

OBJECTIVE:

To assess associations of maternal GDM and pre-pregnancy overweight/obesity with adult offspring cardio-metabolic risk factors.

DESIGN:

Longitudinal cohort study (ESTER and AYLS).

SETTING:

Province of Uusimaa and Northern Finland.

PARTICIPANTS:

At mean age 24.1 years (SD 1.3), we classified offspring to offspring of mothers with 1) GDM regardless of pre-pregnancy BMI (OGDM; n=193), 2) normoglycemic mothers with pre-pregnancy overweight/obesity (ONO, n=157) and 3) normoglycemic mothers with pre-pregnancy BMI<25kg/m2 (controls, n=556).

MAIN OUTCOME MEASURES:

We assessed cardio-metabolic biomarkers from blood and measured resting blood pressure and heart rate.

RESULTS:

Compared with controls, OGDM and ONO had higher fasting glucose [1.6% (95% confidence interval 0.1, 3.1)]; [2.3% (0.5, 4.3), respectively]; and insulin [12.7% (4.4, 21.9)]; [8.7% (0.2, 17.8)]. These differences attenuated to non-significance when adjusted for confounders and/or current offspring characteristics including BMI or body fat percentage. OGDM showed lower sex hormone binding globulin [SHBG; men: -12.4% (-20.2, -3.9), women: -33.2% (-46.3, -16.8)], high-density lipoprotein [-6.6% (-10.9, -2.2)] and apolipoprotein A1 [-4.5% (-7.5, -1.4), these differences survived the aforementioned adjustments. Heart rate and other biomarkers were similar between groups.

CONCLUSIONS:

Adult offspring of mothers with GDM have increased markers of insulin resistance and a more atherogenic lipid profile; these are only partly explained by confounders or current offspring adiposity. Maternal pre-pregnancy overweight/obesity is associated with impaired offspring glucose regulation, which is explained by confounders and/or current adiposity.

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