BMJ Open Diabetes Research & Care

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ISSN / EISSN : 2052-4897 / 2052-4897
Published by: BMJ (10.1136)
Total articles ≅ 1,014
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, , Israel Hora, Lakshmi Sridharan, Mohammed K Ali, Ram Jagannathan, Rachel E Patzer,
Published: 22 October 2021
by BMJ
BMJ Open Diabetes Research & Care, Volume 9; https://doi.org/10.1136/bmjdrc-2021-002377

Abstract:
Introduction Heart failure (HF) is a major contributor to cardiovascular morbidity and mortality in people with diabetes. In this study, we estimated trends in the incidence of HF inpatient admissions and emergency department (ED) visits by diabetes status. Research design and methods Population-based age-standardized HF rates in adults with and without diabetes were estimated from the 2006–2017 National Inpatient Sample, Nationwide ED Sample and year-matched National Health Interview Survey, and stratified by age and sex. Trends were assessed using Joinpoint. Results HF inpatient admissions did not change in adults with diabetes between 2006 and 2013 (from 53.9 to 50.4 per 1000 persons; annual percent change (APC): −0.3 (95% CI −2.5 to 1.9) but increased from 50.4 to 62.3 between 2013 and 2017 (APC: 4.8 (95% CI 0.3 to 9.6)). In adults without diabetes, inpatient admissions initially declined (from 14.8 in 2006 to 12.9 in 2014; APC −2.3 (95% CI −3.2 to –1.2)) and then plateaued. Patterns were similar in men and women, but relative increases were greatest in young adults with diabetes. HF-related ED visits increased overall, in men and women, and in all age groups, but increases were greater in adults with (vs without) diabetes. Conclusions Causes of increased HF rates in hospital settings are unknown, and more detailed data are needed to investigate the aetiology and determine prevention strategies, particularly among adults with diabetes and especially young adults with diabetes.
Qian Shi, Yilu Lin, Vivian A Fonseca, Lizheng Shi
Published: 21 October 2021
by BMJ
BMJ Open Diabetes Research & Care, Volume 9; https://doi.org/10.1136/bmjdrc-2021-002396

Abstract:
Introduction Considerable confusions on treatment target have resulted from recent changes in guidelines. Evidence in medical guidelines came from clinical trials with highly selected patients, whereas treatment goals may differ in some subgroups. This study aimed to assess optimal treatment goals (A1C, blood pressure, low-density lipoprotein cholesterol (LDL-C)) for patients with type 2 diabetes mellitus (T2DM), which lead to optimal health outcomes by different treatment strategies. Research design and methods A retrospective longitudinal study was conducted for veterans with T2DM by using US Veterans Affairs Administrative Database (2005−2015). Medical records were prepared for repeated evaluation performed at 6-month intervals and multivariate longitudinal regression was used to estimate the risk of microvascular and macrovascular complication events. Second-degree polynomial and splines were applied to identify the optimal goals in their associations with lowest risk of clinical outcomes, controlling for demographic characteristics, medical history, and medications. Results A total of 124 651 patients with T2DM were selected, with mean of 6.72 follow-up years. In the general population, to achieve the lowest risk of microvascular and macrovascular complication, the optimal goals were A1C=6.81%, LDL-C=109.10 mg/dL; and A1C=6.76%, LDL-C=111.65 mg/dL, systolic blood pressure (SBP)=130.60 mmHg, respectively. The optimal goals differed between age and racial subgroups. Lower SBP for younger patients and lower LDL-C for black patients were associated with better health outcomes. Conclusions Optimal treatment goals were identified and multi-faceted treatment strategies targeting hyperglycemia and hyperlipidemia and hypertension may improve health outcome in veterans with T2DM. In addition to guidelines’ recommended goals, health systems may examine their own large diverse patients with T2DM for better quality of care.
Elham Memarian, , , Roosmarijn F L Lemmers, Amber A van der Heijden, Femke Rutters, Giel Nijpels, Emma Schoep, Aloysius G Lieverse, Eric J G Sijbrands, et al.
Published: 13 October 2021
by BMJ
BMJ Open Diabetes Research & Care, Volume 9; https://doi.org/10.1136/bmjdrc-2021-002345

Abstract:
Introduction Although associations of total plasma N-glycome (TPNG) with type 2 diabetes have been reported, little is known on the role of TPNG in type 2 diabetes complications, a major cause of type 2 diabetes-related morbidity and mortality. Here, we assessed TPNG in relation to type 2 diabetes complications in subsamples of two Dutch cohorts using mass spectrometry (n=1815 in DiaGene and n=1518 in Hoorn Diabetes Care System). Research design and methods Blood plasma samples and technical replicates were pipetted into 96-well plates in a randomized manner. Peptide:N-glycosidase F (PNGase F) was used to release N-glycans, whereafter sialic acids were derivatized for stabilization and linkage differentiation. After total area normalization, 68 individual glycan compositions were quantified in total and were used to calculate 45 derived traits which reflect structural features of glycosylation. Associations of glycan features with prevalent and incident microvascular or macrovascular complications were tested in logistic and Cox regression in both independent cohorts and the results were meta-analyzed. Results Our results demonstrated similarities between incident and prevalent complications. The strongest association for prevalent cardiovascular disease was a high level of bisection on a group of diantennary glycans (A2FS0B; OR=1.38, p=1.34×10−11), while for prevalent nephropathy the increase in 2,6-sialylation on triantennary glycans was most pronounced (A3E; OR=1.28, p=9.70×10−6). Several other TPNG features, including fucosylation, galactosylation, and sialylation, firmly demonstrated associations with prevalent and incident complications of type 2 diabetes. Conclusions These findings may provide a glance on how TPNG patterns change before complications emerge, paving the way for future studies on prediction biomarkers and potentially disease mechanisms.
Thomas E Hurst, Laura N McEwen, Kevin L Joiner,
Published: 13 October 2021
by BMJ
BMJ Open Diabetes Research & Care, Volume 9; https://doi.org/10.1136/bmjdrc-2021-002468

Abstract:
Introduction The National Diabetes Prevention Program (NDPP) and metformin are interventions to slow progression from pre-diabetes to type 2 diabetes. When coverage for the NDPP was offered by a public research university’s health insurance plan, proactive strategies were used to combat historically low enrollment. Although not specifically targeted by these strategies, metformin use was higher than expected, leading to this evaluation. Research design and methods We used insurance enrollment, claims, pharmacy, and laboratory data for 64 131 adult employees, dependents, and retirees to identify individuals with pre-diabetes and invite them to enroll in the NDPP at no out-of-pocket cost. The characteristics of individuals with pre-diabetes who used metformin before and after their invitation were compared with NDPP enrollees. Results 8131 individuals with pre-diabetes were identified. Of these, 776 (9.5%) enrolled in a NDPP and 802 (9.9%) used metformin. Metformin users were younger, had higher body mass index, were more likely to have comorbidities, and had higher baseline hemoglobin A1c levels than non-users. Timing of metformin use varied with 107 (13%) discontinuing, 426 (53%) continuing, and 269 (34%) initiating metformin use after their NDPP invitation. Of NDPP enrollees, 13 (2%) discontinued, 56 (7%) continued, and 34 (4%) initiated metformin use when they enrolled. Conclusions Despite no active encouragement, use of metformin was similar to the rate of enrollment in the NDPP. Metformin use was higher for individuals with higher likelihood of responding. With the proven cost-effectiveness of metformin, targeted strategies to increase metformin use in individuals with pre-diabetes who are likely to respond, but not willing to enroll in a lifestyle intervention, are needed.
Theis Bjerre-Christensen, Signe A Winther, Nete Tofte, , Tarunveer S Ahluwalia, Maria Lajer, Tine W Hansen, Peter Rossing, Christian Stevns Hansen
Published: 13 October 2021
by BMJ
BMJ Open Diabetes Research & Care, Volume 9; https://doi.org/10.1136/bmjdrc-2021-002289

Abstract:
Introduction We investigated the association between cardiovascular autonomic neuropathy (CAN) and decline in kidney function in type 1 diabetes. Research design and methods We included 329 persons with type 1 diabetes. CAN was assessed by cardiovascular reflex tests (CARTs): heart rate response to deep breathing (E/I ratio), to standing (30/15 ratio) and to the Valsalva maneuvre. Two or more pathological CARTs defined CAN diagnosis. Outcomes were yearly change in albuminuria or yearly change in estimated glomerular filtration rate (eGFR). An endpoint of eGFR decline >30%, development of end-stage kidney disease (ESKD) or death was examined. Associations were assessed by linear and Cox regression. Results Participants were aged 55.2 (9.4) years, 52% were male, with a diabetes duration of 40.1 (8.9) years, HbA1c of 7.9% (62.5 mmol/mol), eGFR 77.9 (27.7) mL/min/1.73 m2, urinary albumin excretion rate of 14.5 (7–58) mg/24 hours, and 31% were diagnosed with CAN. CAN was associated with a 7.8% higher albuminuria increase per year (95% CI: 0.50% to 15.63%, p=0.036) versus no CAN. The endpoint of ESKD, all-cause mortality and ≥30% decline in eGFR was associated with CAN (HR=2.497, p=0.0254). Conclusion CAN and sympathetic dysfunction were associated with increase in albuminuria in individuals with type 1 diabetes suggesting its role as a potential marker of diabetic kidney disease progression.
Hannah Case, David D Williams, Shideh Majidi, Diana Ferro, Mark Allen Clements, Susana R Patton
Published: 13 October 2021
by BMJ
BMJ Open Diabetes Research & Care, Volume 9; https://doi.org/10.1136/bmjdrc-2021-002461

Abstract:
Introduction We prospectively investigated the associations between diabetes-related family conflict, parent engagement in child type 1 diabetes (T1D) care, and child glycated hemoglobin (HbA1c) in 127 families of school-age children who we recruited within the first year of their T1D diagnosis. Research design and methods Parents completed the Diabetes Family Conflict Scale-Revised (DFCS-R) to assess for diabetes-related family conflict and the Diabetes Self-Management Questionnaire-Brief (DSMQ-Brief) to assess parent engagement in child T1D care at the initial study visit (T1) and at 12 (T2) and 27 (T3) months later. We also collected child HbA1c at these time points. Our analyses included Pearson correlations and repeated measures linear mixed models controlling for child age, sex, and T1D duration at T1. Results Parents’ DFCS-R scores negatively correlated with DSMQ-Brief scores (r=−0.13, p<0.05) and positively correlated with children’s HbA1c (r=0.26, p<0.001). In our linear mixed models, parents’ DSMQ-Brief scores were unchanged at T2 (β=−0.71, 95% CI −1.59 to 0.16) and higher at T3 (β=8.01, 95% CI 6.89 to 9.13) compared with T1, and there was an association between increasing DFCS-R and decreasing DSMQ-Brief scores (β=−0.14, 95% CI −0.21 to −0.06). Child HbA1c values were significantly higher at T2 (β=0.66, 95% CI 0.38 to 0.94) and T3 (β=0.95, 95% CI 0.63 to 1.27) compared with T1, and there was an association between increasing DFCS-R scores and increasing child HbA1c (β=0.04, 95% CI 0.02 to 0.06). Conclusions Increasing diabetes-specific family conflict early in T1D may associate with decreasing parent engagement in child T1D care and increasing child HbA1c, suggesting a need to assess and intervene on diabetes-specific family conflict. Trial registration number NCT03698708.
, Hanna Liljebäck, Henrik Hill, Andris Elksnis, José Caballero-Corbalan, Per-Ola Carlsson
Published: 11 October 2021
by BMJ
BMJ Open Diabetes Research & Care, Volume 9; https://doi.org/10.1136/bmjdrc-2021-002442

Abstract:
Introduction Experimentally, gamma-aminobutyric acid (GABA) has been found to exert immune-modulatory effects and induce beta-cell regeneration, which make it a highly interesting substance candidate for the treatment of type 1 diabetes (T1D). In many countries, including those in the European Union, GABA is considered a pharmaceutical drug. We have therefore conducted a safety and dose escalation trial with the first controlled-release formulation of GABA, Remygen (Diamyd Medical). Research design and methods Six adult male subjects with long-standing T1D (age 24.8±1.5 years, disease duration 14.7±2.2 years) were enrolled in an 11-day dose escalation trial with a controlled-release formulation of GABA, Remygen. Pharmacokinetics, glucose control and hormonal counter-regulatory response during hypoglycemic clamps were evaluated at every dose increase (200 mg, 600 mg and 1200 mg). Results During the trial there were no serious and only a few, transient, adverse events reported. Without treatment, the counter-regulatory hormone response to hypoglycemia was severely blunted. Intake of 600 mg GABA more than doubled the glucagon, epinephrine, growth hormone and cortisol responses to hypoglycemia. Conclusions We find that the GABA treatment was well tolerated and established a counter-regulatory response to hypoglycemia in long-standing T1D. Further studies regarding not only the clinical potential of Remygen for beta-cell regeneration but also its potential use as hypoglycemic prophylaxis are warranted. Trail registration number NCT03635437 and EudraCT2018-001115-73.
Alia García, Vanessa Moscardó, Agustín Ramos-Prol, Julián Díaz, Miguel Boronat, Jorge Bondia,
Published: 7 October 2021
by BMJ
BMJ Open Diabetes Research & Care, Volume 9; https://doi.org/10.1136/bmjdrc-2021-002399

Abstract:
Introduction Meal composition is known to affect glycemic variability and glucose control in type 1 diabetes. The objective of this work was to evaluate the effect of high carbohydrate meals of different nutritional composition and alcohol on the postprandial glucose response in patients with type 1 diabetes. Research design and methods Twelve participants were recruited to this randomized crossover trial. Following a 4-week run-in period, participants received a mixed meal on three occasions with the same carbohydrate content but different macronutrient composition: high protein-high fat with alcohol (0.7g/kg body weight, beer), high protein-high fat without alcohol, and low protein-low fat without alcohol at 2-week intervals. Plasma and interstitial glucose, insulin, glucagon, growth hormone, cortisol, alcohol, free fatty acids, lactate, and pH concentrations were measured during 6 hours. A statistical analysis was then carried out to determine significant differences between studies. Results Significantly higher late postprandial glucose was observed in studies with higher content of fats and proteins (p=0.0088). This was associated with lower time in hypoglycemia as compared with the low protein and fat study (p=0.0179), at least partially due to greater glucagon concentration in the same period (p=0.04). Alcohol significantly increased lactate, decreased pH and growth hormone, and maintained free fatty acids suppressed during the late postprandial phase (p<0.001), without significant changes in plasma glucose. Conclusions Our data suggest that the addition of proteins and fats to carbohydrates increases late postprandial blood glucose. Moreover, alcohol consumption together with a mixed meal has relevant metabolic effects without any increase in the risk of hypoglycemia, at least 6 hours postprandially. Trial registration number NCT03320993.
, Jae Il Shin, Hans Oh, Guillermo F López-Sánchez, Lee Smith, Josep Maria Haro, Ai Koyanagi
Published: 7 October 2021
by BMJ
BMJ Open Diabetes Research & Care, Volume 9; https://doi.org/10.1136/bmjdrc-2021-002514

Abstract:
Introduction Previous studies on the diabetes–edentulism relationship have yielded conflicting results. Therefore, the goal of this study was to investigate the association between diabetes and edentulism, and their joint effects on health status in adults from 40 low and middle-income countries (LMICs). Research design and methods Data from the World Health Survey were used for this cross-sectional study (2002–2004). Forty countries (18 low-income and 22 middle-income countries) were included. Edentulism and diabetes were assessed using yes-no questions based on self-report. Health status was assessed in seven different domains (self-care, pain/discomfort, cognition, interpersonal activities, sleep/energy, affect, and perceived stress). The association between diabetes (exposure) and edentulism (outcome) was analyzed using multivariable logistic regression models, while their joint effects on health status were assessed using multivariable linear regression models. Results There were 175 814 adults aged ≥18 years included in this study (mean (SD) age 38.4 (16.0) years; 49.3% men). Overall, the prevalence of edentulism was 6.0% and diabetes was 2.9%. There was a positive and significant association between diabetes and edentulism in the overall sample (OR=1.40, 95% CI 1.18 to 1.66), in low-income countries (OR=1.78, 95% CI 1.21 to 2.62) and in middle-income countries (OR=1.24, 95% CI 1.04 to 1.47). In addition, people with comorbid diabetes and edentulism had worse health status in the domains of cognition, sleep/energy, and perceived stress, compared with those with diabetes only. Conclusions Diabetes was positively associated with edentulism in this sample of more than 175 000 individuals living in LMICs. Providing oral care to individuals with diabetes may potentially lead to a reduction in their risk of edentulism.
Bastian Gaus, Dennis Brüning, Kathrin Hatlapatka, Ingo Rustenbeck
Published: 7 October 2021
by BMJ
BMJ Open Diabetes Research & Care, Volume 9; https://doi.org/10.1136/bmjdrc-2021-002394

Abstract:
Introduction Functional impairment of the stimulus secretion coupling in pancreatic beta cells is an essential component of type 2 diabetes. It is known that prolonged stimulation desensitizes the secretion of insulin and thus contributes to beta cell dysfunction. Beta cell rest, in contrast, was shown to enhance the secretory response. Here, the underlying mechanisms were investigated. Research design and methods To characterize the consequences of desensitization or rest for the number and mobility of submembrane granules, insulin-secreting MIN6 cells were desensitized by 18-hour culture with 500 µM tolbutamide or rested by 18-hour culture with 1 µM clonidine. The granules were labeled by hIns-EGFP or hIns-DsRed E5, imaged by TIRF microscopy of the cell footprint area and analyzed with an observer-independent program. Additionally, the insulin content and secretion were measured. Results Concurrent with the insulin content, submembrane granules were only slightly reduced after desensitization but markedly increased after rest. Both types of pretreatment diminished arrivals and departures of granules in the submembrane space and increased the proportion of immobile long-term resident granules, but desensitization lowered and rest increased the number of exocytoses, in parallel with the effect on insulin secretion. Labeling with hIns-DsRed E5 (‘timer’) showed that desensitization did not affect the proportion of aged granules, whereas rest increased it. Aged granules showed a high mobility and made up only a minority of long-term residents. Long-term resident granules were more numerous after rest and had a lower lateral mobility, suggesting a firmer attachment to the membrane. Conclusion The number, mobility and age of submembrane granules reflect the preceding functional states of insulin-secreting cells. Representing the pool of releasable granules, their quantity and quality may thus form part of the beta cell memory on renewed stimulation.
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