The impact of obstructive sleep apnea treatment on microvascular complications in patients with type 2 diabetes: a feasibility randomized controlled trial.

STUDY OBJECTIVES: Obstructive sleep apnea (OSA) is associated with an increased risk of diabetes-related complications. Hence, it is plausible that continuous positive airway pressure (CPAP) could have a favorable impact on these complications. We assessed the feasibility of conducting a randomized control trial in patients with type 2 diabetes and OSA over 2 years. METHODS: We conducted an open-label multicenter feasibility randomized control trial of CPAP vs no CPAP in patients with type 2 diabetes and OSA. Patients with resting oxygen saturation < 90%, central apnea index > 15 events/h, or Epworth Sleepiness Scale ≥ 11 were excluded. OSA was diagnosed using a multichannel portable device (ApneaLink Air, ResMed). The primary outcome measures were related to feasibility and the secondary outcomes were changes in various clinical and biochemical parameters related to diabetes outcomes. RESULTS: Eighty-three (40 CPAP vs 43 no CPAP) patients were randomly assigned, with a median (interquartile range) follow-up of 645 (545, 861) days. CPAP compliance was inadequate, with a median usage of approximately 3.5 hours/night. Early CPAP use predicted longer-term compliance. The adjusted analysis showed a possible favorable association between being randomly assigned to CPAP and several diabetes-related end points (chronic kidney disease, neuropathy, and quality of life). CONCLUSIONS: It was feasible to recruit, randomly assign, and achieve a high follow-up rate over 2 years in patients with OSA and type 2 diabetes. CPAP compliance might improve by a run-in period before randomization. A full randomized control trial is necessary to assess the observed favorable association between CPAP and chronic kidney disease , neuropathy, and quality of life in patients with type 2 diabetes. CLINICAL TRIAL REGISTRATION: Registry: ISRCTN; Name: The impact of sleep disorders in patients with type 2 diabetes; URL: https://www.isrctn.com/ISRCTN12361838; Identifier: ISRCTN12361838. CITATION: Makhdom EA, Maher A, Ottridge R, et al. The impact of obstructive sleep apnea treatment on microvascular complications in patients with type 2 diabetes: a feasibility randomized controlled trial. J Clin Sleep Med. 2024;20(6):947-957.

Association of hypoglycaemia in screening oral glucose tolerance test in pregnancy with low birth weight fetus.

BACKGROUND: Gestational diabetes mellitus (GDM) is a common metabolic derangement in pregnant women. In the women identified to be at high risk of GDM, a 75 g oral glucose tolerance test (OGTT) at 24-28 wk gestation is the recommended screening test in the United Kingdom as per National Institute for Health and Care Excellence (NICE). Hypoglycaemia following the glucose load is often encountered and the implication of this finding for the pregnancy, fetus and clinical care is unclear. AIM: To determine the prevalence of hypoglycaemia at any time during the screening OGTT and explore its association with birth weight. METHODS: All deliveries between 2009 and 2013 at the local maternity unit of the University hospital were reviewed. Of the total number of 24,154 women without pre-existing diabetes, those who had an OGTT for GDM screening based on NICE recommended risk stratification, who had a singleton delivery and had complete clinical and demographic data for analysis, were included for this study (n = 3537). Blood samples for fasting plasma glucose (FPG), 2-hour plasma glucose (2-h PG) and HbA1c had been obtained. Birth weight was categorised as low (≤ 2500 g), normal or Macrosomia (≥ 4500 g) and blood glucose ≤ 3.5 mmol/L was used to define hypoglycaemia. Binary logistic regression was used to determine the association of various independent factors with dichotomized variables; the differences between frequencies/proportions by χ 2 test and comparison between group means was by one-way ANOVA. RESULTS: Amongst the study cohort (3537 deliveries), 96 (2.7%) women had babies with LBW (< 2500 g). Women who delivered a LBW baby had significantly lower FPG (4.3 ± 0.6 mmol/L, P = 0.001). The proportion of women who had a 2-h PG ≤ 3.5 mmol/L in the LBW cohort was significantly higher compared to the cohorts with normal and macrosomic babies (8.3% vs 2.8% vs 4.2%; P = 0.007). The factors which predicted LBW were FPG, Asian ethnicity and 2-h PG ≤ 3.5 mmol/L, whereas maternal age, 2-h PG ≥ 7.8 mmol/L and HbA1c were not significant predictors. CONCLUSION: A low FPG and 2-h PG ≤ 3.5 mmol/L on 75-gram OGTT are significantly associated with low birth weight in women identified as high risk for GDM. Women of ethnic backgrounds (Asians) appear to be more susceptible to this increased risk and may serve as a separate cohort in whom we should offer more intensive follow up and screening for complications. Cost implications and resources for follow up would need to be looked at in further detail to support these findings.

Potential Clinical Error Arising From Use of HbA1c in Diabetes: Effects of the Glycation Gap.

The glycation gap (GGap) and the similar hemoglobin glycation index (HGI) define consistent differences between glycated hemoglobin and actual glycemia derived from fructosamine or mean blood glucose, respectively. Such a disparity may be found in a substantial proportion of people with diabetes, being >1 U of glycated HbA1c% or 7.2 mmol/mol in almost 40% of estimations. In this review we define these indices and explain how they can be calculated and that they are not spurious, being consistent in individuals over time. We evaluate the evidence that GGap and HGI are associated with variation in risk of complications and mortality and demonstrate the potential for clinical error in the unquestioning use of HbA1c. We explore the underlying etiology of the variation of HbA1c from mean glucose in blood plasma, including the potential role of enzymatic deglycation of hemoglobin by fructosamine-3-kinase. We conclude that measurement of GGap and HGI are important to diabetes clinicians and their patients in individualization of therapy and the avoidance of harm arising from consequent inappropriate assessment of glycemia and use of therapies.

Evidence That Differences in Fructosamine-3-Kinase Activity May Be Associated With the Glycation Gap in Human Diabetes.

The phenomenon of a discrepancy between glycated hemoglobin levels and other indicators of average glycemia may be due to many factors but can be measured as the glycation gap (GGap). This GGap is associated with differences in complications in patients with diabetes and may possibly be explained by dissimilarities in deglycation in turn leading to altered production of advanced glycation end products (AGEs). We hypothesized that variations in the level of the deglycating enzyme fructosamine-3-kinase (FN3K) might be associated with the GGap. We measured erythrocyte FN3K concentrations and enzyme activity in a population dichotomized for a large positive or negative GGap. FN3K protein was higher and we found a striking threefold greater activity (323%) at any given FN3K protein level in the erythrocytes of the negative-GGap group compared with the positive-GGap group. This was associated with lower AGE levels in the negative-GGap group (79%), lower proinflammatory adipokines (leptin-to-adiponectin ratio) (73%), and much lower prothrombotic PAI-1 levels (19%). We conclude that FN3K may play a key role in the GGap and thus diabetes complications such that FN3K may be a potential predictor of the risk of diabetes complications. Pharmacological modifications of its activity may provide a novel approach to their prevention.

Thyrotoxicosis in patients with hypothyroidism is not just overtreatment.

A 62-year-old Caucasian woman presented with hypothyroid symptoms and biochemical thyrotoxic picture. Previously, she underwent right-sided subtotal thyroidectomy and left partial thyroid lobectomy for thyroid lumps, and treated with thyroxine replacement for hypothyroidism. Although there were no significant findings on clinical examination, investigations confirmed thyrotoxicosis with positive autoimmunity against thyroid glandâ€"all in line with a diagnosis of Graves’ hyperthyroidism. We would like to highlight atypical presentations of thyroid dysfunction and conversion of underactive to overactive thyroid status with this case. Early recognition, diagnosis and intervention are essential to prevent and/or reduce associated morbidity and mortality. When encountered with such clinical conundrums, we recommend seeking opinion from an experienced endocrinologist while interpreting such situation.

Splenic abscess as a potential initial manifestation of quiescent infective endocarditis in a patient with bronchopneumonia.

A 78-year-old woman presented to the acute medical unit with a productive cough, dyspnoea and decreased appetite of 4 days duration. Initial assessment supported a diagnosis of right-sided community-acquired pneumonia and she was started on antibiotics. In view of the clinical finding of splenomegaly, she had an ultrasound and, subsequently, a CT of the abdomen, which revealed a large splenic abscess. Pending cultures from a sample obtained from percutaneous drainage of the abscess, she was started on intravenous meropenem. The initial echocardiogram did not suggest any evidence of endocarditis. The pus drained from the abscess on cultures was subsequently positive for Staphylococcus aureus. An MRI of the spine excluded discitis as a source of infection. Owing to a high index of clinical suspicion a repeat echocardiogram was undertaken after 1-week, which confirmed acute endocarditis. The patient was treated with intravenous antibiotics for 6 weeks with improvement in clinical, radiological and biochemical parameters.

Challenges of emerging adulthood-transition from paediatric to adult diabetes.

Diabetes mellitus is a complex condition with far reaching physical, psychological and psychosocial effects. These outcomes can be significant when considering the care of a youth transferring from paediatric through to adult diabetes services. The art of mastering a smooth care transfer is crucial if not pivotal to optimising overall diabetic control. Quite often the nature of consultation varies between the two service providers and the objectives and outcomes will mirror this. The purpose of this review is to analyse the particular challenges and barriers one might expect to encounter when transferring these services over to an adult care provider. Particular emphasis is paid towards the psychological aspects of this delicate period, which needs to be recognised and appreciated appropriately in order to understand the particular plights a young diabetic child will be challenged with. We explore the approaches that can be positively adopted in order to improve the experience for child, parents and also the multi- disciplinary team concerned with the overall delivery of this care. Finally we will close with reflection on the potential areas for future development that will ultimately aim to improve long-term outcomes and experiences of the young adolescent confronted with diabetes as well as the burden of disease and burden of cost of disease.

Association of glycation gap with mortality and vascular complications in diabetes.

OBJECTIVE: The "glycation gap" (G-gap), an essentially unproven concept, is an empiric measure of disagreement between HbA1c and fructosamine, the two indirect estimates of glycemic control. Its association with demographic features and key clinical outcomes in individuals with diabetes is uncertain. RESEARCH DESIGN AND METHODS: The G-gap was calculated as the difference between measured HbA1c and a fructosamine-derived standardized predicted HbA1c in 3,182 individuals with diabetes. The G-gap's associations with demographics and clinical outcomes (retinopathy, nephropathy, macrovascular disease, and mortality) were determined. RESULTS: Demographics varied significantly with G-gap for age, sex, ethnic status, smoking status, type and duration of diabetes, insulin use, and obesity. A positive G-gap was associated with retinopathy (odds ratio 1.24 [95% CI 1.01-1.52], P=0.039), nephropathy (1.55 [1.23-1.95], P<0.001), and, in a subset, macrovascular disease (1.91 [1.18-3.09], P=0.008). In Cox regression analysis, the G-gap had a "U"-shaped quadratic relationship with mortality, with both negative G-gap (1.96 [1.50-2.55], P<0.001) and positive G-gap (2.02 [1.57-2.60], P<0.001) being associated with a significantly higher mortality. CONCLUSIONS: We confirm published associations of G-gap with retinopathy and nephropathy. We newly demonstrate a relationship with macrovascular and mortality outcomes and potential links to distinct subpopulations of diabetes.

Hemoglobin A1c in early postpartum screening of women with gestational diabetes.

AIM: To assess the utility of hemoglobin A1c (HbA1c) in the early postpartum screening of women with gestational diabetes mellitus (GDM). METHODS: Over a 3 years period, HbA1c estimations were undertaken in addition to and simultaneously with the traditional oral glucose tolerance test (OGTT), in 203 women with GDM as a part of early postpartum screening for dysglycaemia, at 6 wk post-partum. World Health Organization criteria was used for diagnosing diabetes: fasting blood glucose (FBG) ≥ 7.0 mmol/L and/or 2-h postprandial blood glucose (PPBG) ≥ 11.1 mmol/L and/or HbA1c ≥ 48 mmol/mol; and impaired glycaemiastate: impaired fasting glucose 6.1-6.9 mmol/L and/or impaired glucose tolerance 7.8-11.0 mmol/L and/or HbA1c: 42-47 mmol/mol. RESULTS: Mean FBG, 2-h PPBG and HbA1c were 4.9 ± 0.7 mmol/L, 5.6 ± 2.0 mmol/L and 38 ± 5 mmol/mol respectively. FBG, 2-h PPBG and HbA1c detected 6 (3%), 7 (3.5%) and 11 (5.4%) cases of diabetes respectively, and 11 (5.4%), 25 (12.3%) and 23 (11.3%) cases of pre-diabetes state respectively. HbA1c values ≥ 48 mmol/mol (≥ 6.5%) showed a diagnostic sensitivity of 71.4% and specificity of 98.5% for diabetes in comparison to OGTT in receiver operating characteristics curve analysis. At HbA1c cut-off 44 mmol/mol, sensitivity and specificity were 100% and 92.3% respectively [area under the curve: 0.98 (95%CI: 0.96-1.00)]. Sensitivity and specificity for detecting high risk "impaired glycaemia" state [HbA1c 42 mmol/mol (6.0%)] were 28% and 80%, respectively. CONCLUSION: HbA1c level ≥ 48 mmol/mol (≥ 6.5%) has reasonable sensitivity and high specificity in comparison to OGTT for early postpartum screening of diabetes in GDM. At 6(th) week postpartum screening, if FBG is normal and HbA1c < 44 mmol/mol OGTT is not recommended.

Evidence for consistency of the glycation gap in diabetes.

OBJECTIVE: Discordance between HbA(1c) and fructosamine estimations in the assessment of glycemia is often encountered. A number of mechanisms might explain such discordance, but whether it is consistent is uncertain. This study aims to coanalyze paired glycosylated hemoglobin (HbA(1c))-fructosamine estimations by using fructosamine to determine a predicted HbA(1c), to calculate a glycation gap (G-gap) and to determine whether the G-gap is consistent over time. RESEARCH DESIGN AND METHODS: We included 2,263 individuals with diabetes who had at least two paired HbA(1c)-fructosamine estimations that were separated by 10 ± 8 months. Of these, 1,217 individuals had a third pair. The G-gap was calculated as G-gap = HbA(1c) minus the standardized fructosamine-derived HbA(1c) equivalent (FHbA(1c)). The hypothesis that the G-gap would remain consistent in individuals over time was tested. RESULTS: The G-gaps were similar in the first, second, and third paired samples (0.0 ± 1.2, 0.0 ± 1.3, and 0.0 ± 1.3, respectively). Despite significant changes in the HbA(1c) and fructosamine, the G-gap did not differ in absolute or relative terms and showed no significant within-subject variability. The direction of the G-gap remained consistent. CONCLUSIONS: The G-gap appears consistent over time; thus, by inference any key underlying mechanisms are likely to be consistent. G-gap calculation may be a method of exploring and evaluating any such underlying mechanisms.