Diabetes and Dyslipidemia Screening in Pediatric Practice.

The incidence of diabetes and hyperlipidemia are increasing at rapid rates in children. These conditions are associated with increased risk of macrovascular and microvascular complications causing major morbidity and mortality later in life. Early diagnosis and treatment can reduce the lifelong risk of complications from these diseases, exemplifying the importance of screening in the pediatric population. The following article presents a summary of the current guidelines for diabetes and hyperlipidemia screening in pediatric patients.

Second international consensus report on gaps and opportunities for the clinical translation of precision diabetes medicine.

Precision medicine is part of the logical evolution of contemporary evidence-based medicine that seeks to reduce errors and optimize outcomes when making medical decisions and health recommendations. Diabetes affects hundreds of millions of people worldwide, many of whom will develop life-threatening complications and die prematurely. Precision medicine can potentially address this enormous problem by accounting for heterogeneity in the etiology, clinical presentation and pathogenesis of common forms of diabetes and risks of complications. This second international consensus report on precision diabetes medicine summarizes the findings from a systematic evidence review across the key pillars of precision medicine (prevention, diagnosis, treatment, prognosis) in four recognized forms of diabetes (monogenic, gestational, type 1, type 2). These reviews address key questions about the translation of precision medicine research into practice. Although not complete, owing to the vast literature on this topic, they revealed opportunities for the immediate or near-term clinical implementation of precision diabetes medicine; furthermore, we expose important gaps in knowledge, focusing on the need to obtain new clinically relevant evidence. Gaps include the need for common standards for clinical readiness, including consideration of cost-effectiveness, health equity, predictive accuracy, liability and accessibility. Key milestones are outlined for the broad clinical implementation of precision diabetes medicine.

Genetic Reduction of Glucose Metabolism Preserves Functional ß-Cell Mass in KATP-Induced Neonatal Diabetes.

ß-Cell failure and loss of ß-cell mass are key events in diabetes progression. Although insulin hypersecretion in early stages has been implicated in ß-cell exhaustion/failure, loss of ß-cell mass still occurs in KATP gain-of-function (GOF) mouse models of human neonatal diabetes in the absence of insulin secretion. Thus, we hypothesize that hyperglycemia-induced increased ß-cell metabolism is responsible for ß-cell failure and that reducing glucose metabolism will prevent loss of ß-cell mass. To test this, KATP-GOF mice were crossed with mice carrying ß-cell-specific glucokinase haploinsufficiency (GCK+/-), to genetically reduce glucose metabolism. As expected, both KATP-GOF and KATP-GOF/GCK+/- mice showed lack of glucose-stimulated insulin secretion. However, KATP-GOF/GCK+/- mice demonstrated markedly reduced blood glucose, delayed diabetes progression, and improved glucose tolerance compared with KATP-GOF mice. In addition, decreased plasma insulin and content, increased proinsulin, and augmented plasma glucagon observed in KATP-GOF mice were normalized to control levels in KATP-GOF/GCK+/- mice. Strikingly, KATP-GOF/GCK+/- mice demonstrated preserved ß-cell mass and identity compared with the marked decrease in ß-cell identity and increased dedifferentiation observed in KATP-GOF mice. Moreover KATP-GOF/GCK+/- mice demonstrated restoration of body weight and liver and brown/white adipose tissue mass and function and normalization of physical activity and metabolic efficiency compared with KATP-GOF mice. These results demonstrate that decreasing ß-cell glucose signaling can prevent glucotoxicity-induced loss of insulin content and ß-cell failure independently of compensatory insulin hypersecretion and ß-cell exhaustion.

SARS-CoV-2 infection of islet ß cells: Evidence and implications.

The health of insulin-producing ß cells is critical for normoglycemia. Wu et al.1 and Tang et al.2 provide evidence in vitro that ß cells can be infected by SARS-CoV-2 virus, possibly contributing to worsening hyperglycemia seen during the COVID-19 pandemic.

High-fat diet prevents the development of autoimmune diabetes in NOD mice.

AIMS: Type 1 diabetes (T1D) has a strong genetic predisposition and requires an environmental trigger to initiate the beta-cell autoimmune destruction. The rate of childhood obesity has risen in parallel to the proportion of T1D, suggesting high-fat diet (HFD)/obesity as potential environmental triggers for autoimmune diabetes. To explore this, non-obese diabetic (NOD) mice were subjected to HFD and monitored for the development of diabetes, insulitis and beta-cell stress. MATERIALS AND METHODS: Four-week-old female NOD mice were placed on HFD (HFD-NOD) or standard chow-diet. Blood glucose was monitored weekly up to 40 weeks of age, and glucose- and insulin-tolerance tests performed at 4, 10 and 15 weeks. Pancreata and islets were analysed for insulin secretion, beta-cell mass, inflammation, insulitis and endoplasmic reticulum stress markers. Immune cell levels were measured in islets and spleens. Stool microbiome was analysed at age 4, 8 and 25 weeks. RESULTS: At early ages, HFD-NOD mice showed a significant increase in body weight, glucose intolerance and insulin resistance; but paradoxically, they were protected from developing diabetes. This was accompanied by increased insulin secretion and beta-cell mass, decreased insulitis, increased splenic T-regulatory cells and altered stool microbiome. CONCLUSIONS: This study shows that HFD protects NOD mice from autoimmune diabetes and preserves beta-cell mass and function through alterations in gut microbiome, increased T-regulatory cells and decreased insulitis. Further studies into the exact mechanism of HFD-mediated prevention of diabetes in NOD mice could potentially lead to interventions to prevent or delay T1D development in humans.

Targeting Cellular Calcium Homeostasis to Prevent Cytokine-Mediated Beta Cell Death.

Pro-inflammatory cytokines are important mediators of islet inflammation, leading to beta cell death in type 1 diabetes. Although alterations in both endoplasmic reticulum (ER) and cytosolic free calcium levels are known to play a role in cytokine-mediated beta cell death, there are currently no treatments targeting cellular calcium homeostasis to combat type 1 diabetes. Here we show that modulation of cellular calcium homeostasis can mitigate cytokine- and ER stress-mediated beta cell death. The calcium modulating compounds, dantrolene and sitagliptin, both prevent cytokine and ER stress-induced activation of the pro-apoptotic calcium-dependent enzyme, calpain, and partly suppress beta cell death in INS1E cells and human primary islets. These agents are also able to restore cytokine-mediated suppression of functional ER calcium release. In addition, sitagliptin preserves function of the ER calcium pump, sarco-endoplasmic reticulum Ca2+-ATPase (SERCA), and decreases levels of the pro-apoptotic protein thioredoxin-interacting protein (TXNIP). Supporting the role of TXNIP in cytokine-mediated cell death, knock down of TXNIP in INS1-E cells prevents cytokine-mediated beta cell death. Our findings demonstrate that modulation of dynamic cellular calcium homeostasis and TXNIP suppression present viable pharmacologic targets to prevent cytokine-mediated beta cell loss in diabetes.

Endoplasmic reticulum stress in beta cells and autoimmune diabetes.

Type 1 diabetes results from the autoimmune destruction of pancreatic ß cells, leading to insulin deficiency and hyperglycemia. Although multiple attempts have been made to slow the autoimmune process using immunosuppressive or immunomodulatory agents, there are still no effective treatments that can delay or reverse the progression of type 1 diabetes in humans. Recent studies support endoplasmic reticulum (ER) as a novel target for preventing the initiation of the autoimmune reaction, propagation of inflammation, and ß cell death in type 1 diabetes. This review highlights recent findings on ER stress in ß cells and development of type 1 diabetes and introduces potential new treatments targeting the ER to combat this disorder.

Hypercalcemia in Patients with Williams-Beuren Syndrome.

OBJECTIVE: To evaluate the timing, trajectory, and implications of hypercalcemia in Williams-Beuren syndrome (WBS) through a multicenter retrospective study. STUDY DESIGN: Data on plasma calcium levels from 232 subjects with WBS aged 0-67.1 years were compared with that in controls and also with available normative data. Association testing was used to identify relevant comorbidities. RESULTS: On average, individuals with WBS had higher plasma calcium levels than controls, but 86.7% of values were normal. Nonpediatric laboratories overreport hypercalcemia in small children. When pediatric reference intervals were applied, the occurrence of hypercalcemia dropped by 51% in infants and by 38% in toddlers. Across all ages, 6.1% of the subjects had actionable hypercalcemia. In children, actionable hypercalcemia was seen in those aged 5-25 months. In older individuals, actionable hypercalcemia was often secondary to another disease process. Evidence of dehydration, hypercalciuria, and nephrocalcinosis were common in both groups. Future hypercalcemia could not be reliably predicted by screening calcium levels. A subgroup analysis of 91 subjects found no associations between hypercalcemia and cardiovascular disease, gastrointestinal complaints, or renal anomalies. Analyses of electrogradiography data showed an inverse correlation of calcium concentration with corrected QT interval, but no acute life-threatening events were reported. CONCLUSIONS: Actionable hypercalcemia in patients with WBS occurs infrequently. Although irritability and lethargy were commonly reported, no mortality or acute life-threatening events were associated with hypercalcemia and the only statistically associated morbidities were dehydration, hypercalciuria, and nephrocalcinosis.

Does pulmonary rehabilitation reduce peripheral blood pressure in patients with chronic obstructive pulmonary disease?

Pulmonary rehabilitation (PR) can improve aerobic exercise capacity, health-related quality of life and dyspnoea in patients with chronic obstructive pulmonary disease (COPD). Recent studies have suggested that exercise training may improve blood pressure and arterial stiffness, albeit in small highly selected cohorts. The aim of the study was to establish whether supervised outpatient or unsupervised home PR can reduce peripheral blood pressure. Resting blood pressure was measured in 418 patients with COPD before and after outpatient PR, supervised by a hospital-based team (HOSP). Seventy-four patients with COPD undergoing an unsupervised home-based programme acted as a comparator group (HOME). Despite significant improvements in mean (95% confidence interval) exercise capacity in the HOSP group (56 (50-60) m, p < 0.001) and HOME group (30 (17-42) m, p < 0.001) systolic blood pressure (SBP), diastolic blood pressure (DBP) and mean arterial blood pressure (MAP) did not change in either the HOSP (SBP: p = 0.47; DBP: p = 0.06; MAP: p = 0.38) or HOME group (SBP: p = 0.67; DBP: p = 0.38; MAP: p = 0.76). Planned subgroup analysis of HOSP patients with known hypertension and/or cardiovascular disease showed no impact of PR upon blood pressure. PR is unlikely to reduce blood pressure, and by implication, makes a mechanism of action in which arterial stiffness is reduced, less likely.

Sarcopenia in COPD: prevalence, clinical correlates and response to pulmonary rehabilitation.

BACKGROUND: Age-related loss of muscle, sarcopenia, is recognised as a clinical syndrome with multiple contributing factors. International European Working Group on Sarcopenia in Older People (EWGSOP) criteria require generalised loss of muscle mass and reduced function to diagnose sarcopenia. Both are common in COPD but are usually studied in isolation and in the lower limbs. OBJECTIVES: To determine the prevalence of sarcopenia in COPD, its impact on function and health status, its relationship with quadriceps strength and its response to pulmonary rehabilitation (PR). METHODS: EWGSOP criteria were applied to 622 outpatients with stable COPD. Body composition, exercise capacity, functional performance, physical activity and health status were assessed. Using a case-control design, response to PR was determined in 43 patients with sarcopenia and a propensity score-matched non-sarcopenic group. RESULTS: Prevalence of sarcopenia was 14.5% (95% CI 11.8% to 17.4%), which increased with age and Global Initiative for Chronic Obstructive Pulmonary Disease (GOLD) stage, but did not differ by gender or the presence of quadriceps weakness (14.9 vs 13.8%, p=0.40). Patients with sarcopenia had reduced exercise capacity, functional performance, physical activity and health status compared with patients without sarcopenia (p<0.001), but responded similarly following PR; 12/43 patients were no longer classified as sarcopenic following PR. CONCLUSIONS: Sarcopenia affects 15% of patients with stable COPD and impairs function and health status. Sarcopenia does not impact on response to PR, which can lead to a reversal of the syndrome in select patients.

Clinical COPD Questionnaire in patients with chronic respiratory disease.

BACKGROUND AND OBJECTIVE: The Clinical Chronic Obstructive Pulmonary Disease (COPD) Questionnaire (CCQ) is an easy to complete, health-related quality of life questionnaire which has been well-validated in COPD. The responsiveness of the CCQ in chronic respiratory disease patients other than COPD has not been previously described. The study aims were to determine if the CCQ in chronic respiratory disease correlates with other health related quality of life questionnaires, to assess the responsiveness of the CCQ to pulmonary rehabilitation and to determine the minimum important difference. METHODS: The CCQ, COPD Assessment Test (CAT), the Chronic Respiratory Questionnaire (CRQ) and St George's Respiratory Questionnaire (SGRQ) were measured in 138 chronic respiratory disease patients completing pulmonary rehabilitation. Change in CCQ with pulmonary rehabilitation was correlated with change in the other questionnaires. The minimum important difference of the CCQ was calculated using distribution and anchor-based approaches. RESULTS: The CCQ, CAT, CRQ and SGRQ improved significantly with rehabilitation with effect sizes of -0.43, -0.26, 0.62, -0.37. Change in CCQ correlated significantly with CAT, CRQ and SGRQ (r = 0.53, -0.64, 0.30, all P < 0.0001). The minimum important difference was -0.42 at the population level and -0.4 at the individual level. CONCLUSIONS: The CCQ is responsive to pulmonary rehabilitation in chronic respiratory disease patients, with an MID estimated at -0.4 at the individual level.

Minimum clinically important difference for the COPD Assessment Test: a prospective analysis.

BACKGROUND: The COPD Assessment Test (CAT) is responsive to change in patients with chronic obstructive pulmonary disease (COPD). However, the minimum clinically important difference (MCID) has not been established. We aimed to identify the MCID for the CAT using anchor-based and distribution-based methods. METHODS: We did three studies at two centres in London (UK) between April 1, 2010, and Dec 31, 2012. Study 1 assessed CAT score before and after 8 weeks of outpatient pulmonary rehabilitation in patients with COPD who were able to walk 5 m, and had no contraindication to exercise. Study 2 assessed change in CAT score at discharge and after 3 months in patients admitted to hospital for more than 24 h for acute exacerbation of COPD. Study 3 assessed change in CAT score at baseline and at 12 months in stable outpatients with COPD. We focused on identifying the minimum clinically important improvement in CAT score. The St George's Respiratory Questionnaire (SGRQ) and Chronic Respiratory Questionnaire (CRQ) were measured concurrently as anchors. We used receiver operating characteristic curves, linear regression, and distribution-based methods (half SD, SE of measurement) to estimate the MCID for the CAT; we included only patients with paired CAT scores in the analysis. FINDINGS: In Study 1, 565 of 675 (84%) patients had paired CAT scores. The mean change in CAT score with pulmonary rehabilitation was -2·5 (95% CI -3·0 to -1·9), which correlated significantly with change in SGRQ score (r=0·32; p<0·0001) and CRQ score (r=-0·46; p<0·0001). In Study 2, of 200 patients recruited, 147 (74%) had paired CAT scores. Mean change in CAT score from hospital discharge to 3 months after discharge was -3·0 (95% CI -4·4 to -1·6), which correlated with change in SGRQ score (r=0·47; p<0·0001). In Study 3, of 200 patients recruited, 164 (82%) had paired CAT scores. Although no significant change in CAT score was identified after 12 months (mean 0·6, 95% CI -0·4 to 1·5), change in CAT score correlated significantly with change in SGRQ score (r=0·36; p<0·0001). Linear regression estimated the minimum clinically important improvement for the CAT to range between -1·2 and -2·8 with receiver operating characteristic curves consistently identifying -2 as the MCID. Distribution-based estimates for the MCID ranged from -3·3 to -3·8. INTERPRETATION: The most reliable estimate of the minimum important difference of the CAT is 2 points. This estimate could be useful in the clinical interpretation of CAT data, particularly in response to intervention studies. FUNDING: Medical Research Council and UK National Institute of Health Research.

Pulmonary rehabilitation following hospitalisation for acute exacerbation of COPD: referrals, uptake and adherence.

RATIONALE: Several randomised controlled trials support the provision of early pulmonary rehabilitation (PR) following hospitalisation for acute exacerbation of chronic obstructive pulmonary disease (AECOPD). However, there is little real-world data regarding uptake, adherence and completion rates. METHODS: An audit was conducted to prospectively document referral, uptake, adherence and completion rates for early post-hospitalisation outpatient PR in Northwest London over a 12-month period. RESULTS: Out of 448 hospital discharges for AECOPD, 90 referrals for post-hospitalisation PR were received. Only 43 patients received and completed PR (9.6% of all hospital discharges) despite a fully commissioned PR service. CONCLUSIONS: Despite the strong evidence base, there are poor referral and uptake rates for early outpatient PR following hospitalisation for AECOPD, with only a small proportion of the intended target population receiving this intervention.

Phenotypic characteristics associated with reduced short physical performance battery score in COPD.

BACKGROUND: The Short Physical Performance Battery (SPPB) is commonly used in gerontology, but its determinants have not been previously evaluated in COPD. In particular, it is unknown whether pulmonary aspects of COPD would limit the value of SPPB as an assessment tool of lower limb function. METHODS: In 109 patients with COPD, we measured SPPB score, spirometry, 6-min walk distance, quadriceps strength, rectus femoris cross-sectional area, fat-free mass, physical activity, health status, and Medical Research Council dyspnea score. In a subset of 31 patients with COPD, a vastus lateralis biopsy was performed, and the biopsy specimen was examined to evaluate the structural muscle characteristics associated with SPPB score. The phenotypic characteristics of patients stratified according to SPPB were determined. RESULTS: Quadriceps strength and 6-min walk distance were the only independent predictors of SPPB score in a multivariate regression model. Furthermore, while age, dyspnea, and health status were also univariate predictors of SPPB score, FEV 1 was not. Stratification by reduced SPPB score identified patients with locomotor muscle atrophy and increasing impairment in strength, exercise capacity, and daily physical activity. Patients with mild or major impairment defined as an SPPB score < 10 had a higher proportion of type 2 fibers (71% [14] vs 58% [15], P = .04). CONCLUSIONS: The SPPB is a valid and simple assessment tool that may detect a phenotype with functional impairment, loss of muscle mass, and structural muscle abnormality in stable patients with COPD.

The Clinical COPD Questionnaire: response to pulmonary rehabilitation and minimal clinically important difference.

BACKGROUND: The Clinical COPD Questionnaire (CCQ) is a simple 10-item, health-related quality of life questionnaire (HRQoL) with good psychometric properties. However, little data exists regarding the responsiveness of the CCQ to pulmonary rehabilitation (PR) or the minimal clinically important difference (MCID). The study aims were to assess the responsiveness of the CCQ to PR, to compare the responsiveness of the CCQ to other HRQoL questionnaires and to provide estimates for the MCID. METHODS: The CCQ, St George's Respiratory Questionnaire (SGRQ), Chronic Respiratory Questionnaire (CRQ) and COPD Assessment Test (CAT) were measured in 261 patients with COPD before and after outpatient PR. Pre to post PR changes and Cohen's effect size were calculated. Changes in CCQ were compared with changes in other HRQoL questionnaires. Using an anchor-based approach and receiver operating characteristic (ROC) curves, the CCQ change cutoffs that identified patients achieving the known MCID for other health status questionnaires with PR were identified. RESULTS: The CCQ, SGRQ, CRQ and CAT all significantly improved with PR with an effect size of -0.39, -0.33, 0.62 and -0.25, respectively. CCQ change correlated significantly with change in SGRQ, CRQ and CAT (r=0.48, -0.56, 0.54, respectively; all p<0.001). ROC curves consistently identified a CCQ change cutoff of -0.4 as the best discriminating value to identify the MCID for the SGRQ, CRQ and CAT (area under curve: 0.71, 0.75 and 0.77, respectively; all p<0.001). CONCLUSIONS: The CCQ is responsive to PR with an estimated clinically important improvement of -0.4 points. The CCQ is a practical alternative to more time-consuming measures of HRQoL.