Shihab Hameed

Early Glucose Abnormalities in Cystic Fibrosis Are Preceded by Poor Weight Gain

OBJECTIVE Progressive β-cell loss causes catabolism in cystic fibrosis. Existing diagnostic criteria for diabetes were based on microvascular complications rather than on cystic fibrosis–specific outcomes. We aimed to relate glycemic status in cystic fibrosis to weight and lung function changes. RESEARCH DESIGN AND METHODS We determined peak blood glucose (BGmax) during oral glucose tolerance tests (OGTTs) with samples every 30 min for 33 consecutive children (aged 10.2–18 years). Twenty-five also agreed to undergo continuous glucose monitoring (CGM) (Medtronic). Outcome measures were change in weight standard deviation score (wtSDS), percent forced expiratory volume in 1 s (%FEV1), and percent forced vital capacity (%FVC) in the year preceding the OGTT. RESULTS Declining wtSDS and %FVC were associated with higher BGmax (both P = 0.02) and with CGM time >7.8 mmol/l (P = 0.006 and P = 0.02, respectively) but not with BG120 min. A decline in %FEV1 was related to CGM time >7.8 mmol/l (P = 0.02). Using receiver operating characteristic (ROC) analysis to determine optimal glycemic cutoffs, CGM time above 7.8 mmol/l ≥4.5% detected declining wtSDS with 89% sensitivity and 86% specificity (area under the ROC curve 0.89, P = 0.003). BGmax ≥8.2 mmol/l gave 87% sensitivity and 70% specificity (0.76, P = 0.02). BG120 min did not detect declining wtSDS (0.59, P = 0.41). After exclusion of two patients with BG120 min ≥11.1 mmol/l, the decline in wtSDS was worse if BGmax was ≥8.2 mmol/l (−0.3 ± 0.4 vs. 0.0 ± 0.4 for BGmax <8.2 mmol/l, P = 0.04) or if CGM time above 7.8 mmol/l was ≥4.5% (−0.3 ± 0.4 vs. 0.1 ± 0.2 for time <4.5%, P = 0.01). CONCLUSIONS BGmax ≥8.2 mmol/l on an OGTT and CGM time above 7.8 mmol/l ≥4.5% are associated with declining wtSDS and lung function in the preceding 12 months.

Diiodothyropropionic Acid (DITPA) in the Treatment of MCT8 Deficiency

CONTEXT Monocarboxylate transporter 8 (MCT8) is a thyroid hormone-specific cell membrane transporter. MCT8 deficiency causes severe psychomotor retardation and abnormal thyroid tests. The great majority of affected children cannot walk or talk, and all have elevated serum T(3) levels, causing peripheral tissue hypermetabolism and inability to maintain weight. Treatment with thyroid hormone is ineffective. In Mct8-deficient mice, the thyroid hormone analog, diiodothyropropionic acid (DITPA), does not require MCT8 to enter tissues and could be an effective alternative to thyroid hormone treatment in humans. OBJECTIVE The objective of the study was to evaluate the effect and efficacy of DITPA in children with MCT8 deficiency. METHODS This was a multicenter report of four affected children given DITPA on compassionate grounds for 26-40 months. Treatment was initiated at ages 8.5-25 months, beginning with a small dose of 1.8 mg, increasing to a maximal 30 mg/d (2.1-2.4 mg/kg · d), given in three divided doses. RESULTS DITPA normalized the elevated serum T(3) and TSH when the dose reached 1 mg/kg · d and T(4) and rT(3) increased to the lower normal range. The following significant changes were also observed: decline in SHBG (in all subjects), heart rate (in three of four), and ferritin (in one of four). Cholesterol increased in two subjects. There was no weight loss and weight gain occurred in two. None of the treated children required a gastric feeding tube or developed seizures. No adverse effects were observed. CONCLUSION DITPA (1-2 mg/kg · d) almost completely normalizes thyroid tests and reduces the hypermetabolism and the tendency for weight loss. The effects of earlier commencement and long-term therapy remain to be determined.

Once daily insulin detemir in cystic fibrosis with insulin deficiency

The aim of this study was to determine if once daily insulin detemir reverses decline in weight and lung function in patients with cystic fibrosis (CF). 12 patients with early insulin deficiency and six with CF related diabetes (aged 7.2–18.1 years) were treated for a median of 0.8 years. Changes in weight and lung function following treatment were compared to pretreatment changes. Before treatment, the change in weight SD score (ΔWtSDS), percentage of predicted forced expiratory volume in 1 s (Δ%FEV1) and percentage of predicted forced vital capacity (Δ%FVC) declined in the whole study population (−0.45±0.38, −7.9±12.8%, −5.8±14.3%) and in the subgroup with early insulin deficiency (−0.41±0.43, −9.8±9.3%, −6.8±10.3%). Following treatment with insulin ΔWtSDS, Δ%FEV1 and Δ%FVC significantly improved in the whole study population (+0.18±0.29 SDS, p=0.0001; +3.7±10.6%, p=0.007; +5.2±12.7%, p=0.013) and in patients with early insulin deficiency (+0.22±0.31 SDS, p=0.003; +5.3±11.5%, p=0.004; +5.8±13.4%, p=0.024). Randomised controlled trials are now needed.

Cystic Fibrosis Related Diabetes (CFRD)—The End Stage of Progressive Insulin Deficiency

In cystic fibrosis, gradual pancreatic destruction causes progressive insulin deficiency, culminating in cystic fibrosis related diabetes (CFRD). As a consequence of insulin deficiency, elevated glucose levels can be detected (well before the diagnosis of CFRD), by continuous ambulatory subcutaneous interstitial fluid glucose monitoring or 30‐min sampled oral glucose tolerance test (OGTT). Current diagnostic criteria for CFRD (based on 0 and 120‐min OGTT blood glucose levels) were originally designed to forecast microvascular disease in type 2 diabetes, rather than CF‐specific outcomes such as declining weight or lung function. In CF, decline in either weight or lung function predicts early mortality. Both may precede the diagnosis of CFRD by several years. Insulin, a potent anabolic hormone, is recommended treatment for CFRD, but use in earlier stages of insulin deficiency is not established. Conventional dosing (with four or more insulin injections per day) is burdensome and carries substantial risk of hypoglycemia. However, recent uncontrolled trials suggest that once‐daily injection of intermediate or long‐acting insulin improves weight and lung function, with minimal hypoglycemia risk, in CFRD and also in early insulin deficiency. It is plausible that insulin may be of greater benefit to respiratory function when given prior to the diagnosis of CFRD, after which structural lung disease may be irreversible. It is also plausible that early insulin treatment may prolong the lifespan of the remaining insulin‐secreting β‐cells. Randomized controlled trials are now needed to determine whether or not current clinical practice should be altered toward the earlier commencement of insulin in CF. Pediatr. Pulmonol. 2011; 46:747–760.

Persistently autoantibody negative (PAN) type 1 diabetes mellitus in children.

Hameed S, Ellard S, Woodhead HJ, Neville KA, Walker JL, Craig ME, Armstrong T, Yu L, Eisenbarth GS, Hattersley AT, Verge CF. Persistently autoantibody negative (PAN) type 1 diabetes mellitus in children.

ISPAD Clinical Practice Consensus Guidelines 2014. Management of cystic fibrosis-related diabetes in children and adolescents.

Cystic fibrosis (CF) is the most common lethal genetic autosomal recessive disease in Caucasians, with a worldwide prevalence of 1 in ~2500 live births. Cystic fibrosis related diabetes (CFRD) is the most common co-morbidity in CF. There are important pathophysiologic differences between CFRD and type 1 and type 2 diabetes Table 1, which necessitate a unique approach to diagnosis and management. Factors specific to CF which impact glucose metabolism include the loss of total islets leading to both insulin and glucagon deficiency, chronic and acute inflammation and infection which cause fluctuating insulin resistance, a requirement for high caloric intake because of increased energy expenditure and malabsorption, risk of life-threatening malnutrition, and gut abnormalities including delayed gastric emptying, altered intestinal motility, and liver disease. This article is protected by copyright. All rights reserved.

Australian standards of care for cystic fibrosis-related diabetes.

Multiple guidelines have been published over the last few years for the diagnosis and management of cystic fibrosis (CF) and cystic fibrosis related diabetes (CFRD), although some of the recommendations are based on extrapolation from other forms of diabetes and/or expert opinions. This document seeks to combine the guidelines to provide an Australian approach to the management of CFRD and establish the guidelines within the Australian CF Standards of Care.

Increased detection of cystic-fibrosis-related diabetes in Australia

Objectives To estimate the incidence of cystic-fibrosis-related diabetes (CFRD) in youth from New South Wales (NSW) and the Australian Capital Territory (ACT), Australia and to examine demographic/clinical features at diagnosis. Methods Incident cases of CFRD in young people aged ≤18 years diagnosed during 2000 to 2008 were identified from four paediatric cystic fibrosis (CF) clinics and the NSW/ACT Australasian Paediatric Endocrine Group Diabetes Register. Results CFRD was diagnosed in 41 cases (59% girls). The estimated mean annual incidence of CFRD among patients with CF was 9.4 per 1000 person years (95% CI 6.8 to 12.8). Incidence increased from 2.0 per 1000 person years in 2000 to 22.1 per 1000 in 2008 (incidence RR 1.3, 95% CI 1.1 to 1.4). Haemoglobin A1c (HbA1c) was abnormal in the majority at diagnosis: median HbA1c was 6.9% (6.2–8.1%). More cases were diagnosed using an oral glucose tolerance test in 2007–2008 compared with previous years (61% vs 6%, p<0.001). Conclusions CFRD is increasingly recognised and now affects approximately one in five young people with CF. The rising incidence is likely to be due to increased detection, resulting from greater awareness and changes in screening practices. Widespread uptake of consensus guidelines for screening will ensure accurate case detection, but will also impact on patient care and resource allocation.

Advances in the detection and management of cystic fibrosis related diabetes.

Purpose of review This review will outline the screening, diagnosis and management of cystic fibrosis related diabetes (CFRD). It will also discuss advances in the detection of early glucose abnormalities, their clinical significance and the emerging role for early insulin therapy. Recent findings Before the onset of diabetes (as currently defined), patients with cystic fibrosis (CF) display glucose abnormalities, detectable either by 30-minutely sampled oral glucose tolerance testing (OGTT), or by continuous ambulatory interstitial glucose monitoring (CGM). These early glucose abnormalities are associated with the presence of glucose in airway fluid, potentially promoting the growth of airway pathogens and contributing to the progression of respiratory disease. Progressive insulin deficiency underlies these glucose abnormalities, and insulin deficiency also causes catabolism. Pilot studies of once-daily insulin therapy in the early stages of insulin deficiency show improved lung function and weight gain (important predictors of survival in CF). Summary Early stages of insulin deficiency may be contributing to catabolism and deteriorating lung function in CF. It is plausible that early insulin therapy may prevent this deterioration, a view supported by pilot studies. Randomized controlled trials of early insulin therapy will now determine whether insulin therapy should be commenced earlier than current practice in CF.

Diagnosing cystic fibrosis-related diabetes: current methods and challenges

ABSTRACT Introduction: Cystic fibrosis-related diabetes (CFRD) is the end-point of a spectrum of glucose abnormalities in cystic fibrosis that begins with early insulin deficiency and ultimately results in accelerated nutritional decline and loss of lung function. Current diagnostic and management regimens are unable to entirely reverse this clinical decline. Areas covered: This review summarises the current understanding of the pathophysiology of CFRD, the issues associated with using oral glucose tolerance tests in CF and the challenges faced in making the diagnosis of CFRD. Medline database searches were conducted using search terms “Cystic Fibrosis Related Diabetes”, “Cystic Fibrosis” AND “glucose”, “Cystic Fibrosis” AND “insulin”, “Cystic Fibrosis” AND “Diabetes”. Additionally, reference lists were studied. Expert commentary: Increasing evidence points to early glucose abnormalities being clinically relevant in cystic fibrosis and as such novel diagnostic methods such as continuous glucose monitoring or 30 minute sampled oral glucose tolerance test (OGTT) may play a key role in the future in the screening and diagnosis of early glucose abnormalities in CF.