Brandon M. Nathan

Cystic Fibrosis Related Diabetes: Current Trends in Prevalence, Incidence and Mortality

OBJECTIVE Cystic fibrosis (CF)-related diabetes (CFRD) diagnosis and management have considerably changed since diabetes was first shown to be associated with a poor prognosis in subjects with CF. Current trends in CFRD prevalence, incidence, and mortality were determined from a comprehensive clinical database. RESEARCH DESIGN AND METHODS Data were reviewed from 872 CF patients followed at the University of Minnesota during three consecutive intervals: 1992–1997, 1998–2002, and 2003–2008. RESULTS CFRD is currently present in 2% of children, 19% of adolescents, and 40–50% of adults. Incidence and prevalence are higher in female subjects aged 30–39 years; otherwise, there are no sex differences. In younger individuals, CFRD without fasting hyperglycemia predominates, but fasting hyperglycemia prevalence rises with age. CFRD mortality has significantly decreased over time. From 1992–1997 to 2003–2008, mortality rate in female subjects dropped by >50% from 6.9 to 3.2 deaths per 100 patient-years and in male subjects from 6.5 to 3.8 deaths per 100 patient-years. There is no longer a sex difference in mortality. Diabetes was previously diagnosed as a perimorbid event in nearly 20% of patients, but of 61 patients diagnosed with diabetes during 2003–2008, only 2 died. Lung function but not nutritional status is still worse in CF patients with diabetes compared with those without diabetes. Nutritional status and pulmonary status are similar between patients without fasting hyperglycemia and those with fasting hyperglycemia. CONCLUSIONS Previously noted sex differences in mortality have disappeared, and the gap in mortality between CF patients with and without diabetes has considerably narrowed. We believe that early diagnosis and aggressive treatment have played a major role in improving survival in these patients.

Metabolic complications of obesity in childhood and adolescence: more than just diabetes.

Purpose of reviewThe alarming increase in the prevalence of pediatric obesity has led to a rise in associated metabolic complications in worldwide pediatric populations. This review summarizes recent literature on detection, pathophysiology, and potential intervention strategies for the metabolic derangements encountered in the overweight pediatric population. Recent findingsDevelopment of metabolic complications associated with obesity during childhood track into adulthood and increase the risk for type 2 diabetes and early cardiovascular disease. Clustering of these metabolic abnormalities, which include insulin resistance, hypertension and dyslipidemia, constitutes the metabolic syndrome, which may affect up to 50% of overweight adolescents. Other serious disorders associated with obesity and insulin resistance include polycystic ovary disease and fatty liver. Family and school-based programs focusing on lifestyle modifications, as well as pharmacotherapy, have shown preliminary promise in reversing some of these derangements. SummaryAs the trend in pediatric obesity continues to rise, providers must effectively identify children at risk for metabolic disturbances and implement long-lasting, successful treatment regimens. Continued research into the predecessors of cardiovascular disease that begin during childhood and how they can be altered is crucial to the future health of our pediatric population.

The effect of glucagon-like peptide-1 receptor agonist therapy on body mass index in adolescents with severe obesity: a randomized, placebo-controlled, clinical trial.

IMPORTANCE Medical treatment options for pediatric obesity remain limited. Glucagon-like peptide-1 (GLP-1) receptor agonists induce weight loss by suppressing appetite and increasing satiety, but few studies have evaluated this therapy as a treatment for obesity. OBJECTIVE To evaluate the effects of exenatide on body mass index (BMI; calculated as weight in kilograms divided by height in meters squared) and cardiometabolic risk factors in adolescents with severe obesity. DESIGN Three-month, randomized, double-blind, placebo-controlled, multicenter clinical trial followed by a 3-month open-label extension. SETTING An academic medical center and an outpatient pediatric endocrinology clinic. PATIENTS A total of 26 adolescents (12-19 years of age) with severe obesity (BMI ≥ 1.2 times the 95th percentile or BMI ≥ 35). INTERVENTION All patients received lifestyle modification counseling and were equally randomized to exenatide or placebo injection, twice per day. MAIN OUTCOME MEASURES The primary end point was the mean percent change in BMI measured at baseline and 3 months. Secondary end points included absolute change in BMI, body weight, body fat, blood pressure, hemoglobin A1c, fasting glucose, fasting insulin, and lipids at 3 months. RESULTS Twenty-two patients completed the trial. Exenatide elicited a greater reduction in percent change in BMI compared with placebo (-2.70% [95% CI, -5.02% to -0.37%]; P = .03). Similar findings were observed for absolute change in BMI (-1.13 [95% CI, -2.03 to -0.24]; P = .02) and body weight (-3.26 kg [95% CI, -5.87 to -0.66 kg]; P = .02). Although not reaching the level of statistical significance, reduction in systolic blood pressure was observed with exenatide. During the open-label extension, BMI was further reduced in those initially randomized to exenatide (cumulative BMI reduction of 4%). CONCLUSIONS AND RELEVANCE These results provide preliminary evidence supporting the feasibility, safety, and efficacy of GLP-1 receptor agonist therapy for the treatment of severe obesity in adolescents. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT01237197.

Exenatide as a weight-loss therapy in extreme pediatric obesity: a randomized, controlled pilot study.

The objective of this pilot study was to evaluate the effects of exenatide on BMI (primary endpoint) and cardiometabolic risk factors in nondiabetic youth with extreme obesity. Twelve children and adolescents (age 9–16 years old) with extreme obesity (BMI ≥1.2 times the 95th percentile or BMI ≥35 kg/m2) were enrolled in a 6‐month, randomized, open‐label, crossover, clinical trial consisting of two, 3‐month phases: (i) a control phase of lifestyle modification and (ii) a drug phase of lifestyle modification plus exenatide. Participants were equally randomized to phase‐order (i.e., starting with control or drug therapy) then crossed‐over to the other treatment. BMI, body fat percentage, blood pressure, lipids, oral glucose tolerance tests (OGTT), adipokines, plasma biomarkers of endothelial activation, and endothelial function were assessed at baseline, 3‐, and 6‐months. The mean change over each 3‐month phase was compared between treatments. Compared to control, exenatide significantly reduced BMI (−1.7 kg/m2, 95% confidence interval (CI) (−3.0, −0.4), P = 0.01), body weight (−3.9 kg, 95% CI (−7.11, −0.69), P = 0.02), and fasting insulin (−7.5 mU/l, 95% CI (−13.71, −1.37), P = 0.02). Significant improvements were observed for OGTT‐derived insulin sensitivity (P = 0.02) and β‐cell function (P = 0.03). Compliance with the injection regimen was excellent (≥94%) and exenatide was generally well‐tolerated (the most common adverse event was mild nausea in 36%). These preliminary data suggest that exenatide should be evaluated in larger, well‐controlled trials for its ability to reduce BMI and improve cardiometabolic risk factors in youth with extreme obesity.

Identification and treatment of metabolic complications in pediatric obesity

Metabolic consequences of obesity including insulin resistance, type 2 diabetes mellitus, hyperlipidemia, hypertension, polycystic ovarian syndrome, and non-alcoholic fatty liver infiltration are rapidly emerging in the pediatric population. Identifying effective strategies for identifying and treating these obesity related co-morbidities in children are crucial to the prevention of future cardiovascular disease and poor health outcomes. This review discusses the pathophysiologic connections between obesity, metabolic disease and cardiovascular risk. Current evidence and recommendations for screening and treatment for the metabolic consequences of pediatric obesity are reviewed.

Recent trends in cystic fibrosis-related diabetes

Purpose of reviewTo provide an updated literature review highlighting important aspects of cystic fibrosis-related diabetes (CFRD) including epidemiology, pathogenesis, complications, screening, and management. Recent findingsAlthough CFRD continues to be associated with increased rates of mortality in the cystic fibrosis (CF) population, this has improved over the past several years, and the previous sex difference is no longer present. Recent studies support that CFRD is primarily caused by insulin deficiency due to loss of β cells, which may occur via a number of mechanisms including oxidative stress. Aggressive screening programs with oral-glucose tolerance testing and early treatment with insulin for patients with CFRD with or without fasting hyperglycemia have led to improvements in nutritional states and lung function. Oral agents do not appear to be effective in CFRD. SummaryCFRD is the most common comorbidity in the CF population and is associated with microvascular complications and protein catabolism leading to worse health outcomes. Recognition of glycemic abnormalities through aggressive screening has led to improvements in nutritional status, pulmonary function, and mortality rates.

Association of Osteocalcin With Obesity, Insulin Resistance, and Cardiovascular Risk Factors in Young Adults

Low levels of osteocalcin (OCN), an osteoblast‐specific hormone, have recently been associated with insulin resistance (homeostasis model assessment‐insulin resistance (HOMA‐IR)) and obesity, particularly in older adults. The aim of this study was to determine whether low levels of OCN would be associated with insulin resistance, obesity, and greater cardiovascular (CV) risk in young adults just emerging from adolescence. Undercarboxylated OCN and carboxylated OCN levels were measured on stored serum samples (total OCN = undercarboxylated OCN + carboxylated OCN) on 137 participants (67 males) at mean age 18.6 years (range 17–22 years). Insulin resistance was measured by hyperinsulinemic—euglycemic clamp (Mlbm). Multivariable regression analyses with ln(OCN) as the independent variable were adjusted for age, sex, ethnicity, and BMI as indicated. Total OCN was inversely related to BMI, waist circumference, systolic blood pressure (SBP), interleukin (IL)‐6, and directly related to Mlbm; only SBP remained significant (with Mlbm P = 0.0560) after further adjustment for BMI. Carboxylated OCN was inversely related to BMI, waist circumference, SBP, low‐density lipoprotein cholesterol (LDL‐C), and directly related to adiponectin; SBP and adiponectin remained significant after further adjustment for BMI. There were no significant associations with undercarboxylated OCN. In summary, most associations with OCN were mediated via BMI. However, the significant associations of OCN with SBP, obesity, and adiponectin and borderline with Mlbm, suggest a potential role for OCN in the development of insulin resistance and CV risk that becomes more apparent with aging into older adulthood.

Managing diabetes in cystic fibrosis

Cystic fibrosis related diabetes (CFRD) is the most common co‐morbidity in persons with cystic fibrosis (CF). As the life expectancy of persons with CF continues to increase, the need to proactively diagnose and aggressively treat CFRD and its potential complications has become more apparent. CFRD negatively impacts lung function, growth and mortality, making its diagnosis and management crucial in a population already at high risk for early mortality. Compared to type 1 and type 2 diabetes, CFRD is a unique entity, requiring a thorough understanding of its unique pathophysiology to facilitate the creation and utilization of an effective medical treatment plan. The physiology of CFRD is complex, likely consisting of a combination of insulin deficiency, insulin resistance and a genetic predisposition towards the development of diabetes. However, the hallmark of CFRD is insulin deficiency, necessitating the use of exogenous insulin as the mainstay of therapy. Insulin administration, in combination with a multidisciplinary team of health professionals with expertise in the care of patients with CF and CFRD, is the cornerstone of the care for these patients. The goals of treatment of the CFRD population are to reverse protein catabolism, maintain a healthy weight, and reduce acute and chronic diabetes complications. Creating a partnership between the treatment team and the patient is the ideal way to accomplish these goals and is essential for successful diabetes care.

Endocrine Disorders in Fanconi Anemia: Recommendations for Screening and Treatment

CONTEXT Endocrine problems are common in patients with Fanconi anemia (FA). About 80% of children and adults with FA have at least one endocrine abnormality, including short stature, GH deficiency, abnormal glucose or insulin metabolism, dyslipidemia, hypothyroidism, pubertal delay, hypogonadism, or impaired fertility. The goal of this report is to provide an overview of endocrine abnormalities and guidelines for routine screening and treatment to allow early diagnosis and timely intervention. EVIDENCE ACQUISITION This work is based on a comprehensive literature review, including relevant articles published between 1971 and 2014, and proceedings of a Consensus Conference held by the Fanconi Anemia Research Fund in 2013. EVIDENCE SYNTHESIS The panel of experts collected published evidence and discussed its relevance to reflect current information about the endocrine care of children and adults with FA before the Consensus Conference and through subsequent deliberations that led to the consensus. CONCLUSIONS Individuals with FA should be routinely screened for endocrine abnormalities, including evaluation of growth; glucose, insulin, and lipid metabolism; thyroid function; puberty; gonadal function; and bone mineral metabolism. Inclusion of an endocrinologist as part of the multidisciplinary patient care team is key to providing comprehensive care for patients with FA.

Intranasal Glucagon for Treatment of Insulin-Induced Hypoglycemia in Adults With Type 1 Diabetes: A Randomized Crossover Noninferiority Study

OBJECTIVE Treatment of severe hypoglycemia with loss of consciousness or seizure outside of the hospital setting is presently limited to intramuscular glucagon requiring reconstitution immediately prior to injection, a process prone to error or omission. A needle-free intranasal glucagon preparation was compared with intramuscular glucagon for treatment of insulin-induced hypoglycemia. RESEARCH DESIGN AND METHODS At eight clinical centers, a randomized crossover noninferiority trial was conducted involving 75 adults with type 1 diabetes (mean age, 33 ± 12 years; median diabetes duration, 18 years) to compare intranasal (3 mg) versus intramuscular (1 mg) glucagon for treatment of hypoglycemia induced by intravenous insulin. Success was defined as an increase in plasma glucose to ≥70 mg/dL or ≥20 mg/dL from the glucose nadir within 30 min after receiving glucagon. RESULTS Mean plasma glucose at time of glucagon administration was 48 ± 8 and 49 ± 8 mg/dL at the intranasal and intramuscular visits, respectively. Success criteria were met at all but one intranasal visit and at all intramuscular visits (98.7% vs. 100%; difference 1.3%, upper end of 1-sided 97.5% CI 4.0%). Mean time to success was 16 min for intranasal and 13 min for intramuscular (P < 0.001). Head/facial discomfort was reported during 25% of intranasal and 9% of intramuscular dosing visits; nausea (with or without vomiting) occurred with 35% and 38% of visits, respectively. CONCLUSIONS Intranasal glucagon was highly effective in treating insulin-induced hypoglycemia in adults with type 1 diabetes. Although the trial was conducted in a controlled setting, the results are applicable to real-world management of severe hypoglycemia, which occurs owing to excessive therapeutic insulin relative to the impaired or absent endogenous glucagon response.