Dana S. Hardin

Diagnosis, screening and management of cystic fibrosis related diabetes mellitus: A consensus conference report

Cystic fibrosis (CF) is the most common lifethreatening autosomal recessive disease of Caucasians in the USA, affecting 1/3000 live births [1]. Gene defects on the long arm of chromosome 7 lead to defective production of a protein called the cystic fibrosis transmembrane regulator (CFTR). CFTR is a cAMP-dependent chloride channel which influences the water and electrolyte composition of secretions from sweat glands, airways, pancreatic ducts, hepatobiliary ducts and intestinal glands. The common pathological finding in these organs is accumulation of thick, viscous secretions associated with progressive obstruction, scarring and destruction; 84% of CF patients die from respiratory disease [2]. Improvements in pulmonary and nutritional care over the last few decades have led to dramatic improvements in the mortality rate, and now many patients with CF live into their third, fourth or fifth decades. The median life expectancy for CF patients at present is 31.3 years [2]. As CF patients Abbre6iations: ADA, American Diabetes Association; CF, cystic fibrosis; CFRD, cystic fibrosis related diabetes mellitus; CFTR, cystic fibrosis transmembrane regulator; DCCT, Diabetes Control and Complications Trial; FPG, fasting plasma glucose; GDM, gestational diabetes mellitus; 2-h PG, 2-h plasma glucose during oral glucose tolerance test; IGT, impaired glucose tolerance; NGT, normal glucose tolerance; OGTT, oral glucose tolerance test; SMBG ,self-monitoring of blood glucose. * Corresponding author. Present address: Pediatric Department Box 404, University of Minnesota, 516 Delaware St. SE, Minneapolis, Minnesota 55455, USA. Tel.: +1-612-624-5409; fax: +1-612-624-2682. E-mail address: moran001@tc.umn.edu (A. Moran)

Insulin resistance is associated with decreased clinical status in cystic fibrosis

Patients with cystic fibrosis (CF) frequently have impaired glucose tolerance and progression to diabetes (DM) with clinical features of both insulin-dependent and non-insulin-dependent diabetes. One feature of non-insulin-dependent DM is decreased insulin sensitivity, also known as insulin resistance. The goal of this study was to determine whether patients with CF exhibit insulin resistance and to determine the potential effect of insulin resistance on clinical status. We also sought to determine whether insulin resistance is associated with a specific CF genotype. We studied 18 patients with CF (8 with normal glucose tolerance, 5 with impaired glucose tolerance, 5 with DM), and 20 lean control subjects matched for age, weight, and sex. All control subjects had normal glucose tolerance. The clinical status for each CF patients was determined according to a modified National Institutes of Health scoring system. Each subject underwent a three-step hyperinsulinemic euglycemic clamp (insulin doses of 10, 40, 120 mU/m2 per minute). Results from the 120 mU/m2 per minute infusion defined maximal glucose disposal rate (defined in milligrams per kilogram body weight per minute) at steady state with peripheral insulin levels 195 +/- 20 mU/ml. Subjects with CF demonstrated insulin resistance (control subjects = 13.6 +/- 1.1, patients with CF = 10.2 +/- 1.6 mg/kg per minute; p = 0.003). When each subgroup was compared separately with control subjects, all subgroups were statistically insulin resistant (glucose disposal rate, patients with CF and normal glucose tolerance = 10.8; those with impaired glucose tolerance = 8.4; those with DM = 10.1 mg/kg per minute), and the patients with CF with impaired glucose tolerance were the most insulin resistant. When plotted versus glucose disposal rate, a striking positive correlation between worsened clinical status and insulin resistance (r = 0.85) is demonstrated. Furthermore, there is no correlation between insulin resistance and fasting blood glucose, subject age, or percent ideal body weight (all r values not significant). In conclusion, patients with CF exhibit insulin resistance that is associated with worsened clinical status. We believe it is the combination of insulin resistance and decreased insulin secretion that is responsible for the high incidence of CF-related diabetes.

Proteolysis Associated With Insulin Resistance in Cystic Fibrosis

Objective. We hypothesized that patients with cystic fibrosis (CF) have higher rates of protein breakdown than normal volunteers and that the infusion of insulin would result in less suppression of proteolysis. Methods. Using [1-13C]leucine and a three-step hyperinsulinemic euglycemic clamp, we measured rates of leucine appearance in 29 adult CF patients and 18 matched-control volunteers. The CF patients were characterized by oral glucose tolerance testing and clinical status scoring. Results. The CF patients had significantly increased proteolysis when compared with that of controls (CF, 123 ± 28 μmol/kg/h; controls, 71 ± 15 μmol/kg/h) and rates of proteolysis were significantly different between CF patients with impaired glucose tolerance and diabetes and those CF patients with normal glucose tolerance. Suppression of proteolysis by insulin was less in all CF subgroups than in the controls at peripheral insulin levels of 16 and 29 μU/mL. At peripheral insulin levels of 100 μU/mL, there was no difference in insulin suppression of proteolysis between CF patients and controls. Importantly, basal rates of proteolysis had an inverse relationship with clinical status in CF patients (r = −.76). Conclusions. Our findings indicate that proteolysis is higher in adult CF patients than in controls and that CF patients exhibit resistance to the anabolic effects of insulin on proteolysis. Most significantly, our findings indicate that basal rates of proteolysis inversely correlate with clinical status in CF.

DIABETES MELLITUS IN CYSTIC FIBROSIS

Glucose intolerance and diabetes are common complications of cystic fibrosis (CF), affecting up to 75% of the adult population. This article discusses the prevalence and pathophysiology of glucose tolerance abnormalities in CF, and reviews recent recommendations for diagnosis, screening, and management of CF-related diabetes (CFRD).

Effects of growth hormone treatment in children with cystic fibrosis: The National Cooperative Growth Study experience

Poor longitudinal growth and low body weight affect many persons with cystic fibrosis (CF). The Cystic Fibrosis Foundation reports that 28% of all persons with CF are below the 10th percentile for height and that 34% are below the 10th percentile for weight. Intensive nutritional supplementation has not resulted in sustained improvement in the poor linear growth and low weight in CF. Because of the significant impact of nutrition in CF, the anabolic effects of growth hormone (GH) may make the agent useful as adjunctive treatment for malnutrition and poor linear growth. To date, 24 patients with CF (16 boys; 87% Tanner stage 1) have been enrolled in the National Cooperative Growth Study. The average age at enrollment was 10.3 years, and there was significant delay in height in all patients (mean height age, 7.1 years). Bone age was also significantly delayed (mean delay, 3.0 years). The mean maximum stimulated GH level was 12.3 micrograms/L and the mean GH dose given was 0.291 +/- 0.038 mg/kg per week. After 1 and 2 years of treatment with GH the growth rate increased in all patients with available growth rate data. The growth rates in these children were slightly lower than in children who were treated with GH for idiopathic GH deficiency. The weight-for-height standard deviation scores improved significantly after 2 years of GH treatment. There were adverse reactions (glucose intolerance) to GH in only two patients; treatment was suspended in one of these patients but was continued in the other. National Cooperative Growth Study data indicate that treatment with GH increases linear growth and weight in prepubertal patients with CF. These data suggest that GH may be useful for treating malnutrition in CF.

Effect of Ingested Interferon-α on β-Cell Function in Children With New-Onset Type 1 Diabetes

OBJECTIVE To evaluate the safety and efficacy of ingested human recombinant interferon-α (hrIFN-α) for preservation of β-cell function in young patients with recent-onset type 1 diabetes. RESEARCH DESIGN AND METHODS Subjects aged 3–25 years in whom type 1 diabetes was diagnosed within 6 weeks of enrollment were randomly assigned to receive ingested hrIFN-α at 5,000 or 30,000 units or placebo once daily for 1 year. The primary outcome was change in C-peptide secretion after a mixed meal. RESULTS Individuals in the placebo group (n = 30) lost 56 ± 29% of their C-peptide secretion from 0 to 12 months, expressed as area under the curve (AUC) in response to a mixed meal. In contrast, children treated with hrIFN-α lost 29 ± 54 and 48 ± 35% (for 5,000 [n = 27] and 30,000 units [n = 31], respectively, P = 0.028, ANOVA adjusted for age, baseline C-peptide AUC, and study site). Bonferroni post hoc analyses for placebo versus 5,000 units and placebo versus 30,000 units demonstrated that the overall trend was determined by the 5,000-unit treatment group. Adverse events occurred at similar rates in all treatment groups. CONCLUSIONS Ingested hrIFN-α was safe at the doses used. Patients in the 5,000-unit hrIFN-α treatment group maintained more β-cell function 1 year after study enrollment than individuals in the placebo group, whereas this effect was not observed in patients who received 30,000 units hrIFN-α. Further studies of low-dose ingested hrIFN-α in new-onset type 1 diabetes are needed to confirm this effect.

The metabolic effects of pregnancy in cystic fibrosis.

Objective: Our purpose was to determine glucose tolerance in pregnant women with cystic fibrosis (CF) and to relate glucose tolerance to insulin sensitivity, hepatic glucose production, and protein turnover. Methods: We studied 8 CF women during pregnancy (CFPreg). Results were compared with those from 9 pregnant controls (PregCont) and 8 nonpregnant CF women (CFCont). The following metabolic studies were conducted: oral glucose tolerance test (OGTT), hyperinsulinemic euglycemic clamp, stable isotope infusion of [1-13C]leucine and [6,6-2H2]glucose for measurement of whole body protein turnover and hepatic glucose production (HGP), respectively. Indirect calorimetry was used to measure resting energy expenditure (REE), and food intake was measured by 3-day food journals. Fat-free mass was measured by total body potassium 40K scan. Results: All but one CFPreg developed diabetes by the end of the second trimester and had significantly lower insulin secretion and more insulin resistance than PregCont. Hepatic glucose production was significantly higher and suppression by insulin was less in CF subjects, and protein breakdown was significantly higher. Insulin resistance and HGP increased during pregnancy similarly in CFPreg and PregCont groups. Conclusion: Pregnancy in CF is associated with decreased insulin sensitivity and high HGP, in addition to inherent decreased insulin secretion. Pregnancy in CF is also associated with increased protein turnover and less response to insulin’s anticatabolic effect. These changes appear to predispose the pregnant CF women to early development of diabetes and poor weight gain. Level of Evidence II-2

Growth hormone improves bone mineral content in children with cystic fibrosis

AIM Osteoporosis and osteopenia have been reported as common complications of cystic fibrosis (CF); however, little is known about accrual of bone mineral in CF. The goal of our study was to measure bone mineral content (BMC) in non-acutely-ill, but poorly growing children with CF, and to determine the relationship between height, lean body mass and BMC. Our second aim was to evaluate the effect of one year of treatment with human recombinant growth hormone (GH) on total body BMC. METHODS We measured total-body BMC using dual energy X-ray absorptiometry in 32 poorly growing (height < or =10th percentile for age) prepubertal Caucasian children (ages 7 years 6 months-12 years 9 months, 17 M and 15, F) with CF. BMC and lean tissue mass (LTM) were measured at baseline, at 6 months and one year. One half of the children were randomly assigned to receive treatment with GH (GHTX). Results were compared to reference data maintained for healthy children matched for age and ethnicity. Sex steroid and IGF-I levels were also measured. RESULTS Children with CF exhibited lower total body BMC and LTM than age-, ethnicity- and gender-matched controls. This was still apparent when the data were matched for height and bone age. BMC correlated with height, LTM, and IGF-I levels. Although at baseline the groups were similar, the GHTX group demonstrated significantly greater increase in height, weight, LTM and BMC than the NonTX group. These differences remained despite correction for increase in height CONCLUSION Our study is the first to evaluate BMC in children with CF and suggests that poor accumulation of bone mineral is a problem. We have further demonstrated that GH treatment improves accumulation of bone mineral.

Improvement in insulin sensitivity and dyslipidemia in protease inhibitor-treated adult male patients after switch to atazanavir/ritonavir.

Background Treatment of human immunodeficiency virus (HIV) with protease inhibitors (PIs) is associated with insulin resistance, triglyceride-rich dyslipidemia, and fat redistribution. Atazanavir (ATV), a potent once-daily PI, has been recognized for its convenience to patients, and some studies describe improved lipid metabolism. However, its effects on insulin sensitivity have not been elucidated. We conducted this study to test the hypothesis that ATV improves insulin resistance and dyslipidemia. Methods We prospectively studied 9 HIV-infected men with dyslipidemia (median age, 53 years; baseline triglyceride level, >200 mg/dL) on stable PI-containing antiretroviral therapy who elected to change PI therapy to ritonavir-boosted ATV therapy, dose of 300/100 mg. We measured insulin resistance at baseline and after 12 weeks of therapy using a hyperinsulinemic euglycemic clamp (insulin dose, 200 mU/m2 minute). Fasting lipid profiles and body composition (whole-body dual energy x-ray absorptiometry) were also measured at baseline and after 12 weeks. Results All 9 patients completed the study and maintained undetectable viral loads (<50 copies/mL) and stable CD4 counts. After 12 weeks, insulin sensitivity significantly improved (+28%; P = 0.008) in all patients. Triglyceride levels also improved. Conclusions Using the gold-standard euglycemic clamp, ritonavir-boosted ATV therapy improved PI-induced insulin resistance among dyslipidemic HIV-infected men on PI-based antiretroviral therapy. These findings were not attributable to a change in body weight and provide further evidence for ATVs unique metabolic profile among the PIs.

A retrospective study of growth hormone use in adolescents with cystic fibrosis.

Objectives Studies of growth hormone (GH) effectiveness in prepubertal children with cystic fibrosis (CF) have been published previously. We present a retrospective study of GH treatment in adolescents with CF.