Insulin Production and Resistance in CF: Effect of Age, Disease Activity and Genotype

J Endocrinol Invest. 2011 Apr 6. [Epub ahead of print]

INSULIN PRODUCTION AND RESISTANCE IN CYSTIC FIBROSIS: EFFECT OF AGE, DISEASE ACTIVITY, AND GENOTYPE.

Street ME, Spaggiari C, Ziveri MA, Rossi M, Volta C, Viani I, Grzincich GL, Sartori C, Zanzucchi M, Raia V, Terzi C, Pisi G, Zanetti E, Boguszewski MC, Kamoi TO, Bernasconi S.

Department of Paediatrics, University Hospital of Parma, Via Gramsci, 14, 43126 Parma, Italy.

Abstract

Aim: To assess the major determinants of glucose tolerance between age, genotype and clinical status in cystic fibrosis (CF) patients, and study if defects of insulin secretion and insulin sensitivity were associated with the onset of CF related diabetes (CFRD). Subjects and Methods: 119 patients, in stable clinical condition were studied. They were subdivided into 3 groups based on age, and 2 groups based on Schwachman-Kulczycki clinical score. All patients were genotyped, and subsequently divided into 3 groups. Ninety-four healthy normal-weight controls, comparable for sex and age also were also studied. All subjects had baseline blood samples taken for glucose and insulin, C-peptide, and glycated hemoglobin. HOMA-IR, fasting glucose/insulin ratio(FGIR) were calculated as indices of insulin resistance and insulinogenic index as a marker of pancreatic β cell function. All patients underwent an OGTT, and 57 underwent an IVGTT for the calculation of first phase(FPIR) and acute insulin responses(AIR).

 Results:The F508del homozygous patients had an increased chance of developing impaired glucose tolerance (IGT) and significantly lower FPIR, decreased HOMA-IR, and insulinogenic index. Heterozygote F508del patients had an increased chance of having normal glucose tolerance. HOMA-IR, FGIR, and insulinogenic index did not change with age or clinical score. HOMA-IR correlated with FPIR. FPIR correlated positively with insulinogenic index. AIR correlated negatively with FGIR, and positively with C-reactive protein. In multiple linear regression analyses glucose tolerance was related to the age-group, and to the HOMA-IR ans insulinogenic indexes. Conclusions: IGT and CFRD were related mainly to genotype, although as expected the prevalence increased with age. The data suggested a possible combined contribution of insulin deficiency, β-cell function and reduced insulin sensitivity to the onset of CFRD, however further studies are warranted to better elucidate this aspect.

Low prevalence of glucose intolerance in racially mixed children with cystic fibrosis

Pediatr Diabetes. 2010 Feb 8.

Low prevalence of glucose intolerance in racially mixed children with cystic fibrosis.

Alves C, Lima DS, Cardeal M, Santana A.

Federal University of Bahia, Salvador-Bahia, Brazil.

Alves C, Lima DS, Cardeal M, Santana A.

Objective: To evaluate glucose tolerance in racially mixed Brazilian youth with cystic fibrosis (CF).

Methods: Cross-sectional study conducted between August and September 2007, at a reference service for CF, evaluating: glycated hemoglobin (HbA1c), blood glucose, and insulin levels, before and 2 h after a glucose overload.

Results: There were 46 patients aged between 6 yr and 16 yr and 2 months (median: 9 yr and 10 months) of whom 64% were boys. Of these, 26% were Whites; 54.4% Mulattoes; and 19.6% Blacks. HbA1c was normal in all patients. Only one participant (12-yr old) had glucose intolerance. Insulin levels ranged from 1 to 23 microIU/mL (median: 4.5 microIU/mL) at baseline and from 3.2 to 192.1 microIU/mL (median: 11 microIU/mL) after a glucose overload. Insulin resistance evaluated by the HOMA index, stratified by sex and age, was present in three patients. The DeltaF508 mutation was present in only 4.3% of the sample, all of them being heterozygous.

Conclusions: The low prevalence of carbohydrate intolerance in this population is probably a result of their young age. Another possibility is the low frequency of the DeltaF508 mutation. Although not conclusive, these data suggest that in addition to age, the genotype:phenotype ratio may influence the development of glucose intolerance in patients with CF.
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American Diabetes Association Revises Diabetes Guidelines to include CF

For its 2010 Guidelines, the American Diabetes Assocation has decided to include CFRD! Nice.

December 29, 2009 — The American Diabetes Association (ADA) revised clinical practice recommendations for diabetes diagnosis promote hemoglobin A1c (A1c) as a faster, easier diagnostic test that could help reduce the number of undiagnosed patients and better identify patients with prediabetes. The new recommendations are published December 29 in the January supplement of Diabetes Care.

"We believe that use of the A1c, because it doesn't require fasting, will encourage more people to get tested for type 2 diabetes and help further reduce the number of people who are undiagnosed but living with this chronic and potentially life-threatening disease," Richard M. Bergenstal, MD, ADA president-elect of medicine & science, said in a news release. "Additionally, early detection can make an enormous difference in a person's quality of life. Unlike many chronic diseases, type 2 diabetes actually can be prevented, as long as lifestyle changes are made while blood glucose levels are still in the pre-diabetes range."

The A1c test, which measures average blood glucose levels for a period of up to 3 months, was previously used only to evaluate diabetic control with time. An A1c level of approximately 5% indicates the absence of diabetes, and according to the revised evidence-based guidelines, an A1c score of 5.7% to 6.4% indicates prediabetes, and an A1c level of 6.5% or higher indicates the presence of diabetes.

For optimal diabetic control, the recommended ADA target for most people with diabetes is an A1c level no greater than 7%. It is hoped that achieving this target would help prevent serious diabetes-related complications including nephropathy, neuropathy, retinopathy, and gum disease.

Unlike fasting plasma glucose testing and the oral glucose tolerance test, A1c testing does not require overnight fasting. Compliance with screening may therefore be improved through use of the A1c test, which can be determined from a single nonfasting blood sample.

Recommendation Changes for 2010

Specific changes in the 2010 Clinical Practice Recommendations are as follows:

A section on diabetes related to cystic fibrosis has been added to "Standards of Medical Care in Diabetes." New evidence has shown that early diagnosis of cystic fibrosis-related diabetes and aggressive treatment with insulin have narrowed the gap in mortality between patients with cystic fibrosis with and without diabetes and have eliminated the sex difference in mortality rates. New recommendations for the clinical management of cystic fibrosis-related diabetes, based on a 2009 consensus conference, will be published in 2010 in a consensus report.

Revision of the section "Diagnosis of Diabetes" now includes the use of the A1c level for diabetes diagnosis, with a cutoff point of 6.5%.

The section formerly named "Diagnosis of Pre-diabetes" is now named "Categories of Increased Risk for Diabetes." Categories suggesting an increased risk for future diabetes now include an A1c range of 5.7% to 6.4%, as well as impaired fasting glucose and impaired glucose tolerance levels.

Revisions to the section "Detection and Diagnosis of GDM [Gestational Diabetes Mellitus]" now include a discussion of possible future changes in this diagnosis, according to international consensus. Screening recommendations for gestational diabetes are to use risk factor analysis and an oral glucose tolerance test, if appropriate. Women diagnosed with gestational diabetes should be screened for diabetes 6 to 12 weeks postpartum and should have subsequent screening for the development of diabetes or prediabetes.

Extensive revisions to the section "Diabetes Self-Management Education" are based on new evidence. Goals of diabetes self-management education are to improve adherence to standard of care, to educate patients regarding appropriate glycemic targets, and to increase the percentage of patients achieving target A1c levels.

Extensive revisions to the section "Antiplatelet Agents" now reflect evidence from recent trials suggesting that in moderate- or low-risk patients, aspirin is of questionable benefit for primary prevention of cardiovascular disease. The revised recommendation is to consider aspirin treatment as a primary prevention strategy in patients with diabetes who are at increased cardiovascular risk, defined as a 10-year risk greater than 10%. Patients at increased cardiovascular risk include men older than 50 years or women older than 60 years with at least 1 additional major risk factor.

Fundus photography may be used as a screening strategy for retinopathy, as described in the section "Retinopathy Screening and Treatment." However, although high-quality fundus photographs detect most clinically significant diabetic retinopathy, they should not act as a substitute for an initial and dilated comprehensive eye examination. Retinal examinations should be carried out annually or at least every 2 to 3 years among low-risk patients with normal eye examination results in the past.

Extensive revisions to the section "Diabetes Care in the Hospital" now question the benefit of very tight glycemic control goals in critically ill patients, based on new evidence.
Extensive revisions to the section "Strategies for Improving Diabetes Care" are based on newer evidence. Successful strategies to improve diabetes care, which have resulted in improved process measures such as measurement of A1c levels, lipid levels, and blood pressure, include the following:

Delivery of diabetes self-management education.

Adoption of practice guidelines developed with participation of healthcare professionals and having them readily accessible at the point of service.

Use of checklists mirroring guidelines, which help improve adherence to standards of care.
Systems changes, including providing automated reminders to healthcare professionals and patients and audit and feedback of process and outcome data to providers.

Quality improvement programs, in which continuous quality improvement or other cycles of analysis and intervention are combined with provider performance data.

Practice changes, which may include access to point-of-care A1c testing, scheduling planned diabetes visits, and clustering dedicated diabetes visits into specific times.

Tracking systems with either an electronic medical record or patient registry to improve adherence to standards of care.

Availability of case or (preferably) care management services using nurses, pharmacists, and other nonphysician healthcare professionals following detailed algorithms under physician supervision.

"The most successful practices have an institutional priority for quality of care, involve all of the staff in their initiatives, redesign their delivery system, activate and educate their patients, and use electronic health record tools," the guidelines authors conclude. "It is clear that optimal diabetes management requires an organized, systematic approach and involvement of a coordinated team of dedicated health care professionals working in an environment where quality care is a priority."

Diabetes Care. December 29, 2009; January 2010 Supplement.

Diabetes Care. 2009 Nov 16. [Epub ahead of print]

Diabetes as a Determinant of Mortality in Cystic Fibrosis.

Chamnan P, Shine BS, Haworth CS, Bilton D, Adler AI.

1. MRC Epidemiology Unit, Institute of Metabolic Science, Cambridge.

Background: Diabetes is increasingly common in cystic fibrosis (CF), but little exists describing its influence on mortality. Using national UK data, this study documents diabetes-specific mortality rates, estimates the impact of diabetes on survival, and estimates population attributable fractions.

Methods: This retrospective cohort study identified 8,029 individuals aged 0-65 years from the UK CF Registry (1996-2005). 5,892 patients were included in analyses of mortality rates and 4,234 in analyses of risk factors. We calculated age-adjusted mortality rates using Poisson regression, standardized mortality ratios using the population of England and Wales, and relative risks using proportional hazards modeling.

Findings: During 17,672 person-years of follow-up, 393 subjects died. The age-adjusted mortality rate was 1.8/100 person-years (95% CI 1.6 to 2.0).

The age-adjusted mortality rates per 100 person-years were 2.0 (CI 1.8 to 2.4) in women and 1.6 (95% CI 1.4 to 1.9) in males, and 4.2 (95% CI 3.4-5.1) in individuals with diabetes vs 1.5 (95% CI 1.3 to 1.7) in those without diabetes.

Independent risk factors for death included diabetes (hazard ratio, 95% confidence interval, 1.31 (1.03 to 1.67), female sex (1.71, 1.36 to 2.14) plus poorer pulmonary function, lower body mass index, B. cepacia infection, absence of S. aureus infection, allergic bronchopulmonary aspergillosis, liver disease, prior organ transplantation, and corticosteroid use.

Interpretation: Individuals with CF die earlier with diabetes, which, if delayed or better treated, might reasonably extend survival, and merits testing.

PMID: 19918014 [PubMed - as supplied by publisher]

Nutrition proactivity in CF

When was the last time you got your Oral Glucose Tolerance Test and your DEXA (bone density) scan?!

Semin Respir Crit Care Med. 2009 Oct;30(5):579-86. Epub 2009 Sep 16.

Nutrition in cystic fibrosis.

Matel JL, Milla CE.

The Stanford Cystic Fibrosis Center, Center for Excellence in Pulmonary Biology, Department of Pediatrics, Stanford University School of Medicine, Palo Alto, California 94304, USA.

Cystic fibrosis (CF) is mostly recognized for its pulmonary morbidity, but the earliest manifestations of the disease are related to its gastrointestinal and nutritional derangements. Destruction of acinar pancreatic tissue, pancreatic ductular obstruction, and lack of enzymatic activity lead to malabsorption (particularly of fats), diarrhea, and failure to thrive. A minority of CF patients carrying milder CF transmembrane conductance regulator (CFTR) mutations have preserved pancreatic secretory activity and are free from significant malabsorption early in life. However, these patients are at risk for losing pancreatic function over time. Nutritional status plays an important role in the progression of the pulmonary disease in CF. Further, CF patients with better nutritional status have a survival advantage. Several factors contribute to impaired nutritional status in CF (e.g., pancreatic insufficiency, chronic malabsorption, recurrent sinopulmonary infections, chronic inflammation, increased energy expenditure, suboptimal intake). Progressive lung disease further increases calorie requirements by increasing the work of breathing. Treatment programs that place an emphasis on higher caloric intake and more aggressive nutritional management in CF patients report better outcomes. Basic tenets of nutritional repletion in CF include the use of pancreatic enzyme replacement therapy and following a high calorie, high protein, unrestricted diet. At the Stanford Cystic Fibrosis Center, nutritional status is assessed on an ongoing basis through anthropometric parameters and annual assessment of body composition, bone density, glucose tolerance, and various biochemical and micronutrient levels. Based on the anthropometric data obtained on routine clinical encounters, patients are categorized as to their nutritional risk. This proactive approach for the early identification of nutritional risk has become a major theme within the network of US CF centers. Aggressive nutritional support with adequate pancreatic replacement management should lead to both normal growth and lung function preservation. In addition, nutritional status has to be monitored closely during routine encounters to allow for early intervention once derangements are noted. This will include increasing calories in the early stages of lung disease and being vigilant of gastrointestinal symptomatology and complications. Copyright Thieme Medical Publishers.

PMID: 19760545 [PubMed - in process]

Diabetes and bone disease in CF

Semin Respir Crit Care Med. 2009 Oct;30(5):514-30. Epub 2009 Sep 16.

Diabetes mellitus and bone disease in cystic fibrosis.

Curran DR, McArdle JR, Talwalkar JS.

Section of Pulmonary and Critical Care Medicine, Yale University School of Medicine, New Haven, Connecticut 06520-8057, USA.

Patients with cystic fibrosis are frequently affected with pancreatic insufficiency and are predisposed to the development of diabetes mellitus (DM) and bone demineralization. Cystic fibrosis-related diabetes mellitus is a clinical entity distinct from type 1 and type 2 diabetes, with important implications for the nutritional and pulmonary health of cystic fibrosis patients. This form of diabetes owes largely to insulin deficiency, but alterations in insulin sensitivity and hepatic glucose production have also been described. Therapy for cystic fibrosis-related diabetes differs substantially from type 2 DM, with careful attention to prandial glycemic excursions crucial to controlling its metabolic effects. Bone disease, including osteopenia and osteoporosis, also occurs with increased frequency in cystic fibrosis, owing to defects in intestinal absorption, chronic inflammation, lung disease, low body weight, and gonadal dysfunction. The pathogenesis, implications, diagnosis, and therapy of cystic fibrosis-related bone demineralization are discussed, with attention to recommended approaches to prevention of and treatment of established bone disease. Copyright Thieme Medical Publishers.

CFRD incidence, mortality rates narrowed

Cystic fibrosis-related diabetes is present in 2% of children, 19% of adolescents and 45% to 50% of adults aged older than 30 years, according to a review of data from 1992 to 2008.

The review revealed that previously noted differences in cystic fibrosis-related diabetes between sexes and gaps in mortality have disappeared and considerably narrowed, with the exception of a higher prevalence in women aged 30 to 39 years.

“Diabetes is exceptionally common in cystic fibrosis, especially as cystic fibrosis patients get older,” Antoinette Moran, MD,told Endocrine Today.

“In the past, the added diagnosis of diabetes has meant a patient (especially a woman) with cystic fibrosis is at increased risk for early death — this is no longer the case,” she said. “We believe the difference is that we are now screening effectively so that we diagnose early and we are treating it aggressively.”

Moran and colleagues at the University of Minnesota examined current trends in the incidence, prevalence and mortality related to cystic fibrosis-related diabetes using a comprehensive clinical database. The review included 872 patients with cystic fibrosis followed at the University of Minnesota during 1992 to 1997, 1998 to 2002 and 2003 to 2008.

Current trends

During 15 years, cystic fibrosis-related diabetes mortality rates decreased by more than 50% in women, from 6.9 deaths per 100 patient-years in 1992 to 1997 to 3.2 deaths per 100 patient-years in 2003 to 2008. Rates also decreased in men — 6.5 deaths per 100 patient-years in 1992 to 1997 to 3.8 deaths per 100 patient-years in 2003 to 2008.

The overall incidence of cystic fibrosis-related diabetes was 2.7 cases per 100 patient-years, with the exception of women aged 30 to 39 years in whom the incidence more than doubled.

Previously, diabetes was diagnosed as a perimorbid event in nearly 20% of patients with cystic fibrosis. During 2003 to 2008, only two of 61 patients diagnosed with diabetes died.

Cystic fibrosis-related diabetes without fasting hyperglycemia predominated in younger patients; however, the presence of fasting hyperglycemia rose with age.

Still, lung function is worse in patients with cystic fibrosis-related diabetes compared with patients without diabetes. Nutritional and pulmonary statuses were similar between patients with and without fasting hyperglycemia.

The data are “encouraging” because “diabetes is an expected condition as individuals with cystic fibrosis grow older,” Moran said during the interview.

The researchers attributed several reasons to the improved incidence, prevalence and mortality rates related to cystic fibrosis-related diabetes, including more aggressive treatment and early diagnosis.

Better antibiotics, digestive enzymes and respiratory therapies may have also contributed to the changes. “However, these therapies affect all people with cystic fibrosis and it is those with diabetes who have shown the greatest improvement,” Moran said.

Moran A. Diabetes Care. 2009;32:1626-1631.

Insulin Therapy to Improve BMI in CFRD

Diabetes Care. 2009 Jul 10. [Epub ahead of print]

Insulin Therapy to Improve BMI in Cystic Fibrosis Related Diabetes Without Fasting Hyperglycemia: Results of the CFRDT Trial.

Moran A, Pekow P, Grover P, Zorn M, Slovis B, Pilewski J, Tullis E, Liou TG, Allen H; the CFRDT Study Group.

From the University of Minnesota, Minneapolis (AM, TG); University of Massachusetts, Amherst (PP, MZ); Vanderbilt University, Nashville, Tennessee (BS); University of Pittsburgh, Philadelphia (JP); St. Michael's Hospital, Toronto, Canada (ET); University of Utah, Salt Lake City (TL); and Baystate Medical Center, Springfield, Massachusetts (HA).

Objective: Cystic fibrosis related diabetes (CFRD) without fasting hyperglycemia (FH-) is not associated with microvascular or macrovascular complications, leading to controversy about the need for treatment. The CFRD Therapy Trial (CFRDT) sought to determine whether diabetes therapy improves body mass index (BMI) in these patients. Research Design and

Methods: A 3-arm multi-center randomized trial compared 1 year of therapy with pre-meal insulin aspart, repaglinide, or oral placebo in CF subjects with abnormal glucose tolerance.

Results: One hundred adult patients were enrolled. Eighty-one completed the study including 61 with CFRD FH- and 20 with severely impaired glucose tolerance (IGT). During the year before therapy, BMI declined in all groups. Amongst CFRD FH-, insulin-treated patients lost 0.30+/-0.21 BMI units the year before therapy; after one year of insulin therapy, this pattern reversed and they gained 0.39+/-21 BMI units (p=0.02). No significant change in the rate of BMI decline was seen in placebo-treated patients (p=0.45).

Repaglinide-treated patients had an initial significant BMI gain (0.53+/-0.19 BMI units, p=0.01) but this effect was not sustained. After 6 months of therapy they lost weight so that by 12 months there was no difference in the rate of BMI change during the study year compared to the year before (p=0.33). Amongst IGT patients, neither insulin nor repaglinide affected the rate of BMI decline. No significant differences were seen in the rate of lung function decline or the number of hospitalizations in any group.

Conclusions: Insulin therapy safely reversed chronic weight loss in patients with CFRD FH-.

PMID: 19592632 [PubMed - as supplied by publisher]

Modifier genes influence CFRD (full text!)

Diabetologia. 2009 Jul 8. [Epub ahead of print]

A susceptibility gene for type 2 diabetes confers substantial risk for diabetes complicating cystic fibrosis.

Blackman SM, Hsu S, Ritter SE, Naughton KM, Wright FA, Drumm ML, Knowles MR, Cutting GR.

Division of Pediatric Endocrinology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.

AIMS/HYPOTHESIS: Insulin-requiring diabetes affects 25-50% of young adults with cystic fibrosis (CF). Although the cause of diabetes in CF is unknown, recent heritability studies in CF twins and siblings indicate that genetic modifiers play a substantial role. We sought to assess whether genes conferring risk for diabetes in the general population may play a risk modifying role in CF.

METHODS: We tested whether a family history of type 2 diabetes affected diabetes risk in CF patients in 539 families in the CF Twin and Sibling family-based study. A type 2 diabetes susceptibility gene (transcription factor 7-like 2, or TCF7L2) was evaluated for association with diabetes in CF using 998 patients from the family-based study and 802 unrelated CF patients in an independent case-control study.

RESULTS: Family history of type 2 diabetes increased the risk of diabetes in CF (OR 3.1; p = 0.0009). A variant in TCF7L2 associated with type 2 diabetes (the T allele at rs7903146) was associated with diabetes in CF in the family study (p = 0.004) and in the case-control study (p = 0.02; combined p = 0.0002). In the family-based study, variation in TCF7L2 increased the risk of diabetes about three-fold (HR 1.75 per allele, 95% CI 1.3-2.4; p = 0.0006), and decreased the mean age at diabetes diagnosis by 7 years. In CF patients not treated with systemic glucocorticoids, the effect of TCF7L2 was even greater (HR 2.9 per allele, 95% CI 1.7-4.9, p = 0.00011).

CONCLUSIONS/INTERPRETATION: A genetic variant conferring risk for type 2 diabetes in the general population is a modifier of risk for diabetes in CF.

PMID: 19585101 [PubMed - as supplied by publisher]

Full Text:


http://www.springerlink.com/content/m12u8536p6r922k9/fulltext.pdf

Sex disparities in effects of cystic fibrosis-related diabetes on clinical outcomes: A matched study

Sex disparities in effects of cystic fibrosis-related diabetes on clinical outcomes: A matched study

RJ Miller, HD Tildesley, PG Wilcox, H Zhang, SH Kreisman

BACKGROUND: Cystic fibrosis-related diabetes (CFRD) is an increasingly prevalent comorbidity factor for patients with cystic fibrosis (CF). CFRD has been associated with an accelerated decline in clinical parameters and an increased mortality rate.

OBJECTIVES: To investigate the clinical impact of CFRD on pulmonary function and clinical status using a matched study design to further explore potential causality.

METHODS: Charts from the adult CF clinic at St Paul's Hospital (Vancouver, British Columbia) were retrospectively reviewed. Forty CFRD patients with and without fasting hyperglycemia were matched to CF patients with nondiabetic glucose tolerance based on sex, age and forced expiratory volume in 1 s (FEV₁).

RESULTS: Sixteen of 40 CFRD patients (40%) died compared with nine of 40 patient controls (23%) (P=0.13). CFRD patients were more likely to experience declines in FEV₁ (P<0.01), especially women (P<0.01). Patients with CFRD were not more likely to be hospitalized (P=0.39). Body mass index did not differ between groups.

CONCLUSIONS: Patients with CFRD had higher rates of FEV₁ deterioration than nondiabetic patients with CF, and showed a trend toward increased mortality. The present study suggests that CFRD has a significant clinical impact and should be carefully considered when evaluating the status of CF patients.


http://www.pulsus.com/journals/abstract.jsp?HCtype=Physician&sCurrPg=abstract&jnlKy=4&atlKy=8328&isuKy=811&isArt=t&fromfold=Current&

Genetic Modifiers Play a Substantial Role in Diabetes Complicating Cystic Fibrosis

http://snipurl.com/fcwmz