Abstract
Disturbance of glucose metabolism and diabetes is an increasing complication in adult patients with cystic fibrosis (CF). The aim of the present study was to evaluate the impact of insulin and glucagon-like peptide-1 (GLP-1) secretion on early disturbance of glucose metabolism and clinical status in an unselected cohort of CF patients. 34 adult CF patients and 10 matched healthy subjects underwent an oral glucose tolerance test. Blood samples were taken to measure indices for insulin secretion and insulin sensitivity. Metabolic parameters were correlated with anthropometric and clinical data. In CF patients, there was a decrease in first phase insulin secretion (FPIR) with progressive delay of insulin peak, which was correlated with worsening glucose tolerance (Stumvoll index: normal glucose tolerance: 450±291; impaired fasting glucose: 252±203; impaired glucose tolerance: 309±254; CF related diabetes: 18±41; controls: 950±388) and high early post-challenge glucose peak (p<0.01 vs. controls). However, total insulin secretory capacity was not decreased in CF patients resulting to low glucose levels in the late phase (120–180 min). We found neither a difference in basal or maximal GLP-1 levels nor in insulin resistance between study groups. Maximum glucose levels correlated with impaired FEV1 (rs=−0.5, p=0.002). Our data demonstrate that alteration of FPIR, but not insulinopenia, insulin resistance, or disturbed GLP-1 secretion is present in the prediabetic state in CF patients. Correlation between high glucose levels and worse clinical status suggest that diabetes treatment should be initiated more early in the state of glucose intolerance.
Key words
cystic fibrosis - glucose intolerance - insulin secretory defect - diabetes
References
-
1
Adler AI, Shine BS, Chamnan P, Haworth CS, Bilton D.
Genetic determinants and epidemiology of cystic fibrosis-related diabetes: results from a British cohort of children and adults.
Diabetes Care.
2008;
31
1789-1794
-
2
Foundation CF
.
Cystic Fibrosis Foundation Patient Registry
2007;
-
3
Brennan AL, Geddes DM, Gyi KM, Baker EH.
Clinical importance of cystic fibrosis-related diabetes.
J Cyst Fibros.
2004;
3
209-222
-
4
Moran A, Dunitz J, Nathan B, Saeed A, Holme B, Thomas W.
Cystic fibrosis-related diabetes: current trends in prevalence, incidence, and mortality.
Diabetes Care.
2009;
32
1626-1631
-
5
Bismuth E, Laborde K, Taupin P, Velho G, Ribault V, Jennane F, Grasset E, Sermet I, de Blic J, Lenoir G, Robert JJ.
Glucose tolerance and insulin secretion, morbidity, and death in patients with cystic fibrosis.
J Pediatr.
2008;
152
540-545
-
6
Lanng S, Thorsteinsson B, Nerup J, Koch C.
Influence of the development of diabetes mellitus on clinical status in patients with cystic fibrosis.
Eur J Pediatr.
1992;
151
684-687
-
7
Mohan K, Israel KL, Miller H, Grainger R, Ledson MJ, Walshaw MJ.
Long-term effect of insulin treatment in cystic fibrosis-related diabetes.
Respiration.
2008;
76
181-186
-
8
Wilmshurst EG, Soeldner JS, Holsclaw DS, Kaufmann RL, Shwachman H, Aoki TT, Gleason RE.
Endogenous and exogenous insulin responses in patients with cystic fibrosis.
Pediatrics.
1975;
55
75-82
-
9
Preumont V, Hermans MP, Lebecque P, Buysschaert M.
Glucose homeostasis and genotype-phenotype interplay in cystic fibrosis patients with CFTR gene deltaF508 mutation.
Diabetes Care.
2007;
30
1187-1192
-
10
Austin A, Kalhan SC, Orenstein D, Nixon P, Arslanian S.
Roles of insulin resistance and beta-cell dysfunction in the pathogenesis of glucose intolerance in cystic fibrosis.
J Clin Endocrinol Metab.
1994;
79
80-85
-
11
Baggio LL, Drucker DJ.
Biology of incretins: GLP-1 and GIP.
Gastroenterology.
2007;
132
2131-2157
-
12
Nauck MA.
Unraveling the science of incretin biology.
Eur J Intern Med.
2009;
20
(S 02)
303-308
-
13
Laakso M, Zilinskaite J, Hansen T, Boesgaard TW, Vanttinen M, Stancakova A, Jansson PA, Pellme F, Holst JJ, Kuulasmaa T, Hribal ML, Sesti G, Stefan N, Fritsche A, Haring H, Pedersen O, Smith U.
Insulin sensitivity, insulin release and glucagon-like peptide-1 levels in persons with impaired fasting glucose and/or impaired glucose tolerance in the EUGENE2 study.
Diabetologia.
2008;
51
502-511
-
14
Vilsboll T, Krarup T, Sonne J, Madsbad S, Volund A, Juul AG, Holst JJ.
Incretin secretion in relation to meal size and body weight in healthy subjects and people with type 1 and type 2 diabetes mellitus.
J Clin Endocrinol Metab.
2003;
88
2706-2713
-
15
Muscelli E, Mari A, Natali A, Astiarraga BD, Camastra S, Frascerra S, Holst JJ, Ferrannini E.
Impact of incretin hormones on beta-cell function in subjects with normal or impaired glucose tolerance.
Am J Physiol Endocrinol Metab.
2006;
291
E1144-E1150
-
16
American Diabetes Association
.
Diagnosis and classification of diabetes mellitus.
Diabetes Care.
2005;
28
(S 01)
37-42
-
17
Matthews DR, Hosker JP, Rudenski AS, Naylor BA, Treacher DF, Turner RC.
Homeostasis model assessment: insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man.
Diabetologia.
1985;
28
412-419
-
18
Stumvoll M, Mitrakou A, Pimenta W, Jenssen T, Yki-Jarvinen H, Van Haeften T, Renn W, Gerich J.
Use of the oral glucose tolerance test to assess insulin release and insulin sensitivity.
Diabetes Care.
2000;
23
295-301
-
19
Hammana I, Potvin S, Tardif A, Berthiaume Y, Coderre L, Rabasa-Lhoret R.
Validation of insulin secretion indices in cystic fibrosis patients.
J Cyst Fibros.
2009;
8
378-381
-
20
Stumvoll M, Van Haeften T, Fritsche A, Gerich J.
Oral glucose tolerance test indexes for insulin sensitivity and secretion based on various availabilities of sampling times.
Diabetes Care.
2001;
24
796-797
-
21
Sterescu AE, Rhodes B, Jackson R, Dupuis A, Hanna A, Wilson DC, Tullis E, Pencharz PB.
Natural history of glucose intolerance in patients with cystic fibrosis: ten-year prospective observation program.
J Pediatr.
2010;
156
613-617
-
22
Lombardo F, De Luca F, Rosano M, Sferlazzas C, Lucanto C, Arrigo T, Messina MF, Crisafulli G, Wasniewska M, Valenzise M, Cucinotta D.
Natural history of glucose tolerance, beta-cell function and peripheral insulin sensitivity in cystic fibrosis patients with fasting euglycemia.
Eur J Endocrinol.
2003;
149
53-59
-
23
Tofé S, Moreno JC, Máiz L, Alonso M, Escobar H, Barrio R.
Insulin-secretion abnormalities and clinical deterioration related to impaired glucose tolerance in cystic fibrosis.
Eur J Endocrinol.
2005;
152
241-247
-
24
Mohan K, Miller H, Dyce P, Grainger R, Hughes R, Vora J, Ledson M, Walshaw M.
Mechanisms of glucose intolerance in cystic fibrosis.
Diabet Med.
2009;
26
582-588
-
25
O’Riordan SM, Robinson PD, Donaghue KC, Moran A.
Management of cystic fibrosis-related diabetes in children and adolescents.
Pediatr Diabetes.
2009;
10
(S 12)
43-50
-
26
Holl RW, Buck C, Babka C, Wolf A, Thon A.
HbA1c is not recommended as a screening test for diabetes in cystic fibrosis.
Diabetes Care.
2000;
23
126
-
27
Godbout A, Hammana I, Potvin S, Mainville D, Rakel A, Berthiaume Y, Chiasson JL, Coderre L, Rabasa-Lhoret R.
No relationship between mean plasma glucose and glycated haemoglobin in patients with cystic fibrosis-related diabetes.
Diabetes Metab.
2008;
34
568-573
-
28
Cucinotta D, De Luca F, Gigante A, Arrigo T, Di Benedetto A, Tedeschi A, Lombardo F, Romano G, Sferlazzas C.
No changes of insulin sensitivity in cystic fibrosis patients with different degrees of glucose tolerance: an epidemiological and longitudinal study.
Eur J Endocrinol.
1994;
130
253-258
-
29
Lanng S, Thorsteinsson B, Røder ME, Orskov C, Holst JJ, Nerup J, Koch C.
Pancreas and gut hormone responses to oral glucose and intravenous glucagon in cystic fibrosis patients with normal, impaired, and diabetic glucose tolerance.
Acta Endocrinol.
1993;
128
207-214
-
30
Ntimbane T, Comte B, Mailhot G, Berthiaume Y, Poitout V, Prentki M, Rabasa-Lhoret R, Levy E.
Cystic fibrosis-related diabetes: from CFTR dysfunction to oxidative Stress.
Clin Biochem Rev.
2009;
30
153-177
-
31
Couce M, O’Brien TD, Moran A, Roche PC, Butler PC.
Diabetes mellitus in cystic fibrosis is characterized by islet amyloidosis.
J Clin Endocrinol Metab.
1996;
81
1267-1272
-
32
Stalvey MS, Muller C, Schatz DA, Wasserfall CH, Campbell-Thompson ML, Theriaque DW, Flotte TR, Atkinson MA.
Cystic fibrosis transmembrane conductance regulator deficiency exacerbates islet cell dysfunction after beta-cell injury.
Diabetes.
2006;
55
1939-1945
-
33
Knop FK, Vilsbøll T, Larsen S, Madsbad S, Holst JJ, Krarup T.
Glucagon suppression during OGTT worsens while suppression during IVGTT sustains alongside development of glucose intolerance in patients with chronic pancreatitis.
Regul Pept.
2010;
164
144-150
-
34
Milla CE, Warwick WJ, Moran A.
Trends in pulmonary function in patients with cystic fibrosis correlate with the degree of glucose intolerance at baseline.
Am J Respir Crit Care Med.
2000;
162
891-895
-
35
Mohan K, Israel KL, Miller H, Grainger R, Ledson MJ, Walshaw MJ.
Long-term effect of insulin treatment in cystic fibrosis-related diabetes.
Respiration.
2008;
76
181-186
-
36
Mozzillo E, Franzese A, Valerio G, Sepe A, De Simone I, Mazzarella G, Ferri P, Raia V.
One-year glargine treatment can improve the course of lung disease in children and adolescents with cystic fibrosis and early glucose derangements.
Pediatr Diabetes.
2009;
10
162-167
-
37
Ning F, Tuomilehto J, Pyörälä K, Onat A, Söderberg S, Qiao Q.
for the DECODE Study Group
.
Cardiovascular Disease Mortality in Europeans in Relation to Fasting and 2 h Plasma Glucose levels Within a Normoglycemic Range.
Diabetes Care.
2010;
33
2211-2216
-
38
Bibra H, Siegmund T, Ceriello A, Volozhyna M, Schumm-Draeger PM.
Optimized postprandial glucose control is associated with improved cardiac/vascular function – comparison of three insulin regimens in well-controlled type 2 diabetes.
Horm Metab Res.
2009;
41
109-115
-
39
Roman G, Hancu N.
Early insulin treatment to prevent cardiovascular disease in prediabetes and overt diabetes.
Horm Metab Res.
2009;
41
116-122
-
40
Yeh HC, Punjabi NM, Wang NY, Pankow JS, Duncan BB, Cox CE, Selvin E, Brancati FL.
Cross-sectional and prospective study of lung function in adults with type 2 diabetes: the Atherosclerosis Risk in Communities (ARIC) study.
Diabetes Care.
2008;
31
741-746
-
41
Davis WA, Knuiman M, Kendall P, Grange V, Davis TM.
Fremantle Diabetes Study
.
Glycemic exposure is associated with reduced pulmonary function in type 2 diabetes: the Fremantle Diabetes Study.
Diabetes Care.
2004;
27
752-757
-
42
Battezzati A, Battezzati PM, Costantini D, Seia M, Zazzeron L, Russo MC, Dacco V, Bertoli S, Crosignani A, Colombo C.
Spontaneous hypoglycemia in patients with cystic fibrosis.
Eur J Endocrinol.
2007;
156
369-376
-
43
Iannucci A, Mukai K, Johnson D, Burke B.
Endocrine pancreas in cystic fibrosis: an immunohistochemical study.
Hum Pathol.
1984;
15
278-284
-
44
Moran A, Diem P, Klein DJ, Vitt MD, Robertson RP.
Pancreatic endocrine function in cystic fibrosis.
J Pediatr.
1991;
118
715-723
Correspondence
J. SeisslerMD
Diabetes Center
Medical Clinic Innenstadt
Ludwig Maximilians University
Munich
Ziemssenstraße 1
80336 Munich
Germany
Telefon: +49/8951/602 200
Fax: +49/8951/604 956
eMail: jochen.seissler@med.uni-muenchen.de
