Consensus on the diagnosis and management of changes in carbohydrate metabolism in cystic fibrosis

Abnormal glucose tolerance and diabetes mellitus are a common complication of cystic fibrosis (CF). Cystic fibrosis related diabetes (CFRD) is due to decreased insulin secretion, secondary to pancreatic insufficiency. Patients with CFRD have increased morbidity and mortality and are subject to the same microvascular complications as patients with other types of diabetes. Prompt diagnosis and aggressive management of CFRD is important.A consensus conference on CFRD was held in Madrid in May 2000to define the current standards for the diagnosis and management of this disease in Spain.     

Cystic fibrosis related diabetes

Diabetes is a frequent complication seen in cystic fibrosis patients as they reach adulthood. Cystic fibrosis related diabetes (CFRD) is distinguished as a separate entity with features that include progressive loss of islet beta cell mass and insulin deficiency, as well as insulin resistance. Abnormalities in glucose tolerance may be detectable for many years prior to the development of overt diabetes. Therefore oral glucose tolerance testing is the preferred screening method for the identification of those patients at the highest risk for progression to diabetes. Progression to diabetes has been linked to poor outcomes in CF including loss of pulmonary function and increased mortality among females. Given the role that insulin deficiency plays in CFRD, insulin replacement therapy remains the only recommended intervention. In the absence of definitive supportive data, the use of oral antidiabetic agents is not considered standard therapy and needs further study. As with other forms of diabetes, CFRD patients also experience microvascular complications and should be periodically evaluated for manifestations.     

Carbohydrate tolerance in cystic fibrosis is closely linked to pancreatic exocrine function

We evaluated carbohydrate tolerance in nine thin cystic fibrosis (CF) patients and in six controls, measuring responsiveness to the following insulinotropic secretagogues: oral glucose, IV glucose, and IV tolbutamide. Glucose responses segregated patients into two groups: Group I with normal carbohydrate tolerance associated with normal to slightly increased insulin responses, and Group II with impaired carbohydrate tolerance associated with insulinopenia. This latter group included one patient with frank diabetes. The CF patients demonstrated a significant positive correlation between insulin secretion, in response to each secretagogue, and pancreatic exocrine function as measured by serum pancreatic amylase isoenzyme concentration. Pancreatic alpha-cell function, as reflected by basal plasma glucagon concentrations, also correlated well with exocrine function in the CF patients, excluding the diabetic individual. The enteroinsular axis of the CF group was intact as reflected by normal plasma gastric inhibitory polypeptide concentrations in Group I and by elevated levels, basally and in response to oral glucose, in the insulinopenic Group II patients. Furthermore, those patients with impaired tolerance demonstrated a greater magnitude of insulinopenia compared to controls following IV glucose and possibly IV tolbutamide, than following oral glucose. Thus, these data suggest that loss of carbohydrate tolerance in patients with CF, like that seen with classical chronic pancreatitis, 1) parallels the loss of exocrine function, 2) is associated with appropriate enteroinsular signaling, and 3) can be detected earlier or more easily following testing with direct IV secretagogues than following oral glucose stimulation.     

Hyperglycaemia and insulinopenia in a neonate with cystic fibrosis

Abnormal glucose tolerance is a frequent late complication of cystic fibrosis (CF), but the prevalence of CF-related diabetes mellitus (CFRD) in children less than 10 y old is less than 2%. The youngest child with CFRD reported to date was 6 mo of age. Insulinopenia is the primary cause of abnormal glucose tolerance/CFRD, but it is unknown whether it may begin in the neonatal period. We describe a case of a neonate with CF who presented with hyperglycaemia in the diabetic range and marked insulinopenia. Insulinopenia and impaired glucose tolerance were permanent findings at 6 and 15 mo of age. CONCLUSION: This case suggests that abnormal glucose tolerance/diabetes may occur much earlier in the course of CF, even during neonatal age. Careful follow-up and further studies in CF infants could reveal that the real incidence of glucose intolerance and diabetes in this age group has been underestimated.     

Research of factors for glucose intolerance in mucoviscidosis]

Glucose tolerance has been assessed in cystic fibrosis (CF) children using HbA1C and plasma glucose and insulin determinations during an oral glucose tolerance test (OGTT), along with the determination of HLA-DR and islet-cell (ICA) and anti-insulin (IAA) antibodies. Of 49 patients (25 males, 24 females), aged 2 to 21 years (mean = 10.9 years), 29 had normal glucose tolerance (WHO criteria) during OGTT, 14 had impaired glucose tolerance (IGT) and 6 had an isolated hyperglycemia at 120 min. Fasting plasma glucose and HbA1C were significantly higher in IGT than in normoglycemic patients. However, these two parameters showed poor individual predictive value of disturbance in glucose tolerance. Of 14 patients with abnormal OGTT, 7 were aged below 10 years, with 2 as young as 5 years; 8 patients were females. HLA antigens characteristic of type I diabetes tended to be found less frequently in CF patients than in the general population: 9% were DR3, 7% were DR4 and none was DR3/DR4. There were no HLA differences according to glucose tolerance. ICA and IAA were respectively detected in only one patient. Stimulated plasma insulin was low but did not correlate with glucose tolerance. In conclusion, impaired glucose tolerance is common in cystic fibrosis and can be found early in life. Although insulin secretion is decreased in this population, it does not seem to be the only factor responsible for impaired glucose intolerance. The absence of the genetical and immunological characteristics of type I diabetes confirms that glucose intolerance in cystic fibrosis is due to other pathogenetic mechanisms.     

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 patient 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/m ² per minute). Results from the 120 mU/m ² 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. (J Pediatr 1997;130:948-56)     

Insulin sensitivity and beta-cell secretion in thalassaemia major with secondary haemochromatosis: assessment by oral glucose tolerance test

Diabetes mellitus in patients with thalassaemia major is caused by secondary haemochromatosis due to transfusional iron overload. The pathogenetic mechanisms leading from siderosis to diabetes are still poorly understood. This study aimed at assessing the influence of insulin resistance and insulin deficiency on that process. Glucose, insulin and C-peptide levels during oral glucose tolerance tests (OGTT) from 36 thalassaemic patients with normal ( n=23), impaired ( n=6), or diabetic glucose tolerance ( n=7) and 32 control subjects were examined. Insulin secretion and insulin sensitivity were assessed by established calculated indices. Fasting, 2h and integrated glucose concentration were significantly increased in thalassaemic patients with normal glucose tolerance compared to controls (5.01/4.59 mmol/l, 6.33/5.17 mmol/l, and 844.2/739.3 mmol/l per min, respectively; all P<0.03). Patients with impaired glucose tolerance presented hyperinsulinaemia and delayed peak insulin during OGTT. The C-peptide/insulin ratio was decreased in patients with abnormal glucose tolerance compared to controls (5.85/7.33 x 10(3)pmol/l per min, P<0.03). It was negatively correlated with age in patients ( r=-0.45, P<0.01), but positively in controls ( r=0.43, P<0.03). Insulin sensitivity was significantly reduced in patients with impaired glucose tolerance or diabetes compared to controls. In addition, a significant decrease in patients with normal glucose tolerance was shown by two insulin sensitivity indices (all P<0.05). In thalassaemia patients, insulin sensitivity was negatively correlated with age. Insulin secretion capacity according to the homeostasis assessment model was significantly reduced in patient groups compared to controls (Kruskal-Wallis-test, P<0.004). CONCLUSION: Insulin resistance is of central importance for the development of diabetes mellitus in patients with secondary haemochromatosis. An additional early defect in beta-cell secretion cannot be excluded.     

Glucose homeostasis in mucoviscidosis

In patients with cystic fibrosis (CF) of the pancreas an endocrine imbalance especially of insulin secretion due to progressive structural abnormalities of the pancreas must be expected. 30-75 percent of CF-patient exhibit impaired oral glucose tolerance tests (oGTT). Deterioration of the glucose homeostasis leads to a secondary diabetes mellitus that mimics a type II diabetes in the early stage, in the later course of disease it resembles a type I diabetes with absolute insulinopenia. In this study glucose homeostasis was investigated after an oral glucose load with 1.75 g glucose/kg bodyweight. Glucose, C-peptide and insulin were measured during 180 minutes. 32 nondiabetic CF-patients were studied. 16 patients revealed an impaired oral glucose tolerance according to the criteria of the National Diabetes Data Group. 6 patients showed a normal glucose tolerance and 10 patients with normal fasting and 120 minute glucose concentrations were hyperglycemic at midtest determinations. Impaired oGTTs were observed in malnourished CF-patients in a higher rate than in normal weight patients. A delayed and exceeded C-peptide and insulin response to the oral glucose load was determined with deteriorating glucose tolerance. Glucose values did not drop to fasting values at the 180 minute determination in cases of impaired oral glucose tolerance.     

Reduced pancreatic insulin release and reduced peripheral insulin sensitivity contribute to hyperglycaemia in cystic fibrosis

Traditional opinion holds that patients with cystic fibrosis (CF) develop impaired glucose tolerance or diabetes due to insulinopenia caused by fibrosis of the pancreas. However, studies on the dynamics of insulin secretion and peripheral insulin action have yielded confliciting results. We studied 18 patients with CF (9 , 9 , age 15–29 years) and 17 healthy control subjects (8 , 9 , 20–32 years). Oral glucose tolerance tests and combined i.v.-glucose-tolbutamide-tests were performed on separate days in fasting subjects. Bergman's Minimal Model was used to quantitate both peripheral insulin sensitivity (S_I) and insulin-independent glucose disposal (glucose effectiveness; S_G). Based on National Diabetes Data Group criteria, 4 patients were classified as diabetic 922%; CF-DM), 3 patients (17%) had impaired glucose tolerance (CF-IGT) while glucose metabolism was normal in 11 patients (61%; CF-NGT). Irrespective of the degree of glucose tolerance, the insulin response to oral glucose was not reduced but delayed, up to 60 min in the CF-IGT/DM group. First-phase insulin release (0–10 min) after i.v.-glucose was significantly lower in CF patients (29% of healthy controls;P<0.0001), with no difference between the CF-NGT and CF-IGT/DM groups. Insulin release following tolbutamide injection was only marginally reduced in CF patients (64% of controls). In contrast, S_I was significantly reduced in the subgroup of CF patients with abnormal glucose metabolism (CF-IGT/DM: 0.97±0.16·10^–4 l/min/pmol; control group: 1.95±0.25;P<0.05).Conclusion The early insulin release is reduced in response to i.v.-glucose, while in the oral glucose tolerance test, insulin secretion is quantitatively preserved, but delayed. Reduced peripheral insulin sensitivity is a major factor for impaired glucose tolerance and diabetes mellitus in CF patients.     

Early detection of impaired glucose tolerance in patients with cystic fibrosis and predisposition factors

INTRODUCTION: The number of patients with glucose tolerance alterations associated with cystic fibrosis (CF) has increased, probably due to the greater survival rate among sufferers of this disease. We studied impaired glucose tolerance (IGT) in patients with CF and investigated whether its appearance has any relationship with age, sex, genetic mutation and/or the degree of clinical involvement. We assessed the parameters that might allow early detection. PATIENTS AND METHODS: In 28 patients with CF (14 M, 14 F; aged 22 months to 18 years), sex, genetic mutation, nutritional status and the degree of pancreatic and pulmonary involvement were recorded. The metabolic study included glycosylated hemoglobin (HbA1c) determination, oral glucose tolerance test (OGTT) and intravenous glucose tolerance tests (IVGTT). RESULTS: In the patients with CF, 35.71% showed impaired glucose tolerance (IGT) and 3.57% had diabetes mellitus. The patients with IGT and CF were 3.2 years older than those with normal glucose tolerance (NGT; p<0.05), but no significant differences were found regarding sex, anthropometric measurements, percentage of pulmonary gammagraphic involvement, Shwachman-Kulczycki test or HbA1c. In the OGTT, the patients homozygous for the deltaF508 mutation had higher blood glucose values than the heterozygous group (p=0.03), but these values were not higher than those in patients with other mutations. During the OGTT, blood insulin values at 30' were reduced in patients with IGT compared to patients with NGT (p<0.02) and the insulin peak occurred at 100.9+/-24.3 min compared to 65.3+/-21.8, respectively (p<0.05). In the IVGTT, 82.14% of the patients had reduced insulin levels at 1 and 3 min (I1'+3'). No differences in the blood glucose levels during the OGTT were found between patients with normal I1'+3' values and patients with reduced values. CONCLUSIONS: A high percentage of patients with CF also present with IGT. This increases with age and is more common among patients homozygous for the deltaF508 mutation and is not related to clinical status. Alterations in the kinetics of insulin secretion play an important role in the appearance of IGT and CF. We suggest that the OGTT is a more sensitive method than IVGTT for identifying early alterations in CF-related diabetes mellitus.     

Factors affecting diabetes mellitus onset in cystic fibrosis: evidence from a 10-year follow-up study

This study reports the results of genotype characterization and of a 10-y prospective evaluation of clinical status, glucose tolerance and insulin secretion in 28 originally normoglycaemic patients with cystic fibrosis (CF). The aim of the study was to assess whether any genetic, clinical or metabolic parameters could identify in advance those patients at risk of developing diabetes mellitus over time. During the follow-up 42.8% of patients became diabetic. Neither gender, age nor clinical parameters were significantly different at entry in the patients who eventually developed diabetes compared with those who did not. Insulin secretion during oral glucose tolerance tests (OGTT) deteriorated over time in both groups, whereas a progressive deterioration of glucose tolerance was only evident in the patients who developed diabetes and increased baseline glucose areas were the only predictive parameter of diabetes onset. Genotype analysis revealed significant differences between patients with and without diabetes: ΔF508 homozygosis was more frequent in the first group and N1303K mutation in the second group. In conclusion, in CF: (i) increased glucose areas during OGTT and deterioration of glucose tolerance over time can predict the evolution towards diabetes; and (ii) ΔF508 homozygosis may predispose to the risk of diabetes, whilst N1303K mutation seems to play a protective role.     

Impaired glucose homeostasis in young adult thalassemic patients: a pilot study with acarbose

This study investigated the effects of the alpha-glucosidase inhibitor, acarbose, on glycemic control and insulin secretion in thalassemic patients with impaired glucose tolerance. The safety and tolerability of the drug were also evaluated. Nine patients (4 men and 5 women, aged 20-34 years) with beta-thalassemia major received a standardized nutritional test load prior to and following 3 months treatment with acarbose 100 mg t.i.d. Blood glucose, insulin and C-peptide levels were measured at 0, 60, 90 and 120 min post-loading. Plasma glucose levels after 3 months of acarbose treatment tended to be slightly lower than pre-treatment levels. Although fasting serum insulin and plasma C-peptide levels were unchanged after acarbose therapy, postprandial serum levels of both hormones were markedly reduced (by 24-47% and 19-32%, respectively, at 60-120 min post-loading). Body mass index, liver enzymes and serum lipids were unaltered following acarbose treatment. Gastrointestinal disturbances were mild and tended to decrease during the course of acarbose therapy. Acarbose is a well-tolerated agent for the management of thalassemic patients with glucose intolerance and normal or increased insulin secretion. It is possible that acarbose may prevent or delay progression from impaired glucose homeostasis to frank insulin-dependent diabetes mellitus.     

Verbesserung der Glukosetoleranz von Patienten mit Zystischer Fibrose unter pseudomonaswirksamer Chemotherpie

Background. For many patients with cystic fibrosis impaired glucose tolerance or even diabetes mellitus is becoming relevant with growing age. The influence of an anti-Pseudomonas chemotherapy on glucose homeostasis of cystic fibrosis patients was investigated. Patients and methods. In fourteen cystic fibrosis patients aged between 7 and 35 years glucose tolerance was tested by standard oral glucose tolerance test in the beginning and at the end of a routine anti-Pseudomonas chemotherapy of fourteen days. Beside the blood glucose serum insulin was determinated. Results. According to the criteria of the American Diabetes Association three of the fourteen patients had an impaired glucose tolerance and another three had diabetes mellitus when tested at the beginning of anti-Pseudomonas chemotherapy. In four of these six patients glucose tolerance was normal at the end of the chemotherapy. Of the remaining two patients one fulfilled the criteria for impaired glucose tolerance and one for diabetes mellitus. In these patients insulin secretion was lower in the second test. Peak insulin was reached earlier while there was no significant improvement of early insulin response. Conclusion. The treatment of chronic airway infection in cystic fibrosis patients with impaired glucose tolerance or diabetes mellitus results in an improvement of glucose homeostasis by a better insulin sensitivity and less by improvement of early insulin response. In developing diagnostic protocols for screening of cystic fibrosis-related diabetes mellitus the impact of the concomitant therapy on glucose homeostasis should be considered.     

Endocrine pancreas function in mucoviscidosis

Patients with cystic fibrosis of the pancreas show an incidence of diabetes mellitus tenfold higher than is found in the general pediatric population. Considering this fact glucagon and insulin responses to oral glucose and intravenous arginine were studied in 22 CF children and adolescents. Some investigated patients had suffered from the disease for ten years and more. On the one hand the results show that pancreatic alpha cell function is normal. The kinetics of endogenous glucagon release are unaltered. On the other hand the data reveal that there is only a defect in the beta cell function consisting in a delayed insulin release selective to glucose whereas responsiveness to other stimuli for example tolbutamide and arginine is undisturbed. Furthermore there is a diminution in insulin-output to oral glucose as well as to intravenous arginine. Yet in patients with normal oral glucose tolerance endogenous insulin secretion is significantly reduced. Their regular carbohydrate tolerance may be a function of the patient's ability to maintain increased receptor numbers in the face of hypoinsulinemia. Despite greater quantities of secreted hormone a degree of relative peripheral insulin insensitivity has developed in the presence of hyperglycemia. This may be a consequence of impaired affinity of the specific target cell receptors. The insulin secretion pattern is proven to be identical to that of chemical diabetes mellitus in adults. Quantitative diminution in arginine stimulated insulin-output has been found to be independent of the degree of carbohydrate intolerance.(ABSTRACT TRUNCATED AT 250 WORDS)     

Glucose Tolerance and Insulin Receptor Binding to Monocytes and Erythrocytes in Patients with Cystic Fibrosis

ABSTRACT. Cystic fibrosis (CF) is the most frequent life threatening hereditary disease in the Western World with an incidence of approximately 1:2000. Due to increasing survival rates the high frequency of abnormal glucose tolerance has become an important problem. We compared insulin concentrations during oral glucose tolerance test and insulin receptor binding to both monocytes and erythrocytes from 9 patients with CF, with results from 10 healthy controls of similar body weight. The insulin: glucose ratio was increased in the fasting state ( p < 0.05) in patients with CF compared to controls, indicating an increased insulin resistance in CF-patients. The total insulin secretion during oral glucose tolerance test as judged by the area beneath the insulin curve was similar in the two groups, but insulin secretion was significantly delayed in patients with CF. Insulin receptor binding to monocytes and the number of receptors were significantly increased ( p < 0.01 and 0.02, respectively) in patients with CF whereas the dissociation constant was similar in patients with CF and controls. No difference was observed in insulin receptor binding to erythrocytes between the two groups. No correlations were found between insulin receptor binding to monocytes or erythrocytes and glucose tolerance or insulin concentrations.     

Glucose tolerance and insulin receptor binding to monocytes and erythrocytes in patients with cystic fibrosis

Cystic fibrosis (CF) is the most frequent life threatening hereditary disease in the Western World with an incidence of approximately 1:2000. Due to increasing survival rates the high frequency of abnormal glucose tolerance has become an important problem. We compared insulin concentrations during oral glucose tolerance test and insulin receptor binding to both monocytes and erythrocytes from 9 patients with CF, with results from 10 healthy controls of similar body weight. The insulin: glucose ratio was increased in the fasting state (p less than 0.05) in patients with CF compared to controls, indicating an increased insulin resistance in CF-patients. The total insulin secretion during oral glucose tolerance test as judged by the area beneath the insulin curve was similar in the two groups, but insulin secretion was significantly delayed in patients with CF. Insulin receptor binding to monocytes and the number of receptors were significantly increased (p less than 0.01 and 0.02, respectively) in patients with CF whereas the dissociation constant was similar in patients with CF and controls. No difference was observed in insulin receptor binding to erythrocytes between the two groups. No correlations were found between insulin receptor binding to monocytes or erythrocytes and glucose tolerance or insulin concentrations.     

Prevalence of type 2 diabetes mellitus and impaired glucose tolerance in obese Argentinean children and adolescents

The aim of this study was to evaluate the prevalence of type 2 diabetes mellitus (DM2) and impaired glucose tolerance (IGT) in obese children and adolescents and to examine insulin resistance and insulin secretion. We studied 427 asymptomatic obese patients. DM2 and IGT were diagnosed by an oral glucose tolerance test. Insulin resistance and P-cell function were assessed by using homeostasis model assessment (HOMA), insulin/glucose index (I/GI), fasting insulin and insulin sensitivity index (ISI-composite). Thirty patients showed IGT (7%) and seven had DM2 (1.6%). The mean age was 10.7 +/- 3.5 years, the diabetic group being significantly older than the normal group (p < 0.01). The mean body mass index was 30 +/- 5.3 kg/m2 without significant differences between groups. beta-Cell function declined significantly in the patients with IGT and DM2, and insulin resistance increased significantly. Given the rather high prevalence of glucose metabolism impairment, children with obesity should undergo glucose tolerance testing for appropriate therapeutic intervention.     

Low-dose insulin therapy in patients with cystic fibrosis and early-stage insulinopenia prevents deterioration of lung function: a 3-year prospective study

Cystic fibrosis related diabetes (CFRD) is an insulinopenic condition. We aimed to detect insulinopenia early and to evaluate the impact of low dose insulin on nutritional status and forced expiratory volume in first second (FEV1). Out of 142 cystic fibrosis patients (CFpts) older than 10 years, 28 with abnormal oral glucose tolerance test in spite of normal fasting glycemia were found to have decreased first phase insulin release and started low dose insulin therapy (median age 15.4 years). Sex and age matched CFpts with normal glucose tolerance (NGT) were observed for comparison. Whereas nutritional status improved following 3 years of insulin administration, FEV1 stabilized in insulin-treated insulinopenic subjects (73.8 +/- 4.3% vs. 73.5 +/- 4.4%), but decreased in the parallel group with NGT who remained without insulin treatment (71.1 +/- 3.8% vs. 61.0 +/- 4.0%; p = 0.001). We conclude that low dose insulin improves nutritional status and stabilizes pulmonary functions. Regular estimation of stimulated insulin secretion in CFpts may allow optimizing treatment.     

Diabetes mellitus in Danish cystic fibrosis patients: prevalence and late diabetic complications

Lanng S, Thorsteinsson B, Lund-Andersen C, Nerup J, Schiatz PO, Koch C. Diabetes mellitus in Danish cystic fibrosis patients: prevalence and late diabetic complications. Acta Pzdiatr 1994;83: 72–7. Stockholm. ISSN 0803–5253.
The prevalences of impaired glucose tolerance (IGT), diabetes mellitus and late diabetic complications were studied in all Danish cystic fibrosis (CF) patients. A total of 311 CF patients were identified with an estimated ascertainment rate above 98%. Glucose tolerdnce was classified in 278 (89%) patients: the prevalences of IGT and diabetes mellitus were 13.7% (38 patients) and 14.7% (41 patients), respectively, with no sex differences. The prevalence of diabetes mellitus increased with age but not with the severity of CF as compared with age- and sex-matched non-diabetic CF patients. Diabetes was diagnosed at a median age of 20 years (range 3–40 years) and the duration of diabetes was 1.7 years (0.1–17 years). Twenty-eight of the diabetic patients (70%) were trcated with insulin, on average 20 (4–90) IU per day. Late diabetic complications were identified in 4 patients (10%) with a duration of diabetes mellitus of 1–17 years: background retinopathy (2 patients), diabetic nephropathy (1 patient), microalbuminuria (1 patient) and neuropathy (2 patients). Thus diabetic CF patients are probably not less prone to develop late diabetic complications than patients with other types of diabetes of equally long duration and comparable glycemic control.     

Glucose tolerance in cystic fibrosis.

Glucose tolerance was evaluated in 356 living and dead patients with cystic fibrosis who were recorded at the Danish Cystic Fibrosis Centre. Twenty two patients (6%) were treated elsewhere, 25 (7%) were unable, unwilling or too young (age less than 2 years) to participate; 309 patients (87%) were therefore eligible for the study of whom 99 (32%) were dead and 210 (68%) were alive. Of the dead patients, 13 also had diabetes mellitus (13%). Of the living patients (median age 14 years, range 2-40), nine (4%) were known to have diabetes and all were being treated with insulin. In the remaining 201 patients an oral glucose tolerance test (1.75 g/kg body weight, maximum 75 g) was carried out. A total of 155 patients (74%) had normal glucose tolerance, 31 (15%) had impaired glucose tolerance, and 15 (7%) had diabetes mellitus according to the WHO criteria. The percentage of glycated haemoglobin (HbA1c) (reference range 4.1-6.4%) increased significantly as glucose tolerance decreased: when glucose tolerance was normal the median was 5.2%; when it was impaired the figure was 5.5%; in patients whose diabetes was diagnosed by the oral glucose tolerance test it was 5.9%; and in patients already known to have diabetes mellitus it was 8.6%. The incidence and prevalence of impaired glucose tolerance and diabetes mellitus increased with age. From the age of 15 to 30 years the decrease in the prevalence of normal glucose tolerance was almost linear. Within this age span the proportion of patients with cystic fibrosis with normal glucose tolerance was reduced by roughly 5%/year. Only 35% (95% confidence interval (CI) 22 to 48%) of the patients with cystic fibrosis who were alive at the age of 25 years had normal glucose tolerance; 32% (95% CI 14 to 49%) were diabetic. The prevalence of glucose intolerance in cystic fibrosis is rapidly increasing with age; its potentially harmful effect on the prognosis of cystic fibrosis is of increasing importance as the length of survival of these patients increases.