Diabetes in
Cystic Fibrosis
Thea Pfeifer, M.D.
Introduction is the lethal ~ genetic disorder in the white population, with an incidence of approximately 1:2,500.~ The primary defect appears to be an abnormal chloride channel,2 which results in inspissated secretions with subsequent damage to the pancreas, lungs, and reproductive tract. Up to 95% of patients with CF have pancreatic exocrine insufficiency.3 Once thought to be rela-
cystic
fibrosis
(CF)
most common
tively
pancreatic insufficiency is increasingly recognized, particularly as the life span of CF patients increases. Impaired glucose toleruncommon,
endocrine
in 50% to 75% of with overt diabeCF, patients tes reported in 5% to 15%. 4-7 ance
is
seen
with
The purpose of this review is to summarize current knowledge of the pathophysiology of glucose intolerance and diabetes in CF; describe the clinical characteristics and distinguishing features seen; and discuss issues relating to diagnosis, management, and complications of diabetes in patients with CF.
Pathophysiology Histology At 35 weeks postconceptual age, the pancreas of patients with CF is histologically similar to that of conFrom the Division of
trols.
Changes in the exocrine pancreas are quickly evident, however. As early as 42 weeks, acinar volume is quantitatively decreased in patients with CF compared with controls.’ As inspissated secretions
patients, in which islets embedded in sclerotic tissue have fewer beta cells than those in normal parenchyma, suggesting that fibrosis may impair local circulation and glucose diffusion.&dquo; As
accumulate, ductal dilatation and fibrosis of the acinar pancreas ensue. With advancing disease, fibrosis subsides as the exocrine pancreas is replaced by fatty infil-
the pancreatic changes in CF are similar to those seen in chronic pancreatitis, although diabetes is much more frequent in the latter condition. 14 The islets of patients with insulin-dependent diabetes mellitus (IDDM), in contrast, are characterized by a severe reduction in beta-cell mass, with no change in the mean total mass of alpha or
tration.9-11 With
progressive disthe endocrine pancreas is also involved, as islets of Langerhans become surrounded and disrupted by fibrotic tissue. 9,10,12 Their numbers decrease as destruction continuesy,12 In addition, the proportion of cell types within the islets is altered. Normal islets are composed of approximately 70% insulin-producing beta cells; 20% alpha cells, which make glucagon; and the remaining 10% mostly somatostatinproducing delta cells. 11,13,14 In CF, the number of beta cells is diminished, while the number of delta cells is increased.9,l0 Alpha cell numbers may be unchanged’ or increased 10,11 when compared with normal islets. These changes are seen in all patients with CF, although some investigators have found more severe changes in CF patients with diabetes than in those who are euglycemic.9,1 1,12 Islet distortion and strangulation may be involved in the alteration of islet composition. This is seen with chronic pancreatitis in ease,
Endocrinology, Department of Pediatrics, University of Florida, Gainesville.
Address
correspondence to: Thea Pfeifer, M.D., Division of Endocrinology, Department of Pediatrics, P.O. Box 100296, University of Florida, Gainesville, FL 32610-0296
682
Downloaded from cpj.sagepub.com at CARLETON UNIV on June 14, 2015
non-CF
expected,
delta cells.13,15 Insulitis, the lymphocytic infiltration of the islets, is seen in the early stages ofIDDM,16 but is absent in patients with CFy,12 In non-insulin-dependent diabetes mellitus (NIDDM), the mean total mass of beta cells is not typically reduced, although a wide range is seen; alpha cells show an increase, while somatostatin-producing cells
unchanged in density.&dquo; Islet dysfunction in CF is thought to be secondary to fibrosis of the exocrine pancreas, which disrupts islet architecture and results in ischemia and altered function of the beta cells.17,l8 The percentage of intact beta cells varies greatly, however, and is usually much higher than that seen in IDDM,9 in which 90% or more of the beta cells have been destroyed. Islet strangulation also fails to explain why only some patients with advanced CF develop diabetes or why diabetes has developed in young children with CF, presumably before the progression to severe pancreatic fibrosis has are
taken place. Diabetes unrelated to CF may explain a few of these cases, such as the patient, described by Rodman et al,5 who developed diabetes 12 years before the diagnosis of CF was made. While fibrosis is likely to be important in the pathogenesis of diabetes in CF, other factors may play a role. Somatostatin inhibits the secretion of both insulin and glucagon. While insulin acts to deblood glucose crease levels,
glucagon
serves a
counterregula-
tory function, increasing blood
glucose concentrations through gluconeogenesis and glycogenolysis. The relative increase in delta cells seen in CF may play a role in regulating insulin and glucagon balance. With mild beta-cell dysfunction, increased somatostatin may inhibit glucagon secretion such that glucose homeostasis is maintained. If this balance is shifted by further beta-cell destruction, insulin-
openia may predominate, resulting in glucose intolerance.9,11 Budding of islet cells off the exocrine ducts, or nesidioblastosis, is sometimes seen in patients with CF, not unlike findings in both IDDM and NIDDM. This is more pronounced in younger patients and is infrequent when fibrosis has destroyed the ducts. It has been proposed that these neoislets may offer a protective effect against glucose intolerance in younger patients, although their significance remains unclear.11,12
Endocrine Function Basal insulin secretion may be normal, as evidenced by normal fasting Gpeptide levels,’ but insulin response to various stimuli is impaired in patients with CF. Following an oral load of glucose, peak insulin or Gpeptide response is reached at 60 to 120 min, compared with 30 to 60 min in controls,3,19,20 In addition, the area
under the curve, or total insulin response, is smaller. Insulin secretion is also impaired in response to intravenous glucose, as well as to other secretagogues. 3,18,19,21 Basal glucagon secretion has been reported as either normal3 or decreased22 in CF. Peak glucagon response to insulin-induced hypoglycemia is impaired.’ In normal children, arginine stimulates secretion of both insulin and glucagon. Patients with CF have a blunted response of both hormones.3°19~22 These abnormalities in insulin and glucagon secretion are strongly correlated with the presence of exocrine insufficiency, as
determined
lase and the cess
by pancreatic amy-
isoenzyme concentration,3,21 support the hypothesis that destructive prowithin the pancreas is re-
underlying
sponsible for glucose intolerance. Rarely, other genetic factors may be involved. Geffner et a123 reported the occurrence of hyperin-
sulinemia,
hyperglucagonemia,
and insulin resistance in an obese patient with mild CF whose parents were also obese and hy-
perinsulinemic. Although it was once thought that an abnormality in the gut-derived signals to insulin secretion may be present in CF, this hypothesis has not been supported by research findings. Gastric inhibitory peptide (GIP) is the main hormonal mediator of the enteroinsular axis and is secreted in response to ingested nutrients. It augments glucose-stimulated insulin release and is controlled by feedback inhibition by insulin. Children with CF have increased secretion of this in-
increased insulin sensitivity. Insulin inhibits lipolysis in adipose tissue, with a resultant decrease in free fatty acids (FFAs). Compared with controls, patients with CF have a significantly greater drop in FFAs following oral glucose, in spite of diminished insulin secretion, suggesting increased adipose tissue sensitivity to endogenous insulin. This may explain, in part, the rarity of ketoacidosis in CF25 and the relatively mild carbohydrate intolerance compared with the degree of insulinopenia. Increased sensitivity to exogenous insulin is also reported. Wilmshurst et a125 found that during intravenous insulin infusion, patients with CF had blood glucose concentrations similar to those of controls, despite less immunoreactive insulin in their infusions, when
expressed per kg body weight, again suggesting that there is enhanced peripheral-tissue sensitivity to insulin. Later studies supported this concept. Dandona et a126 found a markedly diminished beta-cell reserve in patients with CF, in the absence of diabetes mellitus (DM), compared with that of controls (as evidenced by lower
fasting C-peptide concentrations, nearing those seen in IDDM). In spite of this, the patients with CF had normal glycosylated hemoglobin (HbAic), which is elevated with chronic hyperglycemia, and normal fasting blood glucose values, suggesting an enhanced insulin sensitivity. Increased numbers of insulin
receptor sites in target tis-
may account for this increased sensitivity.27 sues
sulinotropic hormone, compared with normals, which may account for their relative preservation of insulin response to oral as opposed to intravenous glucose. 21,24 Patients with CF also differ from normal in that they appear to have
Clinical Features Since the pathophysiology of diabetes in CF differs from both IDDM and NIDDM, it is not surprising that its clinical course is also dif-
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683
ferent.
Proposals of terminology to emphasize this distinction include &dquo;insulin-requiring diabetes mellitus,&dquo;~$ or more specifically, &dquo;CF-related diabetes (GFRD).&dquo;29 Insulin-dependent diabetes mellitus has its major incidence at puberty.3° Its hallmark is pancreatic
develop
severe
prevent ments
recently,
locus. The absence of aspartate at the 56 locus of the beta chain of the HLA DQ gene is associated with increased susceptibility to IDDM in certain populations. 31 Antibodies directed against a cytoplasmic antigen common to all islet cells (islet cell antibodies, or ICAS) are present in 70% to 80% of children with IDDM at the time of diagnosis. Although it is unlikely that ICAs are responsible for betacell destruction, they serve as an important marker for disease risk.32 An antibody against a 64K islet antigen has been detected in 280% of newly diagnosed patients with IDDM, often several years before clinical onset of the disease. This antibody was recently identified as the enzyme glutamic acid decarboxylase.33 Clinically, IDDM is characterized by profound insulinopenia, with dependence on insulin injections and proneness to ketosis.34 Typically, NIDDM occurs after age 40, although it may also develop in young persons. Sixty percent to 90% of patients with NIDDM are obese, with weight loss usually resulting in improved glucose tolerance. Insulin levels may be the
DQ
normal, decreased,
or
increased,
and there is an association with peripheral insulin resistance. These patients are not prone to ketosis but
during periods
of
In contrast to both IDDM and NIDDM, CFRD typically occurs in the second decade (mean age, 17 to 20 years) but has been reported in patients as young as 2 years. 7,9,12 Ketosis is rare,’ which may be due to insufficient glucagon to stimulate ketone production22 associated with increased adipose tissue
and/or DR-4, and,
more
it
stress.34
beta-cell destruction, with evidence of an autoimmune etiology, often in association with other autoimmune diseases (particularly thyroiditis). The occurrence of IDDM has been linked with particular class II HLA-D antigens, notably DR-3 to
684
may
sensitivity25 or adequate basal insu(as reflected by normal fasting Gpeptide levels in some studies) to lin
lipolysis.~ Insulin require-
may be
quite variable,
de-
the
presence of pending pulmonary disease, steroid use, and other factors. Islet cell antibodies, common in IDDM at diagnosis and preceding the onset of disease, were negative in studies of 21 CF patients, many with glucose intolerance, and 30 CF patients with normal glucose tolerance. 35,36 In contrast, Stutchfield et al 37 found ICAs in 15% of 46 patients with CF, five of seven who were glucose-intolerant. These investigators and others have found no significant increase in the IDDM-associated HLA DR3 or DR4 frequency, however.37,38 It is unlikely that autoimmunity plays a role in the etiology of CFRD. It is generally agreed that diabetes in persons with CF will become more common as survival improves, but it is uncertain whether carbohydrate intolerance has a significant effect on morbidity and mortality. In 24 patients with CFRD, Rodman et a15 found no difference in pulmonary function or clinical scores (based on physical examination, growth and nutrition, general activity, and chest on
roentgenograms), compared with control CF patients. More important, they found no difference in of deterioration in clinical scores or in survival. Similar findings were seen in a large series by rate
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Reisman et al .6 In contrast, Finkel-
stein et al’ found that poorer glycemic control was associated with more
severely impaired pulmonary
function and worse clinical score in 34 patients with CFRD. He also noted that their patients with CFRD showed a deterioration in clinical status during the two years following diagnosis of diabetes, compared with their euglycemic counterparts, with a rapid decline in survival after age 20?7 Hyperglycemia has been associated with impairment in multiple immunologic parameters in vitro,
including chemotaxis,3g granulocyte adherence, 41 opsonization, and
phagocytosis.1’
In
addition,
a
positive correlation between mean plasma glucose level and prevalence of infection has been reported in patients with IDDM.42
Complications Microvascular complications are well-described in patients with long-standing diabetes. There are several reports of microangiopathy complicating diabetes in CE5,43,14 In a recent study of 19 patients with CFRD, 21 % were found to have evidence of microangiopathy. All but one had diabetes for more than 10 years, and all had chronically poor glycemic control .41 As patients with CFRD survive longer, their risk of diabetes-related complications increases. Routine monitoring for these complications has been suggested.45
Diagnosis tes
Making the diagnosis of diabein patients with CF is straight-
forward
when the classical of symptoms polyuria, polydipsia, and rapid weight loss are present, together with an unequivocally ele-
vated plasma glucose.’ Diagnostic criteria have been established by the National Diabetes Data Group for both adults and children when symptoms are less apparent, based on multiple elevations in fasting or random plasma glucose levels or following a standardized oral glucose
load.34
Establishing the diagnosis of diabetes may be complicated, however, by individual variability in glucose tolerance, depending on disease status, use of hyperalimentation and steroids, and other factors. 5,29 Patients may have transient diabetes during an illness or steroid therapy that will require temporary control measures, only to be glucose-tolerant during periods of relative wellness. High-dose prednisone (2 mg/kg on alternate days) in particular has been associated with significant glucose-tolerance abnormalities when compared with lower doses (1 mg/kg every other day) and with controls. 46 Appropriate therapy for control of steroid-induced hyperglycemia is indicated, followed by reevaluation once steroids are discontinued or infection is controlled. 29 Because of the known complications of long-standing hyperglycemia in patients with diabetes, the
controversy
surrounding hyper-
and morbidity in patients with CF, and the potential to overlook classic signs and symptoms of glucose intolerance in the latter (such as poor weight gain and fatigue) , a CF Foundation Consensus Conference on CFRD was organized to establish criteria for diagnosis and treatment of diabetes in patients with CF. The group recommended that all patients with CF be screened for hyperglycemia. This includes examinations for glycosuria two to three times per year, as well as the
glycemia
determination of fasting and twohour postprandial glucose level every two
to
four years during late
childhood. As the incidence increases with age, plasma glucose levels should be evaluated every two years or as indicated after the
mid-teenage years.29 Levels of HbA1c correlate well with blood glucose levels over the one to two months preceding the HbAic determination and have been proposed as a method of monitoring glucose intolerance in patients with CF.2° Conflicting data exist over its role in the diagnosis of DM in CF, however. Handwerger et all8 found a positive correlation between the age of the patients and oral glucose intolerance, but no such age dependency is seen with HbAic levels, which are above normal in 30% to 45% of patients with CF.2°°47,48 Elevated values in the face of normal glucose tolerance may reflect an abnormality in glucose homeostasis that occurred in the preceding weeks and that has resolved .41 In spite of these limitations, HbAic may be a useful supplemental tool in monitoring for glucose intolerance and is of unquestioned importance in assessing diabetes control Oral glucose tolerance tests (OGTT), while frequently used for establishing the diagnosis of IDDM,34 serve little purpose in diagnosing CFRD. DeSchepper et a148 found an abnormal OGTT in 33% of 48 patients with CF. Although these patients differed from those with normal OGTTs by having a delayed insulin response to a carbohydrate load, the mean peak insulin concentrations, as well as areas under the insulin-response curves, were comparable. Their fasting glucose and insulin levels were also similar, as were clinical scores. Although mean HbAic levels were generally higher in the glucose-intolerant patients, several of these patients had a normal HbA1c, while many with normal tolerance had elevated values. Criteria necessary
for performing an interpretable OGTT include normal nutritional status and absence of underlying illness conditions difficult to meet in patients with CF. 34 In the absence of a known elevated fasting blood glucose level or symptomatic DM, the information provided by OGTT has little clinical significance. -
Management Once the decision is made to hyperglycemia, the goal is to optimize metabolic conditions for normal cellular function and growth while avoiding hypoglycemia.29 The role of oral agents in CFRD has not been studied systematically. They may be useful in glucose intolerance but are considered ineffective during the stress of infections or steroid use.29 Oral hypoglycemics may have another benefit in CF, however. Zipf et a149 recently showed that in poorly growing, nondiabetic children with CF, oral tolbutamide (a sulfonylurea compound) more than doubled linear growth and increased lean body-mass accretion fourfold. Since the children’s insulin secretion did not change, the investigations proposed that insulin responsiveness in peripheral tissues had improved. If the increase in lean body mass was mostly in skeletal muscle, they felt that strengthened respiratory muscles and increased exercise capacity might result from this treatment. Insulin injection remains the standard treatment for CFRD, either with the usual two-injections-per-day schedule or with multreat
tiple
daily injections
(MDIs)
administered before meals .29 Sheehan et al50 were able to improve HbAic levels significantly, as well as obtain substantial weight gain in 14 patients with CFRD, using one of two MDI schedules and
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685
titrating the doses according to carbohydrate consumption. Even with this intense regimen, no episodes of hypoglycemia resulting in unconsciousness occurred. For
transient
ple carbohydrates. Providing optimal nutrition for CF patients is of paramount importance, since this disease has a debilitating on
al’ of 24 patients with CFRD,
3.
of
episodes hypoglycemia, including coma, seizures, and transient hemiplegia, while on insulin therapy.
4.
nutritional
status.
Rec-
ommendations by the Consensus Conference include establishing consistent timing of meals and snacks, as well as incorporating
or
oral medicine is
adjusted accordingly to provide optimal glucose control. Ongoing patient education should include instruction on the interaction of exercise, diet, and insulin or other hypoglycemic agents. Recognition, avoidance, and treatment of hypoglycemia should be emphasized, as this can have profound consequences. In the series of Rod-
686
J Pediatr. 1991;118:715-723. brosis. Cystic Fibrosis: A Disease in Search of Ideas. Education &
5.
Conclusion
improved therapy for CF, patients are now living longer because of increasing recognition of glucose abnormalities and diabetes. The incidence of complications secondary to chronic
hyperglycemia also appears to be increasing. The addition of another chronic illness complicates an already demanding medical regimen for patients with CF. Because of this, management must be individualized to both the patients’ needs and their ability to cope with these additional stressors. Until more is known about the effects of diabetes on morbidity and mortality in CF, prudent management goals include maintenance of reasonable blood glucose control with avoidance of hypoglycemic reactions.
6.
7.
8.
Welfare
publication
no.
79-1643:33-34. Rodman HM, Doershuk CF, Roland JM. The interaction of 2 diseases: diabetes mellitus and
With
cystic
fibrosis. Medicine.
1986;65:389-397. Reisman J, Corey M, Canny G,
Levison H. Diabetes mellitus in patients with cystic fibrosis: effect on survival. Pediatrics. 1990;86:374-377. Finkelstein SM, Wielinski CL, Elliot GR, et al. Diabetes mellitus associated with
cystic 1988;112:373-377. J Pediatr. fibrosis. ImrieJR, Fagan DG, SturgessJM. Quantitative evaluation of the development of the exocrine pancreas in cystic fibrosis and control infants. Am J Pathol. 1979;95:697-708.
9.
10.
Abdul-Karim FW, Dahms BB, Velasco ME, Rodman HM. Islets of Langerhans in adolescents and adults with cystic Arch Pathol Lab Med. fibrosis.
1986;110:602-606. M, Goertchen P, Nizze H,
Lohr
et
al.
fibrosis-associated islet changes may provide a basis for diabetes. Virchows Archiv [A]. 1989;414:179-185. Soejima K, Landing BH. Pancreatic islets in older patients with cystic fibrosis with and without diabetes mellitus:
Cystic
11.
13.
and immunocytologic studies. Pediatr Pathol. 1986;6:25-46. lannucci A, Mukai K, Johnson D, Burke B. Endocrine pancreas in cystic fibrosis: an immunohistochemical study. Hum Pathol. 1984;15:278-284. Gepts W. The pancreatic islets in diabe-
14.
Kloppel G,
morphometric
Acknowledgments The author gratefully acknowDr. Arlan Rosenbloom for his editorial assistance and Mrs. Margaret Stanley for preparation of the manuscript.
ledges
12.
tes.
Am J Med. 1981;70:105-115. Bommer L, Commandeur
Heitz P. The endocrine pancreas in chronic pancreatitis. Virchows Arch [A].
G,
protein, fat, and carbohydrate (including &dquo;simple sugars&dquo;) into each. Insulin
Moran A, Diem P, Klein DJ, et al. Pancreatic endocrine function in cystic fi-
Bethesda, MD: National Institutes of Health; 1979. U.S. Dept. of Health,
hyperglycemia
associated with hyperalimentation, insulin may be added to the solution or &dquo;piggybacked&dquo; to allow for independent adjustments of rate. Steroid- or infection-induced hyperglycemia may be managed with a split dose of insulin, starting at 0.3 to 0.5 U/kg/day. Reevaluation of the need for glucose control measures should be done once steroids are decreased or infection is resolved.29 The primary complication associated with pharmacotherapy for hyperglycemia is hypoglycemia. As noted earlier, patients with CF seem to have an increased sensitivity to both endogenous and exogenous insulin, which may account for the frequency of this complication. Nutritional recommendations vary substantially for patients with CF from those with IDDM, particularly in the amount of fat and sim-
effect
man et
four had serious
1978;377:157-174. 15.
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Rahier J, Goebbels RM, Henquin JC. Cellular composition of the human diabetic pancreas. Diabetologia. 1983;24:366-371. Gepts W. Pathologic anatomy of the pancreas in juvenile diabetes mellitus.
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Glucose intolerance in cystic fibrosis. N Engl J Med. 1969;281:451-461. 19. Lippe BM, Sperling MA, Dooley RR. Pancreatic alpha and beta cell functions in cystic fibrosis. J Pediatr. 1977;90:751-755. 20. Bistritzer T, Sack J, Eshkol A, Katznelson D. Hemoglobin A 1 and pancreatic beta cell function in cystic fibrosis. Isr J
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687
Cystic Fibrosis
Thea Pfeifer, M.D.
Introduction is the lethal ~ genetic disorder in the white population, with an incidence of approximately 1:2,500.~ The primary defect appears to be an abnormal chloride channel,2 which results in inspissated secretions with subsequent damage to the pancreas, lungs, and reproductive tract. Up to 95% of patients with CF have pancreatic exocrine insufficiency.3 Once thought to be rela-
cystic
fibrosis
(CF)
most common
tively
pancreatic insufficiency is increasingly recognized, particularly as the life span of CF patients increases. Impaired glucose toleruncommon,
endocrine
in 50% to 75% of with overt diabeCF, patients tes reported in 5% to 15%. 4-7 ance
is
seen
with
The purpose of this review is to summarize current knowledge of the pathophysiology of glucose intolerance and diabetes in CF; describe the clinical characteristics and distinguishing features seen; and discuss issues relating to diagnosis, management, and complications of diabetes in patients with CF.
Pathophysiology Histology At 35 weeks postconceptual age, the pancreas of patients with CF is histologically similar to that of conFrom the Division of
trols.
Changes in the exocrine pancreas are quickly evident, however. As early as 42 weeks, acinar volume is quantitatively decreased in patients with CF compared with controls.’ As inspissated secretions
patients, in which islets embedded in sclerotic tissue have fewer beta cells than those in normal parenchyma, suggesting that fibrosis may impair local circulation and glucose diffusion.&dquo; As
accumulate, ductal dilatation and fibrosis of the acinar pancreas ensue. With advancing disease, fibrosis subsides as the exocrine pancreas is replaced by fatty infil-
the pancreatic changes in CF are similar to those seen in chronic pancreatitis, although diabetes is much more frequent in the latter condition. 14 The islets of patients with insulin-dependent diabetes mellitus (IDDM), in contrast, are characterized by a severe reduction in beta-cell mass, with no change in the mean total mass of alpha or
tration.9-11 With
progressive disthe endocrine pancreas is also involved, as islets of Langerhans become surrounded and disrupted by fibrotic tissue. 9,10,12 Their numbers decrease as destruction continuesy,12 In addition, the proportion of cell types within the islets is altered. Normal islets are composed of approximately 70% insulin-producing beta cells; 20% alpha cells, which make glucagon; and the remaining 10% mostly somatostatinproducing delta cells. 11,13,14 In CF, the number of beta cells is diminished, while the number of delta cells is increased.9,l0 Alpha cell numbers may be unchanged’ or increased 10,11 when compared with normal islets. These changes are seen in all patients with CF, although some investigators have found more severe changes in CF patients with diabetes than in those who are euglycemic.9,1 1,12 Islet distortion and strangulation may be involved in the alteration of islet composition. This is seen with chronic pancreatitis in ease,
Endocrinology, Department of Pediatrics, University of Florida, Gainesville.
Address
correspondence to: Thea Pfeifer, M.D., Division of Endocrinology, Department of Pediatrics, P.O. Box 100296, University of Florida, Gainesville, FL 32610-0296
682
Downloaded from cpj.sagepub.com at CARLETON UNIV on June 14, 2015
non-CF
expected,
delta cells.13,15 Insulitis, the lymphocytic infiltration of the islets, is seen in the early stages ofIDDM,16 but is absent in patients with CFy,12 In non-insulin-dependent diabetes mellitus (NIDDM), the mean total mass of beta cells is not typically reduced, although a wide range is seen; alpha cells show an increase, while somatostatin-producing cells
unchanged in density.&dquo; Islet dysfunction in CF is thought to be secondary to fibrosis of the exocrine pancreas, which disrupts islet architecture and results in ischemia and altered function of the beta cells.17,l8 The percentage of intact beta cells varies greatly, however, and is usually much higher than that seen in IDDM,9 in which 90% or more of the beta cells have been destroyed. Islet strangulation also fails to explain why only some patients with advanced CF develop diabetes or why diabetes has developed in young children with CF, presumably before the progression to severe pancreatic fibrosis has are
taken place. Diabetes unrelated to CF may explain a few of these cases, such as the patient, described by Rodman et al,5 who developed diabetes 12 years before the diagnosis of CF was made. While fibrosis is likely to be important in the pathogenesis of diabetes in CF, other factors may play a role. Somatostatin inhibits the secretion of both insulin and glucagon. While insulin acts to deblood glucose crease levels,
glucagon
serves a
counterregula-
tory function, increasing blood
glucose concentrations through gluconeogenesis and glycogenolysis. The relative increase in delta cells seen in CF may play a role in regulating insulin and glucagon balance. With mild beta-cell dysfunction, increased somatostatin may inhibit glucagon secretion such that glucose homeostasis is maintained. If this balance is shifted by further beta-cell destruction, insulin-
openia may predominate, resulting in glucose intolerance.9,11 Budding of islet cells off the exocrine ducts, or nesidioblastosis, is sometimes seen in patients with CF, not unlike findings in both IDDM and NIDDM. This is more pronounced in younger patients and is infrequent when fibrosis has destroyed the ducts. It has been proposed that these neoislets may offer a protective effect against glucose intolerance in younger patients, although their significance remains unclear.11,12
Endocrine Function Basal insulin secretion may be normal, as evidenced by normal fasting Gpeptide levels,’ but insulin response to various stimuli is impaired in patients with CF. Following an oral load of glucose, peak insulin or Gpeptide response is reached at 60 to 120 min, compared with 30 to 60 min in controls,3,19,20 In addition, the area
under the curve, or total insulin response, is smaller. Insulin secretion is also impaired in response to intravenous glucose, as well as to other secretagogues. 3,18,19,21 Basal glucagon secretion has been reported as either normal3 or decreased22 in CF. Peak glucagon response to insulin-induced hypoglycemia is impaired.’ In normal children, arginine stimulates secretion of both insulin and glucagon. Patients with CF have a blunted response of both hormones.3°19~22 These abnormalities in insulin and glucagon secretion are strongly correlated with the presence of exocrine insufficiency, as
determined
lase and the cess
by pancreatic amy-
isoenzyme concentration,3,21 support the hypothesis that destructive prowithin the pancreas is re-
underlying
sponsible for glucose intolerance. Rarely, other genetic factors may be involved. Geffner et a123 reported the occurrence of hyperin-
sulinemia,
hyperglucagonemia,
and insulin resistance in an obese patient with mild CF whose parents were also obese and hy-
perinsulinemic. Although it was once thought that an abnormality in the gut-derived signals to insulin secretion may be present in CF, this hypothesis has not been supported by research findings. Gastric inhibitory peptide (GIP) is the main hormonal mediator of the enteroinsular axis and is secreted in response to ingested nutrients. It augments glucose-stimulated insulin release and is controlled by feedback inhibition by insulin. Children with CF have increased secretion of this in-
increased insulin sensitivity. Insulin inhibits lipolysis in adipose tissue, with a resultant decrease in free fatty acids (FFAs). Compared with controls, patients with CF have a significantly greater drop in FFAs following oral glucose, in spite of diminished insulin secretion, suggesting increased adipose tissue sensitivity to endogenous insulin. This may explain, in part, the rarity of ketoacidosis in CF25 and the relatively mild carbohydrate intolerance compared with the degree of insulinopenia. Increased sensitivity to exogenous insulin is also reported. Wilmshurst et a125 found that during intravenous insulin infusion, patients with CF had blood glucose concentrations similar to those of controls, despite less immunoreactive insulin in their infusions, when
expressed per kg body weight, again suggesting that there is enhanced peripheral-tissue sensitivity to insulin. Later studies supported this concept. Dandona et a126 found a markedly diminished beta-cell reserve in patients with CF, in the absence of diabetes mellitus (DM), compared with that of controls (as evidenced by lower
fasting C-peptide concentrations, nearing those seen in IDDM). In spite of this, the patients with CF had normal glycosylated hemoglobin (HbAic), which is elevated with chronic hyperglycemia, and normal fasting blood glucose values, suggesting an enhanced insulin sensitivity. Increased numbers of insulin
receptor sites in target tis-
may account for this increased sensitivity.27 sues
sulinotropic hormone, compared with normals, which may account for their relative preservation of insulin response to oral as opposed to intravenous glucose. 21,24 Patients with CF also differ from normal in that they appear to have
Clinical Features Since the pathophysiology of diabetes in CF differs from both IDDM and NIDDM, it is not surprising that its clinical course is also dif-
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683
ferent.
Proposals of terminology to emphasize this distinction include &dquo;insulin-requiring diabetes mellitus,&dquo;~$ or more specifically, &dquo;CF-related diabetes (GFRD).&dquo;29 Insulin-dependent diabetes mellitus has its major incidence at puberty.3° Its hallmark is pancreatic
develop
severe
prevent ments
recently,
locus. The absence of aspartate at the 56 locus of the beta chain of the HLA DQ gene is associated with increased susceptibility to IDDM in certain populations. 31 Antibodies directed against a cytoplasmic antigen common to all islet cells (islet cell antibodies, or ICAS) are present in 70% to 80% of children with IDDM at the time of diagnosis. Although it is unlikely that ICAs are responsible for betacell destruction, they serve as an important marker for disease risk.32 An antibody against a 64K islet antigen has been detected in 280% of newly diagnosed patients with IDDM, often several years before clinical onset of the disease. This antibody was recently identified as the enzyme glutamic acid decarboxylase.33 Clinically, IDDM is characterized by profound insulinopenia, with dependence on insulin injections and proneness to ketosis.34 Typically, NIDDM occurs after age 40, although it may also develop in young persons. Sixty percent to 90% of patients with NIDDM are obese, with weight loss usually resulting in improved glucose tolerance. Insulin levels may be the
DQ
normal, decreased,
or
increased,
and there is an association with peripheral insulin resistance. These patients are not prone to ketosis but
during periods
of
In contrast to both IDDM and NIDDM, CFRD typically occurs in the second decade (mean age, 17 to 20 years) but has been reported in patients as young as 2 years. 7,9,12 Ketosis is rare,’ which may be due to insufficient glucagon to stimulate ketone production22 associated with increased adipose tissue
and/or DR-4, and,
more
it
stress.34
beta-cell destruction, with evidence of an autoimmune etiology, often in association with other autoimmune diseases (particularly thyroiditis). The occurrence of IDDM has been linked with particular class II HLA-D antigens, notably DR-3 to
684
may
sensitivity25 or adequate basal insu(as reflected by normal fasting Gpeptide levels in some studies) to lin
lipolysis.~ Insulin require-
may be
quite variable,
de-
the
presence of pending pulmonary disease, steroid use, and other factors. Islet cell antibodies, common in IDDM at diagnosis and preceding the onset of disease, were negative in studies of 21 CF patients, many with glucose intolerance, and 30 CF patients with normal glucose tolerance. 35,36 In contrast, Stutchfield et al 37 found ICAs in 15% of 46 patients with CF, five of seven who were glucose-intolerant. These investigators and others have found no significant increase in the IDDM-associated HLA DR3 or DR4 frequency, however.37,38 It is unlikely that autoimmunity plays a role in the etiology of CFRD. It is generally agreed that diabetes in persons with CF will become more common as survival improves, but it is uncertain whether carbohydrate intolerance has a significant effect on morbidity and mortality. In 24 patients with CFRD, Rodman et a15 found no difference in pulmonary function or clinical scores (based on physical examination, growth and nutrition, general activity, and chest on
roentgenograms), compared with control CF patients. More important, they found no difference in of deterioration in clinical scores or in survival. Similar findings were seen in a large series by rate
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Reisman et al .6 In contrast, Finkel-
stein et al’ found that poorer glycemic control was associated with more
severely impaired pulmonary
function and worse clinical score in 34 patients with CFRD. He also noted that their patients with CFRD showed a deterioration in clinical status during the two years following diagnosis of diabetes, compared with their euglycemic counterparts, with a rapid decline in survival after age 20?7 Hyperglycemia has been associated with impairment in multiple immunologic parameters in vitro,
including chemotaxis,3g granulocyte adherence, 41 opsonization, and
phagocytosis.1’
In
addition,
a
positive correlation between mean plasma glucose level and prevalence of infection has been reported in patients with IDDM.42
Complications Microvascular complications are well-described in patients with long-standing diabetes. There are several reports of microangiopathy complicating diabetes in CE5,43,14 In a recent study of 19 patients with CFRD, 21 % were found to have evidence of microangiopathy. All but one had diabetes for more than 10 years, and all had chronically poor glycemic control .41 As patients with CFRD survive longer, their risk of diabetes-related complications increases. Routine monitoring for these complications has been suggested.45
Diagnosis tes
Making the diagnosis of diabein patients with CF is straight-
forward
when the classical of symptoms polyuria, polydipsia, and rapid weight loss are present, together with an unequivocally ele-
vated plasma glucose.’ Diagnostic criteria have been established by the National Diabetes Data Group for both adults and children when symptoms are less apparent, based on multiple elevations in fasting or random plasma glucose levels or following a standardized oral glucose
load.34
Establishing the diagnosis of diabetes may be complicated, however, by individual variability in glucose tolerance, depending on disease status, use of hyperalimentation and steroids, and other factors. 5,29 Patients may have transient diabetes during an illness or steroid therapy that will require temporary control measures, only to be glucose-tolerant during periods of relative wellness. High-dose prednisone (2 mg/kg on alternate days) in particular has been associated with significant glucose-tolerance abnormalities when compared with lower doses (1 mg/kg every other day) and with controls. 46 Appropriate therapy for control of steroid-induced hyperglycemia is indicated, followed by reevaluation once steroids are discontinued or infection is controlled. 29 Because of the known complications of long-standing hyperglycemia in patients with diabetes, the
controversy
surrounding hyper-
and morbidity in patients with CF, and the potential to overlook classic signs and symptoms of glucose intolerance in the latter (such as poor weight gain and fatigue) , a CF Foundation Consensus Conference on CFRD was organized to establish criteria for diagnosis and treatment of diabetes in patients with CF. The group recommended that all patients with CF be screened for hyperglycemia. This includes examinations for glycosuria two to three times per year, as well as the
glycemia
determination of fasting and twohour postprandial glucose level every two
to
four years during late
childhood. As the incidence increases with age, plasma glucose levels should be evaluated every two years or as indicated after the
mid-teenage years.29 Levels of HbA1c correlate well with blood glucose levels over the one to two months preceding the HbAic determination and have been proposed as a method of monitoring glucose intolerance in patients with CF.2° Conflicting data exist over its role in the diagnosis of DM in CF, however. Handwerger et all8 found a positive correlation between the age of the patients and oral glucose intolerance, but no such age dependency is seen with HbAic levels, which are above normal in 30% to 45% of patients with CF.2°°47,48 Elevated values in the face of normal glucose tolerance may reflect an abnormality in glucose homeostasis that occurred in the preceding weeks and that has resolved .41 In spite of these limitations, HbAic may be a useful supplemental tool in monitoring for glucose intolerance and is of unquestioned importance in assessing diabetes control Oral glucose tolerance tests (OGTT), while frequently used for establishing the diagnosis of IDDM,34 serve little purpose in diagnosing CFRD. DeSchepper et a148 found an abnormal OGTT in 33% of 48 patients with CF. Although these patients differed from those with normal OGTTs by having a delayed insulin response to a carbohydrate load, the mean peak insulin concentrations, as well as areas under the insulin-response curves, were comparable. Their fasting glucose and insulin levels were also similar, as were clinical scores. Although mean HbAic levels were generally higher in the glucose-intolerant patients, several of these patients had a normal HbA1c, while many with normal tolerance had elevated values. Criteria necessary
for performing an interpretable OGTT include normal nutritional status and absence of underlying illness conditions difficult to meet in patients with CF. 34 In the absence of a known elevated fasting blood glucose level or symptomatic DM, the information provided by OGTT has little clinical significance. -
Management Once the decision is made to hyperglycemia, the goal is to optimize metabolic conditions for normal cellular function and growth while avoiding hypoglycemia.29 The role of oral agents in CFRD has not been studied systematically. They may be useful in glucose intolerance but are considered ineffective during the stress of infections or steroid use.29 Oral hypoglycemics may have another benefit in CF, however. Zipf et a149 recently showed that in poorly growing, nondiabetic children with CF, oral tolbutamide (a sulfonylurea compound) more than doubled linear growth and increased lean body-mass accretion fourfold. Since the children’s insulin secretion did not change, the investigations proposed that insulin responsiveness in peripheral tissues had improved. If the increase in lean body mass was mostly in skeletal muscle, they felt that strengthened respiratory muscles and increased exercise capacity might result from this treatment. Insulin injection remains the standard treatment for CFRD, either with the usual two-injections-per-day schedule or with multreat
tiple
daily injections
(MDIs)
administered before meals .29 Sheehan et al50 were able to improve HbAic levels significantly, as well as obtain substantial weight gain in 14 patients with CFRD, using one of two MDI schedules and
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685
titrating the doses according to carbohydrate consumption. Even with this intense regimen, no episodes of hypoglycemia resulting in unconsciousness occurred. For
transient
ple carbohydrates. Providing optimal nutrition for CF patients is of paramount importance, since this disease has a debilitating on
al’ of 24 patients with CFRD,
3.
of
episodes hypoglycemia, including coma, seizures, and transient hemiplegia, while on insulin therapy.
4.
nutritional
status.
Rec-
ommendations by the Consensus Conference include establishing consistent timing of meals and snacks, as well as incorporating
or
oral medicine is
adjusted accordingly to provide optimal glucose control. Ongoing patient education should include instruction on the interaction of exercise, diet, and insulin or other hypoglycemic agents. Recognition, avoidance, and treatment of hypoglycemia should be emphasized, as this can have profound consequences. In the series of Rod-
686
J Pediatr. 1991;118:715-723. brosis. Cystic Fibrosis: A Disease in Search of Ideas. Education &
5.
Conclusion
improved therapy for CF, patients are now living longer because of increasing recognition of glucose abnormalities and diabetes. The incidence of complications secondary to chronic
hyperglycemia also appears to be increasing. The addition of another chronic illness complicates an already demanding medical regimen for patients with CF. Because of this, management must be individualized to both the patients’ needs and their ability to cope with these additional stressors. Until more is known about the effects of diabetes on morbidity and mortality in CF, prudent management goals include maintenance of reasonable blood glucose control with avoidance of hypoglycemic reactions.
6.
7.
8.
Welfare
publication
no.
79-1643:33-34. Rodman HM, Doershuk CF, Roland JM. The interaction of 2 diseases: diabetes mellitus and
With
cystic
fibrosis. Medicine.
1986;65:389-397. Reisman J, Corey M, Canny G,
Levison H. Diabetes mellitus in patients with cystic fibrosis: effect on survival. Pediatrics. 1990;86:374-377. Finkelstein SM, Wielinski CL, Elliot GR, et al. Diabetes mellitus associated with
cystic 1988;112:373-377. J Pediatr. fibrosis. ImrieJR, Fagan DG, SturgessJM. Quantitative evaluation of the development of the exocrine pancreas in cystic fibrosis and control infants. Am J Pathol. 1979;95:697-708.
9.
10.
Abdul-Karim FW, Dahms BB, Velasco ME, Rodman HM. Islets of Langerhans in adolescents and adults with cystic Arch Pathol Lab Med. fibrosis.
1986;110:602-606. M, Goertchen P, Nizze H,
Lohr
et
al.
fibrosis-associated islet changes may provide a basis for diabetes. Virchows Archiv [A]. 1989;414:179-185. Soejima K, Landing BH. Pancreatic islets in older patients with cystic fibrosis with and without diabetes mellitus:
Cystic
11.
13.
and immunocytologic studies. Pediatr Pathol. 1986;6:25-46. lannucci A, Mukai K, Johnson D, Burke B. Endocrine pancreas in cystic fibrosis: an immunohistochemical study. Hum Pathol. 1984;15:278-284. Gepts W. The pancreatic islets in diabe-
14.
Kloppel G,
morphometric
Acknowledgments The author gratefully acknowDr. Arlan Rosenbloom for his editorial assistance and Mrs. Margaret Stanley for preparation of the manuscript.
ledges
12.
tes.
Am J Med. 1981;70:105-115. Bommer L, Commandeur
Heitz P. The endocrine pancreas in chronic pancreatitis. Virchows Arch [A].
G,
protein, fat, and carbohydrate (including &dquo;simple sugars&dquo;) into each. Insulin
Moran A, Diem P, Klein DJ, et al. Pancreatic endocrine function in cystic fi-
Bethesda, MD: National Institutes of Health; 1979. U.S. Dept. of Health,
hyperglycemia
associated with hyperalimentation, insulin may be added to the solution or &dquo;piggybacked&dquo; to allow for independent adjustments of rate. Steroid- or infection-induced hyperglycemia may be managed with a split dose of insulin, starting at 0.3 to 0.5 U/kg/day. Reevaluation of the need for glucose control measures should be done once steroids are decreased or infection is resolved.29 The primary complication associated with pharmacotherapy for hyperglycemia is hypoglycemia. As noted earlier, patients with CF seem to have an increased sensitivity to both endogenous and exogenous insulin, which may account for the frequency of this complication. Nutritional recommendations vary substantially for patients with CF from those with IDDM, particularly in the amount of fat and sim-
effect
man et
four had serious
1978;377:157-174. 15.
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