CF-Related Diabetes Mellitus

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by Antoinette Moran, M.D., Department of Pediatrics, University of Minnesota, Minneapolis, MN

The bulk of the normal pancreas is composed of acinar cells which synthesize digestive enzymes and the ductular system which transports the enzymes to the gut. Scattered throughout the pancreas are the islets of Langerhans, where insulin is produced by beta cells. In insulin dependent diabetes mellitus (IDDM), autoimmune destruction of beta cells leads to complete absence of insulin secretion. Non-insulin-dependent diabetes mellitus (NIDDM) is believed to be caused by two defects- peripheral insulin resistance, which increases the body’s insulin requirements, and a partial beta cell abnormality rendering the pancreas unable to secrete enough insulin to compensate for insulin resistance. CF related diabetes mellitus (CFRDM) results from a process different than that causing IDDM or NIDDM. Abnormal chloride channel activity in CF leads to hyperviscous secretions, producing obstructive damage to many organs, including the pancreas. This process destroys some but not all of the islets. We studied the pancreases obtained at autopsy in CF patients during the last 10 years at our institution. In the 15 cases with overt diabetes, two-thirds of the beta cells were destroyed. In the remaining 26 cases, overt diabetes was not known to be present but 50% beta cell destruction was seen. Partial loss of islets leads clinically to a wide spectrum of glucose abnormalities, depending upon both the number of remaining islets and the insulin sensitivity (and thus the insulin needs) of the individual.

Insulin secretion in CF has been studied using a variety of methods. Intravenous studies have shown that first phase insulin secretion in response to glucose and other stimulatory agents is impaired in adult CF patients who are exocrine insufficient

  1. We have performed oral glucose tolerance tests (OGTT) annually for the last three years at our CF center. Most CF children have normal glucose tolerance. In the adult population, we find 27% normal glucose tolerance, 39% impaired glucose tolerance, and 25% have a diabetic OGTT response (but normal fasting glucose levels). OGTTs are not performed on the 8% of patients who have fasting hyperglycemia and overt diabetes. Thus, the majority of adult CF patients have abnormal glucose tolerance and insulin deficiency. Despite this, most have normal fasting glucose and hemoglobin A1c levels, normal glucose profiles measured at home by meter, and no glucose present in 24 hr urine samples. CF patients appear to accomplish this via increased peripheral sensitivity to insulin
  2. However, conditions which result in insulin resistance–infection, therapeutic glucorticosteroids, pregnancy–lead to hyperglycemia since the usual compensatory increase in insulin secretion is not possible in these patients.

We reserve the term CFRDM for individuals with fasting glucose levels 140 mg/dl. They are managed by a medical team which includes a pulmonologist, endocrinologist, dietitian and diabetes nurse educator. Our goals are to

  1. control hyperglycemia,
  2. avoid severe hypoglycemia,
  3. maintain optimal nutrition, and
  4. be as flexible as possible within the framework of the patient’s lifestyle and CF.

Patients ideally check their glucose level 4x/day. We treat all CFRDM patients with insulin. About half receive split dose NPH/regular; the remainder receive regular insulin before meals with or without nighttime NPH. Our goal is to maintain fasting glucose levels 80-140 and random glucose levels 80-180 mg/dl. Patients with CFRDM double or triple their insulin needs during acute infections. Insulin needs return to normal 2-8 weeks after the illness resolves. Approximately 5% of our CF population receive insulin during acute illness but do not require insulin to maintain normal glucose levels when they are in their usual state of health. Some CF Centers use oral hypoglycemic agents, but in our experience these drugs are seldom helpful.

Prevention of hyperglycemia has been recognized as an important goal in the treatment of CF, since hyperglycemia is associated with increased morbidity and mortality in this population (3,4). No one questions the role of insulin therapy in the overtly diabetic patient. It is not clear, however, how to best manage the glucose intolerant patient or the patient with normal fasting glucoses but a diabetic pattern on OGTT. Insulin is important both for normal glucose metabolism and for the maintenance of normal body protein status. CF patients are chronically protein catabolic, which may contribute to morbidity and mortality. Insulin deficiency might contribute to protein catabolism in CF patients even when blood glucose levels are relatively normal. Until more data are available, however, insulin cannot be routinely recommended for these subjects except in the context of a controlled research trial.

Our dietary recommendations for diabetic CF patients are similar to those for the CF population as a whole. We suggest three well-balanced meals and three snacks per day. When this is not practical we recommend small frequent meals. We suggest moderation in simple carbohydrate intake. The only dietary item we ask patients to avoid is sugared soda pop. Many patients receive supplemental enteral feedings. We found that high-fat, low-carbohydrate formulas have the most beneficial effect on serum glucose and insulin levels. “Sugar free” does not necessarily mean low carbohydrate. Exercise per se will not control blood glucose levels in CF, but it improves peripheral insulin sensitivity and should be encouraged.

Our diabetic CF patients have quarterly hemoglobin A1c measurements and annual ophthalmologic exams and urinary albumin testing. Because ketones are rarely present (except at initial presentation), we do not routinely teach patients to measure them. Currently there is no consensus on how the results of the OGTT should be interpreted in CF and thus the utility of this test is unclear. We recommend annual A1c and random glucose levels for non-diabetic CF patients. Patients hospitalized for acute illness should have glucose profiles performed for at least the first two days. Patients with a diabetic pattern on OGTT or with elevated A1c levels are sent home with a meter for home glucose monitoring. They check glucose profiles (4x/d) daily for a week. If normal, we ask them to check glucose profiles once a month, and more frequently during illness or if weight loss or symptoms of hyperglycemia are present.

  1. Moran, A, Diem, P, Klein, DJ, Levitt, MD, Robertson, RP. Pancreatic endocrine function in cystic fibrosis. J. Pediatr. 1991; 118:715-23.
  2. Moran, A, Pyzdrowski, K, Weinreb, MD, Kahn, BB, Smith, SA, Adams, KL, Seaquist, ER. Insulin sensitivity in cystic fibrosis. Diabetes 1994; 43:1020-6. 3. Lanng, S, Thorsteinsson, B, Nerup, J, Koch, C. Diabetes mellitus in cystic fibrosis: effect of insulin therapy on lung function and infections. Acta Paediatricia 1994; 83:849-53. 4. Finkelstein, SM, Wielinski, CL, Elliot, GR, Warwick, WJ, Barbosa, J, Wu, SC, Klein, DJ. Diabetes mellitus associated with cystic fibrosis. J. Pediatr. 1988; 112:373-7.

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