OBJECTIVE—Insulin and glucose levels in response to premeal insulin lispro or repaglinide were evaluated in adult patients with cystic fibrosis–related diabetes (CFRD) without fasting hyperglycemia.

RESEARCH DESIGN AND METHODS—Seven patients with CFRD were fed 1,000-kcal liquid mixed meals. Three study conditions were administered in random order on separate mornings: 1) no premeal diabetes medication, 2) insulin lispro, 0.1 unit/kg body wt premeal and 3) repaglinide 1 mg premeal. Glucose and insulin levels were measured every 20 min for 5 h.

RESULTS—Fasting insulin and glucose levels were normal in patients with CFRD, but the peak glucose level was elevated. Insulin lispro significantly decreased the peak glucose level (P = 0.0004) and the 2-h (P = 0.001) and 5-h (P < 0.0001) glucose area under the curve (AUC). Repaglinide significantly decreased the 5-h glucose AUC (P = 0.03). Neither drug completely normalized cystic fibrosis glucose excursion at the doses used for this study. Insulin lispro significantly increased the 5-h insulin AUC (P = 0.04).

CONCLUSIONS—In response to subcutaneous insulin lispro, postprandial glucose excursion was significantly diminished and insulin secretion was enhanced compared with a control meal in which no medication was given to patients with CFRD. The oral agent repaglinide resulted in lesser corrections in these parameters. Neither drug completely normalized glucose or insulin levels, suggesting that the doses chosen for this study were suboptimal. Placebo-controlled longitudinal studies comparing the effectiveness of repaglinide and insulin on glucose metabolic control as well as overall nutrition and body weight are needed to help determine optimal medical treatment of CFRD.

Diabetes and impaired glucose tolerance are common complications of cystic fibrosis (CF). Based on routine annual oral glucose tolerance test screening of the 450 patients with CF followed at the University of Minnesota, we reported a prevalence in adults with CF of ∼15% diabetes with fasting hyperglycemia, 25% diabetes without fasting hyperglycemia, 35% impaired glucose tolerance, and 25% normal glucose tolerance (1). Diabetes is primarily due to insulin deficiency (2), which is caused by fibrotic destruction of pancreatic islets and perhaps by dysfunction of the remaining β-cells related to islet amyloid deposition (3).

In CF, the additional diagnosis of diabetes is associated with significantly increased morbidity and mortality (4,5,6). Patients with CF-related diabetes (CFRD) are more underweight and have worse pulmonary function than those without diabetes (5). Clinical decline may be directly related to the diabetic state and to insulin deficiency. Insulin therapy has been found to reverse negative changes in weight and lung function in CFRD, suggesting a cause-and-effect relationship between insulin deficiency and CF clinical deterioration (6,7). More substantial evidence for this relationship is provided by the observation that both the severity of glucose intolerance and the degree of insulin deficiency in an individual with CF correlate with future decline in pulmonary function (8). Weight loss and more severe pulmonary disease in CF are associated with protein catabolism (9,10), and protein catabolism may be related to the degree of glucose intolerance (11). We have hypothesized that insulin deficiency in CF leads to protein catabolism, thereby negatively influencing weight, pulmonary function, and ultimately, survival (12). Therefore, it is important to determine how to most effectively treat CFRD.

Current recommendations for the management of CFRD are based on clinical experience rather than experimental evidence because so few data exist in the literature. In particular, there is considerable controversy regarding the treatment of CFRD without fasting hyperglycemia (13). In the current study, we evaluated the acute plasma insulin and glucose responses to premeal injection of insulin lispro or to oral administration of repaglinide in adult patients with CF and diabetes without fasting hyperglycemia.

Subjects

Seven patients with CF and a routine oral glucose tolerance test in the previous 3 months who demonstrated CFRD without fasting hyperglycemia were recruited into the study. Patients were excluded who had a history of CF liver disease or who had experienced acute illness or undergone oral or intravenous glucocorticoid therapy during the previous 3 months. Because the study subjects with CF were chronically infected with CF pathogens, they all received chronic suppressive aerosolized antibiotic preparations. Seven healthy, nonathlete, age-, sex- and BMI-matched normal control subjects were recruited by poster advertisement. Approval for this study was obtained from the University of Minnesota Committee for the Use of Human Subjects in Research; informed consent was obtained from all subjects.

Study design

Subjects with CF were studied at the University of Minnesota General Clinical Research Center on three separate occasions during a 1- to 2-month period. They were admitted in the evening and not allowed to eat or drink after 10:00 p.m. An indwelling catheter was inserted retrogradely into a dorsal hand vein for blood sampling, and the hand was placed on a heating pad during the studies.

On each occasion, subjects were fed a 1,000-kcal liquid mixed meal at 7:00 a.m. The meal was consumed within 30 min. The mixed meal, prepared by the University of Minnesota General Clinical Research Center dietary staff, had a milkshake-like consistency and a macronutrient composition of 47% carbohydrate, 17% protein, and 36% fat. Although the percentage of calories derived from fat was somewhat less than that recommended for individuals with CF (40%), the calorie content and macronutrient composition are typical of meals recorded by patients with CF at the University of Minnesota during routine diet histories (unpublished data). Patients with CF took their usual dose of digestive enzymes before consuming this meal; all other morning medications and treatments were held until after the study day was complete. On each day, one of three study conditions was administered in random order: 1) no premeal diabetes medication (baseline meal); 2) insulin lispro, 0.1 unit/kg body wt, subcutaneous injection in the posterior upper arm using a short (3/8-inch) needle syringe, 10 min premeal; and 3) repaglinide 1 mg orally, 10 min premeal.

Typical clinical practice for initiating insulin therapy in clinically stable patients with CFRD involves giving a premeal insulin dose of 0.1 unit insulin per kg body wt or giving 0.5 unit insulin per 15 g carbohydrate (14). The current protocol, based on weight, resulted in insulin doses of 5–7 units. If the dose had been calculated based on carbohydrate counting, each patient would have received 4 units.

Control subjects received the 1,000-kcal test meal under the same conditions on a single occasion with no premeal medication. Plasma insulin and glucose levels were measured at 20-min intervals for 5 h. For reporting purposes, time 0 is considered the beginning of the meal (10 min after medications were given).

Analytical methods

Plasma glucose was measured immediately with a Beckman Glucose Analyzer II (Beckman Instruments, Fullerton, CA). Insulin samples were collected on ice and centrifuged within 20 min. Insulin levels were determined by radioimmunoassay using a double-antibody method.

Statistical analysis

Baseline data are reported as mean ± SD (Table 1); all other data are presented as mean ± SEM. Data were analyzed for different responses to the study conditions by two-way analysis of variance. An α value of 0.05 was used as the cutoff for statistical significance. The SAS statistical software package (SAS Institute, Cary, NC) was used for the statistical analysis. Based on data from previous studies (1), we estimated that with a sample of seven patients studied per condition, we would have a >80% chance of detecting significant differences in the glucose excursion values at the chosen α value for significance.

Subjects

Characteristics of the subjects with CFRD are presented in Table 1. None of the patients with CF had signs or symptoms of acute illness in the 3 months preceding the study. All of them were engaged in relatively normal life styles and were either college students or employed at least part-time. Controls were matched for age, sex, and BMI.

Response to the baseline meal without medication

Fasting insulin and glucose levels were normal in patients with CFRD (Table 1). Postprandial glucose excursion was considerably elevated in the patients with CF, with a peak glucose level of 228 ± 30 mg/dl (12.7 ± 1.7 mmol/l) (Fig. 1). As previously reported for patients with CF (2), the peak insulin levels were markedly delayed and blunted (Fig. 1).

Response to insulin lispro

In response to premeal insulin lispro, patients with CF experienced a reduction in glucose excursion (Table 2). Compared with the untreated baseline meal, improvements were seen in the peak glucose level (P = 0.0004), the 2-h glucose area under the curve (AUC) (P = 0.001), and the 5-h glucose AUC (P < 0.0001). Despite these improvements, glucose excursion was still abnormally elevated in CF (Fig. 1).

Premeal insulin lispro significantly enhanced the insulin AUC for the 5-h study period (65% increase, P = 0.04) (Table 2). Although there was a trend for an increase in the insulin AUC during the first 2 h, this did not achieve statistical significance (64% increase, P = 0.10). The peak insulin level was not significantly different from that seen during the baseline meal (P = 0.37).

Response to repaglinide

In response to premeal oral repaglinide, glucose excursion was somewhat improved in CFRD (Table 2). The 5-h glucose AUC was significantly less than baseline (P = 0.03). No significant differences were seen in the 2-h glucose AUC (P = 0.39) or the peak glucose level (P = 0.17).

After administration of 1 mg repaglinide, insulin levels seemed to rise (Fig. 1), although there was no significant change compared with the baseline meal in the peak insulin level, the 2-h insulin AUC, or the 5-h insulin AUC (all P > 0.20).

Comparison of insulin lispro and repaglinide in CFRD

Insulin lispro seemed to have a more beneficial effect than repaglinide on postprandial glucose excursion in CFRD. Significant differences were seen between the two drugs in the peak glucose level (P = 0.02), the 2-h glucose AUC (P = 0.02), and the 5-h glucose AUC (P = 0.01). However, we cannot exclude the possibility that higher doses of repaglinide might have resulted in greater improvements.

Insulin lispro significantly increased the 5-h insulin AUC in CF (P = 0.04). Neither drug, at the doses used in the present study, significantly changed the peak insulin level or the 2-h insulin AUC compared with baseline.

Adverse events

Four episodes of hypoglycemia (glucose level 48–54 mg/dl, 2.7–3.0 mmol/l) occurred in patients with CF during this study: one after the test meal without medication, two after administration of insulin lispro, and one after administration of repaglinide. In all cases, catecholamine-related symptoms were present but were easily tolerated, and patients were alert, oriented, and aware that they were hypoglycemic. Hypoglycemia occurred an average of ∼4 h after the test meal and resolved spontaneously without glucose administration after 10–15 min.

In patients with CFRD who are not acutely ill, basal insulin needs are fairly low and hyperglycemia is predominantly associated with meal carbohydrate consumption (14). Premeal insulin, given to control postprandial glucose excursion, has become the cornerstone of diabetes management in this population. Until a few years ago, regular insulin was the only short-acting insulin available for premeal therapy. Anecdotally, we found that it frequently caused hypoglycemia several hours after administration in patients with CF. This was not surprising, because it is known that insulin levels may be elevated for 4–6 h after regular insulin injection, even if blood glucose has returned to a fasting level. Insulin lispro was approved for clinical use in the U.S. in 1996. It has more rapid absorption, faster onset, and shorter duration of action than regular human insulin, although its potency is equivalent to that of regular insulin and the systemic clearance rates of both types of insulin are similar. In several studies of patients with type 1 and type 2 diabetes, use of insulin lispro as the premeal insulin led to significantly less hypoglycemia than use of premeal regular human insulin. Because of this and based on clinical experience, insulin lispro has been recommended for premeal insulin coverage in CFRD (14).

The present study was performed to objectively characterize the acute glucose and insulin responses to insulin lispro and the oral agent repaglinide in the CFRD population. Glucose and insulin excursion were significantly improved with administration of insulin lispro, and a greater effect would likely have been seen with a larger dose. Insulin absorption seemed to be delayed, because peak insulin levels after injection of insulin lispro are reported to occur at 41–61 min in individuals with type 1 diabetes (15,16) and in normal control subjects (17), whereas the peak insulin level in patients with CF in the present study occurred at 94 ± 17 min. The factors controlling insulin absorption are complex. There are many abnormalities in CF that might alter insulin absorption kinetics, including interstitial fluid pH and electrolyte composition, structural changes in CF adipose tissue, vascular changes brought about by chronic hypoxia, or increased insulin degradation in the setting of chronic inflammation. Further studies are needed to clarify the question of whether insulin absorption is delayed in CF.

The use of oral agents to treat CFRD remains controversial, and a national consensus conference on CFRD recommended that, until further data are available, these drugs should only be considered within the context of controlled research trials (13). The literature consists primarily of abstracts and uncontrolled studies with small subject numbers (18,19,20,21). There are potential problems with most of the existing oral diabetes agents approved by the Food and Drug Administration. Because the primary problem in CF is insulin deficiency, drugs that improve insulin sensitivity are not likely to be of major benefit. Metformin is contraindicated in patients with hypoxia because of the risk of fatal lactic acidosis, and it has multiple gastrointestinal side effects that may negatively influence the nutritional status of patients with CF. The potential for serious hepatic toxicity with thiazolidinediones may be greater in CF than in the general population because underlying liver damage is common. Drugs that reduce postprandial glucose excursion by limiting intestinal absorption of glucose cannot be recommended to patients who suffer from chronic malabsorption and undernutrition.

Sulfonylureas have been the most commonly used oral agents in CF. Glyburide, however, is not recommended, because 50% of its elimination is in the bile. In the few studies that measured the effect of sulfonylureas on insulin secretion in CF, minimal improvement, if any, was found (19,20,21,22). There are theoretical concerns that these agents may impair the effectiveness of new drugs designed to target the basic defect in CF by improving function of the CF transmembrane conductance regulator, because sulfonylureas bind to and inhibit the CF transmembrane conductance regulator (23). The main practical concern with sulfonylureas has been hypoglycemia, which has anecdotally been found to be a common side effect in CF, even with minimal drug doses, limiting the ability to achieve therapeutic doses.

Of the currently available oral agents, repaglinide and related agents seem to hold the greatest promise in CF. Repaglinide lowers blood glucose levels by stimulating insulin secretion, but in contrast to sulfonylureas, insulin release is glucose-dependent and diminishes at low glucose concentrations (repaglinide product insert; Novo Nordisk Pharmaceuticals, Princeton, NJ). This, combined with its short half-life (1 h), promotes improvement of meal-stimulated insulin secretion while minimizing the chance of between-meal or nocturnal hypoglycemia. Theoretically, this profile of action is ideal for the patient with CFRD without fasting hyperglycemia.

Clearly, the quality of life and the complexity of the medical regimen for patients with CFRD would be improved if multiple daily injections could be replaced by an oral agent. Our data on the acute effects of repaglinide suggest that this drug may have therapeutic potential in CFRD. Improvements in glucose excursion and plasma insulin levels were modest compared with the response to insulin lispro. However, higher doses of repaglinide might have resulted in a greater effect. The manufacturer recommends a starting dose of 0.5 mg for patients whose HbA1c is <8.0 (which would include most patients with CFRD), but doses up to 4 mg can be prescribed. It is well established that patients with CF, who have decreased β-cell mass and lack a first-phase insulin response, have delayed insulin secretion (2). Because repaglinide acts by stimulating endogenous insulin secretion, it is not surprising that the insulin response to this oral agent followed the same delayed pattern as the natural response to the baseline meal.

Glycemic control is not the only concern with diabetes treatment in CF. Maintenance of normal body weight is critical for survival in CF. Although the long-term effect of repaglinide on blood glucose metabolic control is an important consideration, the question of whether repaglinide treatment is able to match the anabolic effect of insulin therapy on weight gain in CFRD may ultimately be far more significant.

In summary, the current study demonstrates the effectiveness of insulin lispro in acutely improving postprandial glucose and insulin levels. The oral agent repaglinide resulted in lesser improvements in these parameters. The doses of insulin and repaglinide, although based on standard practice recommendations, seemed to be too low; therefore, higher doses of these drugs may have had greater therapeutic effect. At present, based on clinical experience, rapid-acting insulin remains the standard premeal diabetes treatment for patients with CFRD. Placebo-controlled longitudinal studies comparing the effectiveness of repaglinide and insulin on not only glucose metabolic control but also on overall nutrition and body weight are needed to help determine the optimal medical treatment of CFRD.

Figure 1—

Mean plasma insulin (A) and glucose (B) levels in patients with CFRD in response to the baseline test meal with no medication and in response to either subcutaneous 0.1 unit/kg insulin lispro or 1 mg oral repaglinide, given 10 min before the mixed meal began at time 0. Control patients were studied in response to a baseline meal only, with no medication.

Figure 1—

Mean plasma insulin (A) and glucose (B) levels in patients with CFRD in response to the baseline test meal with no medication and in response to either subcutaneous 0.1 unit/kg insulin lispro or 1 mg oral repaglinide, given 10 min before the mixed meal began at time 0. Control patients were studied in response to a baseline meal only, with no medication.

Close modal
Table 1—

Characteristics of patients with CFRD without fasting hyperglycemia

CFRD
n  7 
Age, years  24 ± 5 
Sex, F/M  4/3 
Height, inches  64 ± 3 
Weight, kg  55 ± 7 
BMI, kg/m2  21 ± 1 
Fasting plasma glucose, mg/dl (mmol/l) 98 ± 18, 5.4 ± 1.0 
Fasting insulin, μU/ml (pmol/l) 5 ± 1, 30 ± 6 
HbA1c, % 5.6 ± 0.9 (range 3.9–6.6) 
CFRD
n  7 
Age, years  24 ± 5 
Sex, F/M  4/3 
Height, inches  64 ± 3 
Weight, kg  55 ± 7 
BMI, kg/m2  21 ± 1 
Fasting plasma glucose, mg/dl (mmol/l) 98 ± 18, 5.4 ± 1.0 
Fasting insulin, μU/ml (pmol/l) 5 ± 1, 30 ± 6 
HbA1c, % 5.6 ± 0.9 (range 3.9–6.6) 

Data are n, means ± SD, and means ± SD (range).

Table 2—

Plasma glucose and insulin responses in CFRD to a baseline 1,000-kcal liquid test meal and when either 0.1 unit/kg body wt insulin lispro or 1 mg repaglinide were given 10 min before the meal

Baseline meal (no medication)Insulin lispro (0.1 unit/kg)Repaglinide (1 mg)
Glucose, mg/dl (mmol/l)    
 Time to peak level (min) 74 ± 7 66 ± 8 60 ± 7 
 Peak level 228 ± 30 172 ± 9* 208 ± 18 
 (12.7 ± 1.7) (9.6 ± 0.5) (11.6 ± 1.0) 
 2-h AUC 19,574 ± 1,162 14,980 ± 1,056* 18,247 ± 1,559 
 (1,087 ± 65) (832 ± 59) (1,014 ± 87) 
 5-h AUC 40,190 ± 2,121 29,859 ± 1,653* 35,212 ± 2,067* 
 (2,233 ± 118) (1,658 ± 92) (1,956 ± 115) 
Insulin, μU/ml (pmol/l)    
 Time to peak level (min) 117 ± 11 94 ± 17 107 ± 13 
 Peak level 53 ± 11 75 ± 9 70 ± 11 
 (318 ± 66) (450 ± 64) (420 ± 66) 
 2-h AUC 3,050 ± 709 5,006 ± 676 4,298 ± 716 
 (18,300 ± 4,254) (30,036 ± 4,056) (25,788 ± 4,296) 
 5-h AUC 6,446 ± 1,082 10,643 ± 1,753* 8,948 ± 1,162 
 (38,676 ± 6,492) (63,858 ± 10,518) (53,688 ± 6,972) 
Baseline meal (no medication)Insulin lispro (0.1 unit/kg)Repaglinide (1 mg)
Glucose, mg/dl (mmol/l)    
 Time to peak level (min) 74 ± 7 66 ± 8 60 ± 7 
 Peak level 228 ± 30 172 ± 9* 208 ± 18 
 (12.7 ± 1.7) (9.6 ± 0.5) (11.6 ± 1.0) 
 2-h AUC 19,574 ± 1,162 14,980 ± 1,056* 18,247 ± 1,559 
 (1,087 ± 65) (832 ± 59) (1,014 ± 87) 
 5-h AUC 40,190 ± 2,121 29,859 ± 1,653* 35,212 ± 2,067* 
 (2,233 ± 118) (1,658 ± 92) (1,956 ± 115) 
Insulin, μU/ml (pmol/l)    
 Time to peak level (min) 117 ± 11 94 ± 17 107 ± 13 
 Peak level 53 ± 11 75 ± 9 70 ± 11 
 (318 ± 66) (450 ± 64) (420 ± 66) 
 2-h AUC 3,050 ± 709 5,006 ± 676 4,298 ± 716 
 (18,300 ± 4,254) (30,036 ± 4,056) (25,788 ± 4,296) 
 5-h AUC 6,446 ± 1,082 10,643 ± 1,753* 8,948 ± 1,162 
 (38,676 ± 6,492) (63,858 ± 10,518) (53,688 ± 6,972) 

Data are expressed as means ± SEM.

*

P < 0.05 compared with baseline meal;

P < 0.05 insulin versus repaglinide. Time 0 is considered the beginning of the meal, 10 min after administration of medication.

This work was supported by grants from the Cystic Fibrosis Foundation, the National Institutes of Health (grant M01-RR-00400, General Clinical Research Center), and the Minnesota Medical Foundation.

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Address correspondence and reprint requests to Antoinette Moran, MD, Department of Pediatrics, MMC 404, University of Minnesota, 516 Delaware St., Minneapolis, MN 55455. E-mail: moran001@tc.umn.edu.

Received for publication 6 April 2001 and accepted in revised form 22 June 2001.

Antoinette Moran has received a research grant from Novo Nordisk Pharmaceuticals to test repaglinide and Novolog insulin in cystic fibrosis.

A table elsewhere in this issue shows conventional and Système International (SI) units and conversion factors for many substances.