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Division of Endocrinology, Metabolism, and Lipid Research and the General Clinical Research Center and the Diabetes Research and Training Center, Washington University School of Medicine, St. Louis, Missouri 63110
Address all correspondence and requests for reprints to: Philip E. Cryer, M.D., Campus Box 8127, Washington University School of Medicine, 660 South Euclid Avenue, St. Louis, Missouri 63110. E-mail: pcryer{at}wustl.edu.
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Abstract |
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Research Design and Methods: Plasma glucose concentrations were measured every 15 min from 2200 h through 0700 h in 21 patients with type 1 diabetes (mean ± SD HbA1C = 7.1 ± 1.0%) on five occasions with, in random sequence, bedtime (2200 h) administration of 1) no treatment, 2) a snack, 3) the snack plus the 
-glucosidase inhibitor acarbose, 4) an uncooked cornstarch bar, or 5) the ß2-adrenergic agonist terbutaline.
Results: In the absence of a bedtime treatment, 27% of the measured nocturnal plasma glucose concentrations were less than 70 mg/dl (3.9 mmol/liter) in 12 patients; 16, 6, and 1% were less than 60, less than 50, and less than 40 mg/dl (3.3, 2.8, and 2.2 mmol/liter), respectively. Neither the snack (without or with acarbose) nor cornstarch raised the mean nadir nocturnal glucose concentration or reduced the number of low glucose levels or the number of patients with low levels. Terbutaline raised the mean nadir nocturnal glucose concentration (mean ± SE, 127 ± 11 vs. 75 ± 9 mg/dl; P < 0.001), eliminated glucose levels less than 50 mg/dl (P = 0.038), reduced levels less than 60 mg/dl (P = 0.005) to one, and reduced levels less than 70 mg/dl (P = 0.001) to five (four at 2215 h, one at 2230 h). However, it also raised glucose levels the following morning.
Conclusions: Nocturnal hypoglycemia is common in aggressively treated type 1 diabetes. Bedtime administration of a conventional snack or of uncooked cornstarch does not prevent it. That of terbutaline prevents nocturnal hypoglycemia but causes hyperglycemia the following morning. The efficacy of a lower dose of terbutaline remains to be determined.
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Introduction |
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Iatrogenic hypoglycemia often occurs at night, specifically during sleep, in type 1 diabetes (3). That is typically the longest interprandial interval and time between self-monitoring of blood glucose. It also includes the time of maximum sensitivity to insulin (4). In addition, sympathoadrenal responses to hypoglycemia are reduced further during sleep (5, 6), and, probably because of their markedly reduced sympathoadrenal responses, patients with type 1 diabetes are substantially less likely to be awakened by hypoglycemia than nondiabetic individuals (6).
Therapeutic approaches to the prevention of nocturnal hypoglycemia in type 1 diabetes include the use of insulin analogs during the day in multiple daily injection (MDI) regimens (7), continuous sc insulin infusion (CSII) regimens (8, 9, 10, 11), and a variety of bedtime treatments. Among the latter, bedtime snacks are the time-honored approach. However, there is evidence that a bedtime snack exerts an inconsistent effect and does so only in the first half of the night (12). Protein snacks have been thought to be more effective (13), but treatment of hypoglycemia with bread plus meat compared with bread alone was not found to provide prolonged protection against hypoglycemia (14).
Measures intended to produce more sustained exogenous glucose delivery overnight than snacks include bedtime administration of the slowly digested complex carbohydrate uncooked cornstarch (13, 15, 16, 17, 18, 19) and administration of an -glucosidase inhibitor to delay digestion of carbohydrates in the evening meal (20, 21). Bedtime administration of uncooked cornstarch is used to treat hypoglycemia in patients with glucose-6-phosphatase deficiency. However, the doses used to treat such patients (1.75–2.5 g/kg maintained plasma glucose levels for about 6 h, 1.0 g/kg for less than 4 h) (22, 23, 24) are much higher than those of 0.1–0.3 g/kg typically used to attempt to prevent nocturnal hypoglycemia in type 1 diabetes (13, 15, 16, 17, 18, 19).
Measures intended to produce sustained endogenous glucose production overnight include bedtime administration of the glucagon-stimulating amino acid alanine and the epinephrine-simulating ß2-adrenergic agonist terbutaline (12, 25, 26). These approaches were conceptualized on the basis of the pathophysiology of glucose counterregulation in type 1 diabetes, absent glucagon and attenuated epinephrine responses to hypoglycemia (1). In patients receiving neutral protamine Hagedorn (NPH) insulin at bedtime, both bedtime alanine and bedtime terbutaline were shown to more effectively prevent nocturnal hypoglycemia than a conventional bedtime snack (12).
Based on this background, we assessed the efficacy of four putative bedtime (2200 h) treatments, a conventional bedtime snack, that snack plus the -glucosidase inhibitor acarbose, cornstarch, or terbutaline, compared with no bedtime treatment in the prevention of nocturnal hypoglycemia in patients with type 1 diabetes who were maintaining glycemic control that approximated the American Diabetes Association recommended goal with contemporary insulin regimens (CSII or MDI with insulin analogs). We anticipated that plasma glucose measurements every 15 min from 2200 to 0700 h would disclose a high frequency of hypoglycemia in the absence of a bedtime treatment in such patients and therefore permit a critical assessment of each of the four treatments.
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Subjects and Methods |
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Twenty-one patients with type 1 diabetes mellitus gave their written informed consent to participate in this study, which was approved by the Washington University Medical Center Human Studies Committee and conducted at the Washington University General Clinical Research Center (GCRC). Ten were women, and 11 were men. Their mean (± SD) age was 26 ± 10 yr, duration of diabetes 15 ± 10 yr, body mass 26 ± 5 kg/m2, and HbA1C 7.1 ± 1.0%. Eleven were using a CSII regimen and 10 a MDI insulin regimen. Among the latter, eight were using insulin glargine (Lantus; Aventis Pharmaceuticals Inc., Kansas City, MO) as the basal insulin and insulin lispro (Humalog; Eli Lilly and Co., Indianapolis, IN) as the preprandial insulin, one was using both insulin glargine and NPH insulin as basal insulins and insulin aspart (Novolog; Novo Nordisk A/S, Bagsvaerd, Denmark) as the preprandial insulin, and one was using NPH insulin as the basal insulin and insulin lispro as the preprandial insulin. The mean (±SD) insulin dose was 0.7 ± 0.2 U/kg. The patients were selected for a stable HbA1C of no more than 8.0%. The mean (±SE) HbA1C was 6.8 ± 0.1% in those using CSII and 7.3 ± 0.2% in those using MDI (P = 0.043). The mean (±SD) fasting plasma C-peptide concentration was 0.3 ± 0.2 ng/ml (0.1 ± 0.1 nmol/liter). Exclusion criteria included untreated proliferative retinopathy, nephropathy with a serum creatinine concentration greater than 1.5 mg/dl, or autonomic neuropathy (abnormal heart rate variation or postural hypotension); known coronary, cerebral, or peripheral vascular disease; known central nervous system disease including a history of seizures or vascular headaches; a history of cardiac arrhythmias; and use of a potentially interfering medication (e.g. a ß-adrenergic antagonist). None of the patients suffered an episode of severe hypoglycemia in the days before study. None had gastrointestinal symptoms suggestive of malabsorption. They were asked to avoid strenuous exercise on the days before overnight sampling.
Experimental design
The patients pursued their usual activities and used their individual treatment regimens with guidance from their individual physicians throughout the study. These regimens, including insulin dosing, were not altered by the study physicians. The patients were admitted to the GCRC overnight on five occasions. They were admitted early in the evening and discharged shortly after 0700 h the following morning because the intent was to make the study nights as representative of their daily lives as possible. They were confined to bed, and an iv line for blood sampling (and for iv injection of glucose if necessary) was inserted before 2100 h. Blood samples, for plasma glucose measurements, were drawn at 15-min intervals from 2100 h through 0700 h. Any symptoms volunteered were recorded. Plasma glucose concentrations less than 40 mg/dl (2.2 mmol/liter), whether symptomatic or not, were treated with small doses of glucose (e.g. 5.0 g) iv as a safety feature. Arterialized venous blood samples, for measurements of hormone and substrate concentrations (see below), were obtained only at 2200 and 0700 h. Heart rates and blood pressures were recorded at those times. In addition to plasma measurements, sc glucose levels were monitored with the continuous glucose monitoring system (CGMS) (model no. MMT-7002; Medtronic MiniMed, Northridge, CA). A sensor was inserted and initialized for 1 h and calibrated with two measured plasma glucose concentrations early in the evening (and again just before 0700 h the following morning). Sensors that malfunctioned at the time of initial calibration were replaced immediately. Sensors were recalibrated every time there was an alarm. CGMS data corresponding temporally with plasma glucose concentrations were analyzed subsequently using software version 3.0 B.
One of five bedtime treatments was administered, in random sequence, at 2200 h. These included 1) none; 2) a conventional bedtime snack (200 kcal; 26 g carbohydrate, 6 g fat, and 11 g protein); 3) the same snack plus the -glucosidase inhibitor acarbose (Precose; Bayer Pharmaceuticals Corp., West Haven, CT), 100 mg orally; 4) one and one-quarter commercial uncooked cornstarch-containing bar (Extend Bar; Clinical Products Ltd., Indianapolis, IN) [194 kcal; 39 g carbohydrate (6.25 g cornstarch), 4 g fat, and 4 g protein); and 5) the ß2-adrenergic agonist terbutaline (Brethine; Novartis Pharmaceuticals Corp., East Hanover, NJ), 5.0 mg orally.
Analytical methods
Plasma glucose concentrations were measured with a glucose oxidase method (YSI glucose analyzer; Yellow Springs Instruments Corp., Yellow Springs, OH) at the bedside. Plasma insulin, C-peptide, glucagon, pancreatic polypeptide, cortisol, and GH were measured with RIAs; plasma epinephrine and norepinephrine with a single isotope derivative (radioenzymatic) method; and serum nonesterified fatty acids and blood ß-hydroxybutyrate and lactate concentrations with enzymatic techniques as described elsewhere (e.g. Ref. 6).
Statistical methods
In this manuscript, the data are expressed as the mean and the SE except where the SD is specified. Time- and condition-related data were analyzed by mixed-model repeated-measures ANOVA. Specific contrasts were assessed with a t test. The primary outcome variable was the nadir plasma glucose concentration during overnight sampling. Linear regression analysis was used to test relationships between nadir nocturnal and 0700-h plasma glucose concentrations. P values of <0.050 were considered to indicate statistically significant differences.
CGMS data analysis
Plasma glucose and the temporally corresponding sc glucose (CGMS) values less than 70 mg/dl (3.9 mmol/liter) were analyzed to assess the accuracy of the CGMS sensor values. For each plasma and sensor glucose pair, the mean absolute difference (plasma glucose minus sensor glucose divided by plasma glucose, expressed as a percentage) was calculated, and the accuracy criteria recommended by the manufacturer (mean absolute difference, 
28 or 18% if the range of plasma glucose values was less than 100 mg/dl) was applied. CGMS sensor values that met this criterion were considered accurate; those that did not were considered inaccurate.
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Results |
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and 2)
In the absence of a bedtime (2200 h) treatment, mean plasma glucose concentrations declined from 126 ± 11 mg/dl (7.0 ± 0.6 mmol/liter) to 99 ± 12 mg/dl (5.5 ± 0.7 mmol/liter) at 0230 h, stabilized, rose slightly to a peak of 116 ± 14 mg/dl (6.4 ± 0.8 mmol/liter) at 0545 h, and were 106 ± 14 mg/dl (5.9 ± 0.8 mmol/liter) at 0700 h. After the bedtime snack, overall mean nocturnal (2200–0700 h) plasma glucose concentrations were significantly (P = 0.035) higher than after no bedtime treatment, an effect that was negated by administration of the -glucosidase inhibitor acarbose with the snack (Fig. 1). After the bedtime cornstarch-containing bar, overall mean nocturnal plasma glucose concentrations appeared to be higher (P = 0.086) than after no bedtime treatment (Fig. 2). After bedtime terbutaline, mean nocturnal plasma glucose concentrations were significantly (P < 0.001) higher than after no bedtime treatment (Fig. 2). Only bedtime terbutaline raised plasma glucose concentrations during the second half of the night (0245 h through 0700 h) significantly (P < 0.001) (data not shown). Mean morning (0700 h) plasma glucose concentrations after the bedtime snacks and the bedtime cornstarch bar were not different from those after no bedtime treatment but were significantly (P < 0.001) higher after bedtime terbutaline [193 ± 15 mg/dl (10.7 ± 0.8 mmol/liter) compared with 141 ± 12 mg/dl (7.8 ± 0.7 mmol/liter) at 2200 h the previous evening] (Fig. 3).
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Mean pretreatment bedtime (2200 h) plasma glucose concentrations were similar on all five study nights. The mean nadir nocturnal (2200–0700 h) plasma glucose concentration was 75 ± 9 mg/dl (4.2 ± 0.5 mmol/liter) after no bedtime treatment [73 ± 11 mg/dl (4.0 ± 0.6 mmol/liter) in those using CSII and 77 ± 16 mg/dl (4.3 ± 0.9 mmol/liter) in those using MDI; P = 0.842] and was not significantly different after the bedtime snack (without or with acarbose) or after the bedtime cornstarch bar but was significantly (P < 0.001) higher, at 127 ± 11 mg/dl (7.0 ± 0.6 mmol/liter), after bedtime terbutaline (Fig. 3). Nadir nocturnal and morning (0700 h) plasma glucose concentrations were directly related (r = 0.725; P < 0.001).
Low plasma glucose concentrations (Table 1 and Fig. 4)
In the absence of a bedtime treatment, 207 (27%) of the 756 plasma glucose concentrations measured from 2200 h through 0700 h were less than 70 mg/dl (3.9 mmol/liter), and plasma glucose levels less than 70 mg/dl (3.9 mmol/liter) were detected in 12 (57%) of the patients (Table 1); 127 (17%) of the measured plasma glucose concentrations, in nine (43%) of the patients, were less than 60 mg/dl (3.3 mmol/liter) (Table 1); 48 (6%) of the values, in seven (33%) of the patients, were less than 50 mg/dl (2.8 mmol/liter) (Table 1); and eight (1%) of the values, in three (14%) of the patients, were less than 40 mg/dl (2.2 mmol/liter) (Table 1).
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). In contrast, bedtime terbutaline eliminated plasma concentrations less than 50 mg/dl (2.8 mmol/liter) (P = 0.038), reduced the number of plasma glucose levels less than 60 mg/dl (3.3 mmol/liter) (P = 0.005) to one measured value [56 mg/dl (3.1 mmol/liter) at 2215 h], and reduced the number of plasma glucose levels less than 70 mg/dl (3.9 mmol/liter) (P = 0.001) to five, less than 1% of the measured values (Table 1). Indeed, among the four patients with plasma glucose levels less than 70 mg/dl (3.9 mmol/liter), three had only one such value [66, 69, and 65 mg/dl (3.7, 3.8, and 3.6 mmol/liter), respectively, at 2215 h] and the other had only two such values [56 mg/dl (3.1 mmol/liter) at 2215 h and 64 mg/dl (3.6 mmol/liter) at 2230 h].
The times of measured plasma glucose concentrations less than 70 mg/dl (3.9 mmol/liter) are shown in Fig. 4. In the vast majority of instances, plasma glucose levels less than 70 mg/dl (3.9 mmol/liter) were not isolated events; prolonged episodes were the rule. In the absence of a bedtime treatment, there was no difference in the duration of plasma glucose levels less than 70 mg/dl (3.9 mmol/liter) between patients using CSII and those using MDI (P = 0.924). It appears that the bedtime snack (without acarbose) and the bedtime cornstarch bar shifted low plasma glucose levels to later in the night. The absence of low plasma glucose concentrations after 2230 h after bedtime terbutaline (at 2200 h) is noticeable.
Plasma glucose concentrations less than 40 mg/dl (2.2 mmol/liter) were treated with iv glucose (5 g x 3, 5 g x 1, and 5 g x 5) in three patients after no bedtime treatment. (Neither of the two patients using NPH as a basal insulin had glucose levels <40 mg/dl in that limb.) They were treated (5 g, 5 g x 4, and 5 g x 2) in three patients after the bedtime snack, treated (5 g x 3, 10 g, and 5 g x 3) in three patients (including the one using both glargine and NPH as basal insulins) after the bedtime snack plus acarbose, and treated (5 g, 2.5 g, and 5 g) in three patients after the bedtime cornstarch bar. There were no plasma glucose levels less than 40 mg/dl (2.2 mmol/liter) [or <50 mg/dl (2.8 mmol/liter)] after bedtime terbutaline. Only nine (35% of the 26) episodes with a plasma glucose concentration less than 40 mg/dl (2.2 mmol/liter) were symptomatic.
Heart rate and blood pressure and hormone and substrate concentrations
Mean heart rates (79 ± 2 vs. 71 ± 2 beats per minute; P = 0.003) and blood lactate concentrations (1440 ± 230 vs. 740 ± 80 µmol/liter; P = 0.016) were higher at 0700 h after bedtime terbutaline. Systolic and diastolic blood pressures and plasma epinephrine, norepinephrine, insulin, glucagon, pancreatic polypeptide, and cortisol concentrations were unaltered (data not shown); GH levels were reduced slightly (0.8 ± 0.1 vs. 3.8 ± 1.9 ng/ml; P = 0.030). Serum nonesterified fatty acid and blood ß-hydroxybutyrate levels were also unaltered. None of these was altered after the other bedtime treatments (data not shown).
CGMS values
Over the five study nights, 721 of the 3776 measured plasma glucose concentrations (19%) were less than 70 mg/dl (3.9 mmol/liter). The corresponding CGMS value was less than 70 mg/dl (3.9 mmol/liter) in 584 instances and at least 70 mg/dl (3.9 mmol/liter) in 137 instances. Thus, the unadjusted CGMS false-negative rate was 19% (137 of 721). Of the 137 CGMS false negatives, the accuracy criteria recommended by the manufacturer, based on paired plasma glucose and CGMS values, were met for 44 and not met for 85 (there were eight missing corresponding CGMS data points). Assuming those criteria would have been met for the remaining eight and that those meeting the criteria were close enough clinically, the adjusted CGMS false-negative rate was 12% (85 of 721). Over the five study nights, there were 588 CGMS values less than 70 mg/dl (3.9 mmol/liter) when the measured plasma concentrations were at least 70 mg/dl (3.9 mmol/liter). Thus, the unadjusted CGMS false- positive rate was 16% (588 of 3718 CGMS measurements). Of the 588 CGMS false positives, the accuracy criteria were met for 57 and not met for 531. Again assuming the former were close enough clinically, the adjusted CGMS false-positive rate was 14% (531 of 3718).
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Discussion |
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Among the putative bedtime treatments tested, a conventional snack (without or with acarbose) and an uncooked cornstarch-containing bar were ineffective in the prevention of nocturnal hypoglycemia. Compared with no bedtime treatment, none raised the mean nadir nocturnal (2200 h through 0700 h) plasma glucose concentration and none reduced the number of glucose levels less than 70, less than 60, less than 50, or less than 40 mg/dl (3.9, 3.3, 2.8, and 2.2 mmol/liter) or the number of patients with those low values. The snack alone and the cornstarch bar appeared to delay low glucose levels until later in the night. We anticipated that administration of the -glucosidase inhibitor acarbose with the snack at 2200 h might delay digestion of the carbohydrates in the snack and result in increased glucose absorption later during the night when the impact of the snack alone would have waned. Clearly, the latter did not happen. In the earlier studies reporting an effect of -glucosidase inhibitors, the inhibitor was administered with the previous evening meal (20, 21).
Compared with no bedtime treatment, bedtime terbutaline raised the mean nocturnal nadir plasma glucose concentration (by 72%). It eliminated nocturnal glucose levels less than 50 mg/dl (2.8 mmol/liter), reduced nocturnal glucose levels less than 60 mg/dl (3.3 mmol/liter) to a single measurement (at 2215 h), and reduced nocturnal glucose levels less than 70 mg/dl (3.9 mmol/liter) from 27% to less than 1% of the measured values. There were only five measurements less than 70 mg/dl (3.9 mmol/liter), three in three different patients at 2215 h and two in a fourth patient at 2215 and 2230 h, i.e. within 15–30 min of terbutaline administration. Thus, for practical purposes, bedtime terbutaline prevented nocturnal hypoglycemia in these patients with aggressively treated, seemingly well-controlled type 1 diabetes.
However, bedtime terbutaline had undesirable effects. It raised plasma glucose concentrations the following morning. Although morning (0700 h) glucose levels were no higher than bedtime (2200 h) levels under the other four study conditions, morning glucose levels were 37% higher after bedtime terbutaline. It also raised heart rates by 11% and blood lactate concentrations approximately 2-fold the following morning (12). (Systolic and diastolic blood pressures and plasma epinephrine, norepinephrine, insulin, glucagon, pancreatic polypeptide, cortisol, and GH concentrations were not increased.) Although a lower dose of terbutaline would almost assuredly minimize these undesirable effects, its efficacy in the prevention of nocturnal hypoglycemia remains to be established.
Although this study was not designed to contrast CSII and MDI insulin regimens, post hoc analysis disclosed that the former patients had lower HbA1c levels, but there was no difference in the mean nadir nocturnal plasma glucose concentrations or in the duration of glucose levels less than 70 mg/dl (3.9 mmol/liter) during the night.
Estimation of sc glucose levels with the CGMS did not faithfully reflect the measured plasma glucose concentrations or the frequency of hypoglycemia. The CGMS missed at least 12% of plasma glucose concentrations less than 70 mg/dl (3.9 mmol/liter) (the adjusted CGMS false-negative rate) and indicated glucose levels less than 70 mg/dl (3.9 mmol/liter) erroneously at least 14% of the time (the adjusted CGMS false-positive rate). Thus, use of the CGMS does not appear to be optimal for the accurate documentation of the frequency of nocturnal hypoglycemia or for the critical assessment of the efficacy of potential preventive treatments.
In the absence of a bedtime treatment, mean plasma glucose concentrations declined to a nadir of 99 ± 12 mg/dl (5.5 ± 0.7 mmol/liter) at 0230 h and then rose to a peak of 116 ± 14 mg/dl (6.4 ± 0.8 mmol/liter) at 0545 h. Thus, there was only a small mean dawn phenomenon (4, 27) in these patients. In addition, the morning (0700 h) plasma glucose concentrations were directly, rather than inversely, related to the earlier nocturnal nadir plasma glucose concentrations (28). Given the high frequency of nocturnal hypoglycemia, the latter finding provides further evidence against a clinically important Somogyi phenomenon (29, 30).
We conclude that nocturnal hypoglycemia is common in aggressively treated type 1 diabetes and that none of the four putative bedtime treatments tested is acceptable clinically. Bedtime administration of a conventional snack (without or with an -glucosidase inhibitor) does not prevent nocturnal hypoglycemia, nor does that of uncooked cornstarch. Although bedtime administration of the epinephrine-simulating ß2-adrenergic agonist terbutaline in an oral dose of 5.0 mg prevents nocturnal hypoglycemia, it also causes hyperglycemia the following morning. Whether a lower dose of bedtime terbutaline is, or is not, efficacious in the prevention of nocturnal hypoglycemia without causing morning hyperglycemia remains to be determined.
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Acknowledgments |
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Footnotes |
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B.R., A.M.A., and S.M.B. have nothing to declare. P.E.C. has consulted for Novo Nordisk, Takeda, and Mannkind Pharmaceuticals in recent years.
First Published Online February 21, 2006
Abbreviations: CGMS, Continuous glucose monitoring system; CSII, continuous sc insulin infusion; MDI, multiple daily injection; NPH, neutral protamine Hagedorn.
Received December 22, 2005.
Accepted February 13, 2006.
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-glucosidase inhibition. Diabetes Care 6:483–487[Abstract]This article has been cited by other articles:
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  P. E. Cryer, L. Axelrod, A. B. Grossman, S. R. Heller, V. M. Montori, E. R. Seaquist, and F. J. Service Evaluation and Management of Adult Hypoglycemic Disorders: An Endocrine Society Clinical Practice Guideline J. Clin. Endocrinol. Metab., March 1, 2009; 94(3): 709 - 728. [Abstract] [Full Text] [PDF]
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) in 21 patients with type 1 diabetes.
