Drn

ORIGINAL ARTICLES

Morning versus Bedtime Isophane Insulin in Type 2 (Non-insulin dependent) Diabetes Mellitus D.E. Seigler, C.M. Olsson, J.S. Skyler Departments of Medicine, Pediatrics, and Psychology, University of Miami School of Medicine, Miami, Florida, USA

Morning versus bedtime administration of NPH insulin was compared in 12 subjects with Type 2 diabetes and overt fasting hyperglycaemia. Subjects were studied at baseline (diet alone) and after 2 months on each of the two insulin programmes in a random crossover design, in which dosage was increased until at least one daily preprandial blood glucose was consistently in the range of 3.9 to 6.0 mmol I-'. Mean (f SEM) daily total insulin dosage was equivalent for the morning (0.36 f 0.03 units kg-') and for the bedtime (0.37 2 0.03 units kg-') insulin administration schedules. Clycaemic control was improved on both insulin regimens, but was better on bedtime than morning insulin. Fasting plasma glucose (mmol I-') was 12.0 f 0.7 (baseline), 8.6 f 0.7 (morning), and 4.6 f 0.3 (bedtime), respectively. Mean 24 h plasma glucose (mmol I-') was 13.3 f 1.3, 9.0 k0.7, and 7.8 2 0.7. Glycated haemoglobin (96)was 7.65 2 0.35, 6.23 f 0.26, and 5.81 f 0.32. The improvement of basal glycaemia i s a consequence of increased basal metabolic clearance of glucose (baseline, 47.6 f 3.1 mi m-* min-'; morning 63.5 2 5.4, bedtime 103.5 f 7.1). There was no change in hepatic glucose output. It is concluded that bedtime administration of intermediate acting insulin results in increased basal insulinaemia, leadingto improved basal glycaemia and consequent improved overall metabolic control, compared to morning insulin administration. Therefore, bedtime may be the preferable timing of insulin therapy for patients with Type 2 diabetes and overt fasting hyperglycaemia. KEY WORDS Type

I1 diabetes Insulin Timing Bedtime Morning Glycaemia

Introduction In Type 2 diabetes, the importance of controlling basal (fasting) hyperglycaemia has been emphasized by Turner and H ~ l m a n . ' -Most ~ patients with Type 2 diabetes are capable of mounting a sufficient endogenous insulin secretory response to meals such that postprandial glycaemic excursions are restored to basal levels 4 to 5 h after meal c o n s ~ m p t i o n . Thus, ' ~ ~ ~ ~on a theoretical basis, if basal (fasting) hyperglycaemia is corrected, there should be an improvement in overall glycaemic control. This has led several authors to suggest that insulin should be prescribed so that basal glycaemia is ~orrected.'-'~ Experimentally, this has been done even using basal rate intravenous insulin infusion via an implantable insulin p ~ m p .Clinically, ~,~ several groups have championed the use of long acting ultralente insulin to supplement basal i n s ~ l i n a e m i a . ~On ~~~ the ~ "other hand, we have long proposed bedtime intermediate acting insulin to correct fasting glycaemia, since the timing of the peak insulinaemia should then better correct basal hypergly~aemia.~, j 2 , l 3 This approach has also been advocated by Riddle, l4-l6 and used by several other groups as ell.'^-'^ The current study was designed to compare the effects Correspondence to: Dr J.S. Skyler, University of Miami (D-1lo), P.O. Box 016960, Miami, FL 33101, USA.

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0742-3071 /92/090826-08$09.00 1992 by John Wiley & Sons, Ltd.

0

of bedtime administration of intermediate acting NPH insulin with morning administration of NPH insulin, in subjects with Type 2 diabetes with fasting hyperglycaemia. The main objective was to evaluate the efficacy of these dosage schedules on glycaemic control. In addition, the study determined the effects of such treatment on insulin secretion and insulin action, and on metabolic factors contributing to basal hyperglycaemia.

Patients and Methods Subjects The study group consisted of 12 subjects (8 men, 4 women), mean age 56.2 k 2.7 (SEM)years, with Type 2 1.4 years).2o Enrolment diabetes mellitus (duration 8.3 criteria were: fasting hyperglycaemia (plasma glucose > 7.8 mmol I-'); being able to be maintained on a stable diet and activity programme without medication (5 previously treated with insulin, 4 with sulphonylureas, 3 with diet alone); being < 140 % of ideal body weight (mid-point of Metropolitan Life Insurance Company Tables2') at baseline assessment on diet alone (mean IBW 112.1 & 5.1 %); and willingness to participate. The control group consisted of 6 healthy nondiabetic subjects of comparable age (mean 56.5 k 2.6 years) and

*

Accepted 25 June 1992 DIABETIC MEDICINE, 1992; 9: 826-833

DT17

ORIGINAL ARTICLES

*

adiposity (mean IBW 108.8 5.5 %) as the diabetic subjects. Subjects were euthyroid and did not have any evidence of cardiac, renal, or hepatic dysfunction. None of the subjects had other active diseases or were using pharmacological agents known to alter carbohydrate metabolism. All subjects provided written informed consent. The study was approved by the Medical Sciences Subcommittee for the Protection of Human Subjects of the University of Miami, the ethical review committee.

Study Design The basic design was a randomized, crossover study, involving two 2-month study periods. During one period, subjects administered intermediate acting NPH insulin in the morning prior to breakfast. During the other study period, subjects administered NPH insulin at bedtime. Metabolic assessment was conducted at baseline and after each study period. Non-diabetic control subjects underwent the metabolic assessment on a single occasion. Thirty to sixty days prior to baseline metabolic assessment, diabetic subjects were recruited into the study and underwent prebaseline evaluation, which included physical examination and determination of glycated haemoglobin (HbA1,). Diet was stabilized at that time. For that purpose, subjects received 8 h of dietary education,22 after which they devised their own meal plans based on the following guidelines: three meals daily spaced at least 5 h apart, no snacks, no simple sugars. Since subjects were generally non-obese, there was no specific attempt to limit calorie intake. The meal plans selected included a mean energy intake of 1 10 (SEM)kilocalories daily, with the distribution 1785 of calories (mean SEMI being: 45.6 2 1.9 % derived 1 . I % derived from fats, from carbohydrates, 28.0 2.2 % derived from protein. Patients were and 26.4 instructed in self-monitoring of blood glucose using DextrostixR read by a ClucometerR (Ames Division, Miles Laboratories, Elkhart, IN, USA). Blood glucose measurements were recommended to be taken four times daily and data recorded in a diary. During the prebaseline period, insulin or sulphonylureas, if previously used, were discontinued. Subjects were hospitalized for metabolic assessment (vide infra) at baseline (diet alone). After completion of the assessment protocol, they were randomly allocated (according to a randomization table) to either morning or bedtime lsophane (NPH) insulin (Humulin-N, Eli Lilly and Company, Indianapolis, IN, USA). Patients continued to perform self-monitoring of blood glucose at home several times a day before meals and at bedtime, with target preprandial values of 3.9 to 7.2 mmol I-’. Blood glucose measurements were made 86 % of the requested times. Insulin doses were increased until at least one daily preprandial blood glucose was consistently (i.e. at least 3 to 4 consecutive days) in the range of 3.9 to

*

*

*

*

MORNING VERSUS BEDTIME ISOPHANE INSULIN

6.0 mmol 1-l. After completion of a 2-month study period, subjects were re-admitted for repeat metabolic assessment. They then received the alternate treatment for a second 2-month study period, following which they were again re-admitted for repeat metabolic assessment. During both study periods, patients maintained their previously derived diet plans.

Assessment Protocol Each diabetic subject underwent a 5-day assessment protocol on three occasions: at baseline (on diet alone), and upon completion of each of the 2-month study periods (on morning insulin and on bedtime insulin). Each control subject underwent the assessment protocol on one occasion. At the time of each of the assesments, subjects were admitted to the University of Miami Hospital. After an overnight fast, an indwelling intravenous catheter was inserted and samples were obtained for glycated haemoglobin and lipids. On that day (day l),subjects were maintained on their usual diet, and their then current insulin dosage and timing; 24-h profiles were obtained that day. The following morning (day 21, basal (fasting) hepatic glucose production and metabolic clearance rate determinations were made. Insulin was discontinued on day 2 and not resumed during the duration of the assessment protocol. On day 3, subjects had an insulin tolerance test. On day 5, an intravenous glucose tolerance test was performed. Twenty-four hour profiles of glucose, C-peptide, and total and free insulin were obtained by intermittent sampling via the indwelling catheter. Patency was maintained with heparinized saline. Samples were immediately chilled on ice,’subsequently separated, and frozen until analysis. For comparative purposes, profile data were expressed as the mean 24 h value and/or the integrated area for plasma glucose and each peptide. Areas were calculated by the trapezoidal rule. Glycaemic variation was assessed by calculation of mean amplitude of glycaemic excursions and ~ , ~ ~ is calculated as the Schlichtkrull’s M ~ a l u e . * MACE mean of the increase or decrease in plasma glucose+ nadir to peak or vice versa-when both ascending and descending segments exceed one standard deviation of the mean 24 h plasma M value is a dimensionless index based on a logarithmic transformation of the deviations of plasma glucose from 5.0 mmol Basal hepatic glucose output (HGO) and basal metabolic clearance rate (MCR) were determined after completion of the 24-h p r ~ f i l e s . ~ A ~primed-continuous ’~~ infusion of D-3-3H-glucose (New England Nuclear, Cambridge, MA, USA) was started and continued throughout the study via an antecubital vein. The constant infusion rate was approximately 0.25 pCi min-’, and the ratio of the priming dose to the constant infusion rate was 100 in the control subjects. In the diabetic subjects, the prime was increased in proportion to the fasting plasma glucose concentration to a maximum of 75 pCi. 827

Dm

ORIGINAL ARTICLES A period of 120 min (control subjects) or 180 min (diabetic subjects) was allowed for equilibration of tritiated glucose. The specific activity of serum glucose was measured at 5-min intervals during the last half hour of the equilibration period, by which time steady state had been achieved. Basal HGO was calculated as the ratio of the 3H-glucose infusion rate to the steady state plasma 3H-glucose specific activity (mean of six determinations). Since plasma glucose was constant in the basal state, basal MCR was calculated as HGO divided by mean basal plasma glucose. Insulin sensitivity was determined by measuring plasma glucose response to an intravenous bolus (0.1 units kg-’) of i n ~ u l i n . ~ The ~ , ~test ’ was performed after an overnight fast, with samples obtained through an indwelling catheter. Glucose determinations were made at 5-min invervals for 30 min after each dose of insulin. The rate of decline of plasma glucose is linear when plotted after logarithmic transformation. The glucose disappearance constant in response to insulin, K,,, (% plasma glucose disappearance per min), was derived for each subject by multiplying the slope of the linear portion (0 to 30 min) of the regression line of the natural logarithm of plasma glucose versus time by 100.26,27 Intravenous glucose tolerance tests (IVGTT) were performed after an overnight fast, with samples obtained through an indwelling catheter. Glucose (500 mg kg-’, maximum dose 25 g) was administered rapidly as 50 % dextrose in water. Serum was obtained at 0, 2.5, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, and 60 min after administration of glucose, for determination of glucose, total and free insulin, and C-peptide. Glucose disappearance constant after glucose, /((=) (% plasma glucose disappearance per min), was derived for each subject by multiplying the slope of the linear portion (10 to 60 min) of the regression line of the natural logarithm of plasma glucose versus time by First phase insulin secretion after i.v. glucose was defined as the incremental insulin area above baseline from 0 to 5 min after glucose administration. Second-phase insulin secretion was defined as the incremental insulin area above baseline from 10 to 60 min after glucose administration. Areas were calculated by the trapezoidal rule.

Analytical Methods Plasma glucose was measured by the glucose oxidase method using a Beckman II Glucose Analyzer (Beckman .Instruments, Inc., Fullerton, CA, USA). Plasma 3Hglucose radioactivity was determined as described by Pilo et a/.29 Glycated haemoglobin was determined by a microcolumn method designed for measurement of specific ketoamine fraction of haemoglobin Al, (HbA1,) (Bio-Rad Laboratories, Hercules, CA, USA).30lnterassay coefficient of variation is 5.0-6.9 %. Total and free insulin were determined using a double antibody radioimm~noassay.~’ Free insulin was extracted 828

using the modification described by Kuzuya et a/.32 Reagents used included monoiodinated A1 4-[12511-porcine insulin tracer (Eli Lilly and Company, Indianapolis, IN, USA), guinea pig anti-porcine insulin antiserum (Eli Lilly and Company, Indianapolis, IN, USA), and antiguinea pig serum (Biotek Research, Inc., Lenexa, KS, USA). lnterassay coefficient of variation is 15.1-1 5.3 %. Lower limit of detection is 17 pmol I-’. C-peptide was determined by the method of H e d i t ~ g . ~ ~ Reagents used included [1251] -human tyrosylated-C-peptide (Eli Lilly and Company, Indianapolis, IN, USA) and goat antiserum to human C-peptide E 08-732-159-4-G (Eli Lilly and Company, Indianapolis, IN, USA). lnterassay coefficient of variation is 10.1-22.7 %. Lower limit of detection is 0.03 pmol ml-’.

Data Analysis All results are expressed as mean f standard error of the mean (SEMI. Comparisons between assessment periods in diabetic subjects were made using repeated measures analysis of variance and paired Student t-tests. Comparisons between control subjects and diabetic subjects were made using one way analysis of variance and unpaired Student t-tests. All t-tests were two-tailed unless otherwise noted. Values of p = 0.05 or more are considered not significant.

Results

Weight During the prebaseline stabilization period, there was no conscious attempt at weight reduction, except in subject 7 who needed to reduce by 4 kg in order to reach the maximum allowable relative body weight for inclusion in the study. Nevertheless, 11 of the 12 diabetic subjects lost weight, as they paid more careful attention to their diet during the stabilization period. Average weight 0.9 kg from the time of prebaseline lost was 4.4 recruitment to baseline assessment. Thus, there was a statistically significant (p < 0.001 ) decrease of weight from 74.6 f 4.1 kg at prebaseline recruitment to 70.2 3.8 kg at baseline assessment. Subsequently, during the insulin treatment periods, weight remained stable, being 71 .O 3.7 kg at the time of assessment on morning insulin and 71.2 f 3.7 kg at assessment on bedtime insulin. Mean weight of control subjects was 70.5 2 5.1 kg.

*

*

*

Insulin Dosage Subjects adjusted their own insulin by raising the dose by approximately 5 to 10 % every 3 to 5 days until at least one daily blood glucose value was consistently in the range of 3.9 to 6.0 mmol I-’. The algorithm also called for dose reductions for hypoglycaemia or if blood glucose fell below 3.9 mmol I-’. In fact, this was never D.E. SELLER

Er AL.

ORIGINAL ARTICLES needed. Mean daily total insulin dosage at the time of admission for the assessment protocol was equivalent for the morning (0.36 0.03 units kg-') and bedtime (0.37 ? 0.03 units kg-') insulin administration schedules.

*

Metabolic Control The subjects' home blood glucose profiles during the last week of each of the two insulin treatment periods are shown in Figure 1. The only difference (p < 0.001) is in 0.4 mmol 1 - l ; the fasting glucose (morning: 7.7 bedtime: 5.1 ? 0.2 mmol I-'). Depicted in Figure 2 are the overall 24-h plasma glucose profiles obtained during the assessment admissions for diabetic and control subjects. Figure 2 shows that on both insulin programmes there was an improvement in overall glycaemic profile compared to that obtained on diet alone. The 24-h mean plasma glucose values, quantifying this improvement, are listed in Table 1. In addition, it can be seen from the figure that the overnight, fasting, and post-breakfast plasma glucose levels tended to be lower on bedtime insulin than morning insulin. Mean fasting plasma glucose values are listed in Table 1. Values for HbA,, reflected the changes in the plasma glucose profiles, and are listed in Table 1. It is interesting to note that in the diabetic subjects there also was an improvement (p < 0.01) in HbA1, between prebaseline evaluation (9.13 f 0.45 %) and baseline assessment on diet alone (7.65 ? 0.35 %). The M-value, an index of glycaemic variation from

*

SELFMONITORING BLOOD GLUCOSE LAST WEEK OF TREATMENT PERIOD

5.0 mmol I-l, also reflected the overall changes in glycaemia. However, the MAGE on either insulin programme was no different from that on diet alone, reflecting that prolonged postprandial glucose excursions were not altered by the institution of insulin therapy. These values also are included in Table 1. The glucose disappearance constant, K(o, calculated from the IVGTT, showed little variation in glucose disposal amongst diabetic subjects (Table l ) , although there was a marginally significant improvement on morning insulin. The values were in the diabetic range (i.e. < 1 .O) at baseline and on both insulin programmes.

Hepatic Glucose Output HGO was higher in the diabetic subjects at baseline on diet alone (75.4 f 2.3 mg M-2 min-') than in the control subjects (66.9 f 3.5 mg M-* min-') (one-tailed p < 0.05). However, there was no change in HGO on either of the insulin programmes (morning: 78.2 f 4.9 mg MP2 min-'; bedtime: 76.4 f 3.4 mg M-2 min-'1. The steady state plasma glucose levels at the times these measurements were made were as follows: control subjects, 4.7 ? 0.2 mM I-'; diet alone, 9.4 ? 0.6 mM 1-l; morning: 7.1 ? 0.4 m M I-'; bedtime: 4.2 0.2 mM I-l.

*

Insulin Action Metabolic clearance rates of glucose in the basal state were calculated from the tritiated glucose infusion data collected on day 2. The MCR on diet alone (47.6 ? 3.1 ml M-2 min-') was decreased in comparison to control subjects (79.7 ? 2.6 ml MP2min-I), consistent with impaired basal glucose utilization. However, this was improved on morning insulin (63.5 f 5.4 ml M-2 min-'1, and corrected on bedtime insulin (103.5 ? 7.1 ml M-2 min-'). In fact, the value on bedtime insulin exceeded that seen in the control subjects. The insulin sensitivity index, K(,), was not altered by either insulin programme, versus diet alone (Table 1). In comparison to non-diabetic control subjects, the diabetic patients demonstrated insulin resistance.

Insulin Profiles Insulin availability, i.e. the sum of endogenous and exogenous insulin, was reflected in the 24 h profile of free insulin (excluding two subjects who had multiple apparently spurious values), depicted in Figure 2. In comparison to baseline assessment on diet alone, there was an increase in 24-h free insulin on the bedtime programme. The increased level of insulin is achieved during the basal state, i.e. midnight to 8:OO am. Since the patient comes into the morning with a higher ambient level of insulin, the endogenous insulin with meals adds to this throughout the day, resulting in an increased mean value for the 24-h period. Mean value for total

I FASTIN0

BEFORE LUNCH

BEFORE DINNER

AT BEDTIME

Figure 1. Mean (+ SEMI values for preprandial and bedtime blood glucose determinations made by subjects during the last week of the two treatment periods; 0 values on morning insulin; A values on bedtime insulin MORNING VERSUS BEDTIME ISOPHANE INSULIN

829

Dm

ORIGINAL ARTICLES Plasma Glucose 20.0,

Plasma Glucose 12 10

I

'1 0

MgL

MEAL

,

MZL

2.01

MEAL

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MEAL

MEAL

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C-Peptide C-Peptide

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Free Insulin

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Free Insulin

700-

600

200'

0-1, 08.00 10.00 12.00 14.00 16.00' 18.00

20.00 22.00 24.00 02.00 04.00 06.00 08.00

Time 01 day

,

08.00 10.00

12.00 14.00 16.00 18.00 20.00 22.00 24.00 02.00 04.00 06.00 08.00 Time 01 day

Figure 2. Twenty-four hour profiles of glucose, C-peptide, and free insulin (mean ? SEM for each timepoint). Left panels, control subjects; right panels, diabetic subjects; H baseline values on diet alone; 0 values on morning insulin; A values on bedtime insulin

insulin, and integrated areas for both free and total insulin were calculated. The data (not shown) paralleled that for mean free insulin and were essentially equivalent in monitoring insulin availability.

no time did the diabetic subjects show a restoration of first phase insulin secretion.

Glucose After Insulin Withdrawal

Insulin Secretion Insulin secretion was assessed by measuring C-peptide levels during both the 24-h profile and after intravenous glucose. Figure 2 depicts the 24-h plasma C-peptide profile, which i s substantially reduced in the diabetic subjects in comparison to the non-diabetic control subjects. Using 24-h mean C-peptide, there is very little difference in C-peptide on insulin therapy vs diet alone. On the other hand, incremental C-peptide secretion in response to meals (postprandial C-peptide area) is increased on both insulin programmes, more so on bedtime insuIin . We also examined insulin and C-peptide response during the IVGTT, and noted no change in response. At

830

Figure 3 depicts mean fasting plasma glucose over the 5 days that the patients were hospitalized at the time of the assessment protocol. It can be seen that during that time, after withdrawal of insulin therapy (given only on day l ) , there was some deterioration in basal glycaemia during the assessment admissions after both insulin regimens. At the time of the assessment admission after bedtime insulin, after insulin withdrawal basal glycaemia was lower than at the time of the assessment admission after morning insulin. In neither case did the deterioration eventuate in glucose levels similar to those seen on diet alone. D.E. S E L L E R ET AL.

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DTT7

ORIGINAL ARTICLES

Table 1. Comparison with controls and amongst regimens Control subjects

Diabetic subjects Diet alone

Glycaemic control 24-h Mean plasma glucose (mmol 1 - l ) Difference from diet Difference from control Fasting plasma glucose (mmol 1 - l ) Difference from diet Difference from control Haemoglobin A,, (%)

5.2

* 0.2

p < 0.001

* 0.2

12.0

p 7.65

4.91 -C 0.17

p

Glycaemic variation M-value Difference from diet Difference from controls MAGE (mmol I-’) Difference from diet Difference from controls (IVCTT

p < 0.005

p < 0.001 4.8

* 0.7

9.0

13.3 2 1.3

Difference from diet Difference from controls

Glucose tolerance disposal)

Morning insulin

* 0.7

< 0.001 < 0.001

6.23 p p

< 0.001 < 0.005

< 0.001

* 0.35 < 0.001

* 0.6

p < 0.001

p

p 5.1

2.1 2 0.5

f

292 p< p< 4.7

91 2 24

0.6 2 0.2

* 0.7

8.6 p p

< 0.001

*

0.26

11 0.01 0.001 0.6

Bedtime insu Iin

7.8 p p

4.6 ? 0.3‘ p < 0.001 NS 5.81 p

* 0.32”

< 0.001 NS

24 5 10” p < 0.01 p < 0.001 5.1 0.6NS

*

NS

NS

< 0.001

* 0.7b

< 0.001 < 0.05

p

< 0.001

glucose 1.81 2 0.28

K,G)

0.44 2 0.03

Difference from diet Difference from controls

p

Insulin sensitivity (Insulin tolerance test)

41,

4.19

* 0.55

1.98

Difference from diet Difference from controls

p

Insulin profile 24-h Mean free insulin (pmol 1 - l ) Difference from diet Difference from controls Bedtime compared with morning insulin: Results as mean t SEM.

203.8 2 27.3

74.0 p

NS

Not significant;

a

=p

Discussion The current study was designed to assess the impact of morning versus bedtime insulin administration on glycaemic control in subjects with Type 2 diabetes and overt fasting hyperglycaemia. In addition, we examined the effects of these dosage schedules on insulin secretion, hepatic glucose production, and insulin action. We demonstrated that both insulin schedules resulted in marked improvement in glycaemic control compared to that seen at baseline on diet alone (Table 1). However, the bedtime schedule led to the greatest improvement in glycaemic control. The better correction of basal glycaemia with bedtime insulin resulted in improvement in the overall 24-h glucose profile and in glycated haemoglobin. The improvement in glycaemia is similar to results in the UK Prospective Study.34The lowering of basal glycaemia MORNING VERSUS BEDTIME ISOPHANE INSULIN

< 0.001

* 0.27 < 0.001

* 10.3 < 0.001

< 0.05;

0.53 2 0.04 p < 0.05 p < 0.001

0.49 2 0.03NS NS p < 0.001

2.17 ? 0.18 NS p < 0.001

2.28 2 0.25NS

116.5 2 23.7 NS p < 0.001

= p < 0.01 ;

=

p

NS p

< 0.001

129.4 p p

< 0.05 < 0.001

* 26.6NS

< 0.001.

is a consequence of increased basal insulinaemia. These data affirm the notion that correction of basal glycaemia is a critical factor in the treatment of Type 2 diabetes. They are consistent with the hypothesis that endogenous insulin controls meal glucose excursions in such circumstances. Yet, postprandial glycaemia (glucose tolerance) i s not normalized and remains prolonged, as evidenced by lack of change in MAGE. Once-daily insulin administration schedules are simple to use and thus are likely to facilitate patient compliance with therapy. Most physicians prescribe intermediate acting insulin as a morning injection. Many physicians and patients tend to fear that bedtime insulin administration may lead to frequent nocturnal hypoglycaemia. In the current study, near-normalization of basal glycaemia with bedtime insulin was achieved without significant hypoglycaemia. In fact, the study was designed to

83 1

Dr17

ORIGINAL ARTICLES MEAN PLASMA GLUCOSE OVER 5 D A Y S

12.0.

10.0.

-1

1 0 8.0E E

6.0,

4.0

~

J I

1

2

3

4

5

DAY

Figure 3. Mean (+ SEM) fasting glucose level for diabetic subjects during each of the 5 days of metabolic assessment; W baseline values on diet alone; 0 values on morning insulin; A values on bedtime insulin. The horizontal lines indicate the overall mean value for each 5-day assessment period

minimize hypoglycaemia. Insulin doses were raised gradually while fasting glucose levels were measured daily. Since bedtime NPH insulin should peak about the time of awakening, the basal blood glucose measurement should coincide with the glucose nadir. These data support the concept that bedtime is the optimal timing for insulin administration in patients with Type 2 diabetes and overt fasting hyperglycaemia. This study also demonstrated the importance of diet in the management of Type 2 diabetes. In order to avoid confounding influences of obesity per se, we recruited primarily relatively thin subjects with Type 2 diabetes for this study. Nevertheless, with introduction of careful dietary control during the run-in period from prebaseline to baseline, there was a reduction in weight and marked improvement in glycated haemoglobin. These observations reinforce the importance of simple dietary control measures in the management of Type 2 diabetes. We suspect that the marked improvement in glycaemic control seen with both insulin programmes may not have been evident had the subjects not adhered to a careful diet throughout the study. To determine the mechanism of improved basal glycaemia, we measured basal HGO, basal MCR of 832

glucose, insulin secretion, and insulin sensitivity, K,,,. Insulin secretion in response to glucose improved. There was no change in K,,,. There was improvement in MCR on both insulin programmes. On the other hand, we did not detect a change in HGO with institution of insulin therapy. This may be because of the high variance in HGO measurements between subjects in the relatively small number of subjects studied. Indeed, baseline measures of HGO were barely above the values in the control subjects. We do not interpret our findings to mean that HGO was not affected by the insulin therapy given. Rather, we simply were unable to detect any changes that may have occurred. In summary, we have demonstrated that bedtime administration of intermediate acting insulin results in increased basal insulinaemia, leading to improved basal glycaemia and consequent improved overall metabolic control. The improvement of basal glycaemia is a consequence of increased basal metabolic clearance of glucose. Insulin therapy resulted in some improvement in both insulin secretion and insulin action, which may have contributed to the improved metabolic control. Lesser degrees of improvement were seen with morning administration of intermediate acting insulin. The improvement in overall glycaemia on bedtime insulin is at the expense of additional hyperinsulinaemia. The long-term beneficial or harmful effects of hyperglycaemia versus hyperinsulinaemia have not been firmly established. However, since the adverse effects of hyperinsulinaemia are theoretical, and hyperglycaemia has clearly established adverse effects, it may be better to aim for the improved glycaemic control which can be attained with bedtime insulin and this may be a preferable timing of insulin therapy for patients with Type 2 diabetes.

Acknowledgements This work was supported by grants from Eli Lilly and Company, Indianapolis, IN, USA and by grants DT34901 and HL-36588 from the National Institutes of Health, US Public Health Service. We appreciate the technical assistance of Melanie Ashby, the help of the dietary and nursing staff of the University of Miami Hospital and Clinics during the hospitalizations for metabolic assessments, the cooperation of our colleagues in the care of the patients, and the willingness of the subjects to volunteer for these studies. Reagents were provided by Dr Bruce Frank, Eli Lilly and Company, Indianapolis, IN, USA. Insulin assays were performed by Dr Dinesh Kumar, Los Angeles, CA, USA.

References 1 . Turner RC, Holman RR. Insulin use in NIDDM: Rationale based on pathophysiologyof disease. Diabetes Care 1990; 13: 1011-1020. D.E.SEIGLER

ET AL.

Dm 2.

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