Investigation of the Insulin Dose and Characteristics of Continuous Subcutaneous Insulin Infusion in Chinese People with Type 2 Diabetes

Abstract

Background:

Continuous subcutaneous insulin infusion (CSII) for type 2 diabetes mellitus (T2DM) is a promising therapy. CSII therapy is flexible, but the required insulin dose for different people may vary. Few studies have investigated the insulin dose and characteristics of CSII for T2DM, and none has focused on an Asian Chinese population.

Methods:

In total, 171 subjects with T2DM were using CSII and divided into different groups according to their body mass index (BMI) and the course of disease, respectively. The basal rate of CSII was set for four periods per day. We preferentially adjusted the basal insulin dose to control fasting and preprandial blood glucose.

Results:

Good glycemic control was achieved after 4.8±2.5 days. The mean total daily insulin dose was 31.66±9.85 IU, and the dose per unit body weight was 0.48±0.19 IU/kg/day. The total daily basal and bolus doses were 21.14±7.64 IU and 10.38±3.62 IU, respectively (i.e., about 66.7±6.8% and 33.3±6.8% of the total daily dose). We did not observe any significant difference in total dose of insulin or basal and bolus doses of insulin per day among different groups divided by BMI. Only in the group with BMI of <23 kg/m² was the insulin dose of per kilogram of body weight (0.60±0.25 IU/kg/day) significantly higher than in the other two groups (P=0.0001). There was no relationship between the insulin dose and the course of disease.

Conclusions:

In individuals with T2DM on CSII short-term intensive therapy, proper increase of basal dose of insulin and preferential adjustment of the basal rate may be the effective method that can achieve good glycemic control with a lower total daily dose.

Introduction

R ecently, the progressive deterioration of β-cell function has been identified as a major contributing pathophysiology in type 2 diabetes mellitus (T2DM).^1,2 People with T2DM often require insulin therapy, not only for those with disease of longer duration, but also for newly diagnosed patients in remission.^3

–6 Moreover, this treatment may bring the problems of hypoglycemia, weight increase, and iatrogenic hyperinsulinemia, which would increase the potential risks of vascular disease. Therefore, we should pay attention to the insulin dose. Studies by Bruttomesso et al.^7,8 showed that type 1 diabetes mellitus patients with continuous subcutaneous insulin infusion (CSII) need less insulin compared with those receiving multiple daily injections (MDI). In China, insulin pumps are mainly used for T2DM, especially for hospitalized patients receiving short-term treatment. However, there are not enough recent relevant studies on how to optimize the insulin dose in T2DM patients with CSII. In this study, we investigate the dose characteristics of insulin for 171 hospitalized patients with T2DM who were treated with CSII.

Subjects and Methods

We have studied 171 T2DM patients (88 men and 83 women). All the patients were hospitalized between November 2008 to April 2009 in the Department of Endocrinology at Linyi People's Hospital, Linyi, China, excluding those with acute complications, pregnancy, and acute infection. The diagnosis of T2DM was established on the basis of the 1999 diabetes diagnostic criteria of the World Health Organization. All recruited patients provided written informed consent for participation, and the study was approved by the hospital's ethics committee.

The mean age was 51.2±14.5 years, the average body weight was 68.6±12.6 kg, the mean body mass index (BMI) was 24.77±3.66 kg/m², the mean glycosylated hemoglobin (HbA1c) was 10.32±2.15%, the mean fasting blood glucose (FBG) was 14.69±4.13 mmol/L, and the 2-h postprandial blood glucose (2-h PG) was 19.84±7.10 mmol/L. Among these patients, 71 patients were newly diagnosed, 67 patients previously had received oral hypoglycemic drugs, and 33 patients previously had received treatment with insulin therapy. There were 43 patients with peripheral neuropathy, 24 patients with retinopathy, 35 patients with diabetic nephropathy, and 11 patients with large vessel disease.

The 171 patients could be divided into three groups according to their BMI: <23, 23–24.9, and ≥25 kg/m², respectively. There were no significant differences among these three groups in terms of age, HbA1c, blood glucose, and other clinical data (Table 1).

Table 1.

Characteristics of Study Subjects Grouped by Body Mass Index

BMI (kg/m²)	n	Male/female	Age (years)	HbA1c (%)	FBG (mmol/L)	2-h PG (mmol/L)
<23	49	22/27	53.0±16.1	10.8±2.0	16.32±3.84	22.53±7.92
23–24.9	49	28/21	53.0±13.9	10.0±2.4	14.41±3.76	19.75±7.55
≥25	73	38/35	48.7±13.6	10.2±2.1	14.07±4.36	17.31±4.83

BMI, body mass index; FBG, fasting blood glucose; HbA1c, glycosylated hemoglobin; PG, postprandial blood glucose.

Based on the course of diabetes, all the patients could also be divided into three groups: newly diagnosed, <5 years from diagnosis, and >5 years from diagnosis, respectively. There were no significant differences among these groups in terms of age, BMI, HbA1c, blood glucose, and other clinical data (Table 2).

Table 2.

Characteristics of Study Subjects Grouped by Time from Diagnosis

Diagnosis group	n	Male/female	Age (years)	BMI (kg/m²)	HbA1c (%)	FBG (mmol/L)	2-h PG (mmol/L)
Newly diagnosed	71	47/24	48.5±14.4	24.7±4.1	11.0±2.1	15.89±3.70	22.26±6.45
<5 years	50	22/28	49.2±16.0	25.3±3.1	9.9±2.0	12.23±2.62	18.07±7.18
>5 years	50	20/30	57.6±11.1	24.1±3.4	9.6±2.0	15.19±5.09	18.55±7.20

Data are mean±SD values.

BMI, body mass index; FBG, fasting blood glucose; HbA1c, glycosylated hemoglobin; PG, postprandial blood glucose.

In this study, all the patients were treated with insulin aspart (Novo Nordisk, Bagsvaerd, Denmark) using Medtronic (Northridge, CA) insulin pumps. The blood glucose was monitored by a stable blood glucose monitoring device from LifeScan, a Johnson & Johnson Company (Milpitas, CA). The blood glucose was measured from finger-stick blood samples eight times a day. All the patients did not use any other oral hypoglycemic drugs during insulin pump therapy. The total daily dose of insulin was calculated in international units (IU). The initial dose was 0.3–0.4 IU/kg/day, in which the basal dose accounted for 60–70%. The initial basal dose was divided into the following four periods of the day: the period from 00:00 to 04:00 h, the period from 04:00 to 09:00 h, the period from 09:00 to 21:00 h, and the period from 21:00 to 24:00 h. The premeal dose accounted for 30–40% of the total daily amount and was distributed into three premeals evenly. The basal dose was preferentially adjusted to control the FBG well when the fasting plasma glucose was higher than 9 mmol/L or the increased rate of 2-h PG was lower than 6 mmol/L according to the features of the postprandial glucose state in T2DM patients of Chinese descent.⁹ At the end of the CSII treatment, we analyzed the total daily dose of insulin, insulin daily dose per kilogram of body weight, and the distributed features of basal and premeal dose and compared the dose of each group.

Statistical analyses

All statistical analyses were performed with commercial software (SPSS, version 13.0 for Windows, SPSS, Inc., Chicago, IL). Descriptive analyses of the qualitative variables were with proportion and percentages. Quantitative variables were described as mean and SD values. The comparison between groups was performed by analysis of variance. A value of P<0.05 was considered as statistically significant.

Results

The characteristics of the groups divided according to BMI and the course of disease before and after CSII treatment are shown in Tables 1 and 2, respectively. The dose and characteristics of insulin in the subjects of every group after treatment are shown in Table 3.

Table 3.

Comparison of the Insulin in Each Group of Patients with Type 2 Diabetes Mellitus Using Continuous Subcutaneous Insulin Infusion

					Insulin
Group	n	Days to reach glycemic goals	FBG (mmol/L)	2-h PG (mmol/L)	Total daily dose (U/day)	Rate (U/kg/day)	Basic dose (%)	Preprandial (%)
By BMI (kg/m²)
<23	49	4.8±3.1	6.61±1.28	8.49±1.92	31.89±12.03	0.60±0.25	66.7±7.1	33.3±7.1
23–24.9	49	4.3±1.7	6.58±1.10	9.02±1.93	31.26±9.23	0.46±0.17^a	67.2±6.4	32.8±6.4
≥25	73	5.1±2.5	6.72±0.88	9.15±1.34	31.78±8.75	0.41±0.11^a	66.3±7.0	33.7±7.0
By course of disease
Newly diagnosed	71	5.0±2.7	6.51±0.99	9.12±1.75	31.37±8.73	0.46±0.19	65.7±6.4	34.3±6.4
<5 years	50	4.6±2.3	6.69±1.09	8.62±1.37	31.29±11.89	0.48±0.22	66.7±7.9	33.3±7.9
>5 years	50	4.7±2.4	6.80±1.14	8.97±1.95	32.49±9.28	0.50±0.16	68.1±6.1	31.9±6.1

P=0.0001 versus patients with body mass index (BMI) <23 kg/m².

FBG, fasting blood glucose; PG, postprandial blood glucose.

Before CSII treatment, FBG was 14.69±4.13 mmol/L, and 2-h PG was 19.84±7.10 mmol/L. After 4.8±2.5 days of CSII treatment, FBG decreased to 6.65±1.07 mmol/L, and 2-h PG decreased to 8.94±1.71 mmol/L. The total daily dose of insulin was 31.66±9.85 IU (i.e., 0.48±0.19 IU/kg/day). The basal doses for each daily period of (00:00–04:00 h), (04:00–09:00 h), (09:00–21:00 h), and (21:00–24:00 H) were 0.44±0.20, 1.21±0.37, 0.97±0.38, and 0.65±0.26 IU/h, respectively, which accounted for 66.7±6.8% of the total daily dose. The premeal dose was 10.38±3.62 IU/day, and the average preprandial dose was 3.50±1.15 IU (except in three cases where the range was 2–6 IU).

There were no statistically significant differences in terms of the days to reach glycemic goals, the total daily dose of insulin aspart, and the proportion of basal dose and premeal dose in the groups divided according to BMI (P>0.05) (Table 3). However, in the group with BMI <23 kg/m², the daily insulin dose per kilogram of body weight was significantly greater than in the other two groups (P=0.0001). The difference of the above-mentioned index had no statistical significance in the groups divided according to the course of disease (P>0.05) (Table 3).

Discussion

At present, great progress has been made in insulin preparation and medication, but the amount of insulin injected still falls short of the insulin secretion of a normal physiological model. Inevitably when using insulin treatment, potential risks exist such as iatrogenic hyperinsulinemia, hypoglycemia, and weight increase. When the patients have achieved blood glucose control, the insulin dose should be closely monitored in order to reduce the risk of insulin treatment. Many studies have demonstrated that treatment with CSII in type 1 diabetes patients was better than treatment with MDI using insulin neutral protamine Hagedorn^7,10 because CSII can reduce the insulin dose compared with MDI using glargine insulin.^8,11 A study by Torres et al.¹² showed that compared with treatment with insulin glargine once daily and more than three times the amount of preprandial insulin lispro, the requirement of insulin was significantly decreased in type 1 diabetes patients treated with CSII (0.75±0.21 IU/kg/day vs. 0.64±0.21 IU/kg/day, P=0.001). However, Monami et al.¹³ found that, compared with MDI, there was no significant difference in the daily insulin dose with CSII, and this result was obtained from meta-analysis by tetrachoric correlation of T2DM clinical trials in which all the T2DM patients were treated at least 12 weeks.

Postprandial blood glucose in diabetes mellitus comprises three parts: basic blood glucose (fasting glucose), the increase of glycogen output, and the absorption of intestinal glucose. In general, the increased range of 2-h PG mainly includes increased glycogen output and the absorption of gastrointestinal glucose. However, if we compare the absorption of postprandial glucose of the subjects with T2DM with that of healthy people by tracking isotopically tagged glucose, the glucose dose that absorbed in the gastrointestinal tract was the same.¹⁴ Therefore it demonstrated that the absorption of gastrointestinal glucose was not the main factor that caused the increase of postprandial blood glucose in diabetes mellitus. The basal insulin can restrain the output of glycogen.¹⁵ It not only reduces both FBG and premeal blood glucose, but also partially restrains the postprandial hyperglycemia. When basal insulin was used to reduce postprandial blood glucose, a low dose of preprandial insulin can be used as a supplement in order to control the postprandial blood glucose. Therefore, the preprandial insulin dose of CSII can only restrain some of the glycogen output and the increase of blood glucose caused by the absorption of carbohydrates when controlling the diet. We control the fasting and premeal blood glucose mainly through preferentially regulating the basal rate of CSII. For example, under the circumstances when the blood glucose is >9 mmol/L before dinner and the increased range of 2-h PG is<6 mmol/L, we control the preprandial glucose by increasing the basal insulin dose instead of increasing the bolus dose, although 2-h PG was as high as approximately 15 mmol/L. The Henry activity curve for insulin¹⁶ suggested that in the treatment with CSII using insulin aspart, the remaining in vivo insulin still amounted to 40% after 3 h. It is thus clear that the greater the amount of premeal insulin, the greater will the treatment reduce non-meal blood glucose, and the stronger the "tail effect" of the premeal amount, which can result in the extension of the blood glucose decrease is too large from one postmeal to the next premeal or hypoglycemia. A lower premeal amount can reduce the additive effect with the basal rate, thereby avoiding having an effect on the modulation of basal dose.

In our present study, the total daily basal dose (21.14±7.64 IU) was 66.7±6.8% of the total daily dose, and the total daily bolus (10.38±3.62 IU) was 33.3±6.8%, which is quite different with that of the Korean population whose total bolus dose was 64.1±12.1% of the total daily dose.¹⁷ In all, the mean total daily insulin dose was 31.66±9.85 IU (i.e., 0.48±0.19 IU/kg/day) for our 171 patients. As research on the Indian population shows, the daily insulin dose of 46 T2DM patients was 44.0±23.7 U/day¹⁸ (i.e., 0.61 IU/kg/day), when treatment was transitioned from MDI to CSII for 6 months, and the insulin dose was higher than that of our patients. In this study, the insulin from CSII was 0.60±0.25 IU/kg/day in the group with BMI <23 kg/m², which is significantly larger than that of the other two groups. This result is close to the insulin dose of 0.64±0.21 IU/kg/day in the study of Torres et al.¹² for type 1 diabetes patients with CSII. It remains an interesting research topic as to whether the result is caused by the poor islet function in low-weight patients with T2DM. There is no significant difference in the ratio of basal and premeal dose among the groups based on BMI or the course of disease.

Conclusions

In this study, we have showed that T2DM patients treated with CSII using insulin for at least short-term application can achieve the purposes of glycemic control with a lower insulin dose through a small bolus dose and modest increases in the basal dose. In the future, we need to further study the insulin dose in CSII for individuals with T2DM who need to use insulin injection for the long term.

Footnotes

Author Disclosure Statement

No competing financial interests exist.

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