Journal of Diabetes Research

Journal of Diabetes Research / 2017 / Article

Clinical Study | Open Access

Volume 2017 |Article ID 2740372 |

Feng-fei Li, Bing-li Liu, Hong-hong Zhu, Ting Li, Wen-li Zhang, Xiao-fei Su, Jin-dan Wu, Xue-qin Wang, Ning Xu, Wei-Nan Yu, Qun Yuan, Guan-cheng Qi, Lei Ye, Kok-Onn Lee, Jian-hua Ma, "Continuous Glucose Monitoring in Newly Diagnosed Type 2 Diabetes Patients Reveals a Potential Risk of Hypoglycemia in Older Men", Journal of Diabetes Research, vol. 2017, Article ID 2740372, 8 pages, 2017.

Continuous Glucose Monitoring in Newly Diagnosed Type 2 Diabetes Patients Reveals a Potential Risk of Hypoglycemia in Older Men

Academic Editor: Steven F. Abcouwer
Received24 Aug 2016
Revised29 Nov 2016
Accepted28 Dec 2016
Published08 Feb 2017


Objectives. We performed continuous glucose monitoring (CGM) to define the features of patients with newly diagnosed type 2 diabetes (T2D) before and after Continuous Subcutaneous Insulin Infusion (CSII) therapy. Methods. This was a retrospective analysis. Newly diagnosed T2D patients (106) were admitted from eight centers in China. They were divided into a younger patient group (<60 years) and an older patient group (≥60 years). Each group was further divided into male and female patients. CSII therapy was maintained for 3 weeks after the glycemic target was reached. CGM was performed 2 times before and after completion of insulin treatment. Results. CGM data showed the expected significant improvement of mean amplitude glycemic excursion (MAGE) with CSII therapy. The older patients had lower hourly glucose concentrations from 0200 to 0700 o’clock compared to the younger patients at baseline. Surprisingly, in the older patient group, the male patients had a potential risk of hypoglycemia after CSII therapy, especially during periods from 2300 to 2400 and 0400 to 0600. Conclusions. Our data suggested that older male patients with newly diagnosed T2D may have lower nocturnal glucose concentrations. This may potentially increase the risk of nocturnal hypoglycemia during CSII therapy. This study was registered with Chinese Clinical Trial Registry, number CliCTR-TRC-11001218.

1. Introduction

Intensive insulin therapy has been used to treat patients with type 2 diabetes (T2D) in China [1]. A proportion of patients with longstanding type 2 diabetes mellitus respond well to intensive treatment [2] and are able to maintain euglycemia with minimal treatment for a long period [3]. Indeed, patients’ response to insulin intensive therapy is quietly variable, mirroring the heterogeneity of diabetes [2]. A relatively large study did highlight the increased risk of hypoglycemia in the older patients but did not differentiate between the male and female patients [4, 5]. Reports have highlighted the importance of hypoglycemia, defined as glucose concentrations less than 4.0 mmol/L, in intensive insulin therapy compared to conventional therapy with or without the use of an insulin pump [6]. The Diabetes Control and Complications Trial (DCCT) study demonstrated that nearly 20% of patients receiving insulin pump therapy had symptomless nocturnal hypoglycemia [7]. Hypoglycemia, especially nocturnal hypoglycemia, might be an important barrier for patients with diabetes to achieve better glucose control or even resulting in death in severe cases [8]. It is therefore important to identify potential factors and associations for hypoglycemia during intensive insulin therapy [9].

However, there have been no previous studies in Chinese patients where continuous glucose monitoring (CGM) has been used to define the features of such patients before and after treatment. In the current study, we performed 2 times 3-day CGM on all consecutive patients with newly diagnosed T2D before and after intensive insulin therapy to characterize the features of 24-hour plasma glucose profile.

2. Methods

Between February 2010 and December 2014, we recruited a total of 106 patients with newly diagnosed T2D from 8 hospitals in Jiangsu province in China. The inclusion criteria were (1) patients aged between 18 and 80 years and (2) 9.0% < HbA1c 12% at diagnosis. Patients were excluded from analysis if they had chronic kidney disease, if they were positive for antiglutamic acid decarboxylase (aGAD) antibody, or if they had maturity onset diabetes in the young (MODY) or mitochondria diabetes mellitus [1]. The study protocol and patient consent forms were approved by the Institutional Ethical Committee of Nanjing First Hospital, Nanjing Medical University, the First People’s Hospital of Nantong, the First People’s Hospital of Lianyungang, Huai’an Second People’s Hospital, Changzhou Hospital of Traditional Chinese Medicine, and Lianyungang Oriental Hospital. All patients gave written informed consent. The methods were carried out in accordance with the Declaration of Helsinki guidelines, including any relevant details.

We recruited all drug naïve patients with newly diagnosed T2D and HbA1c concentrations > 9%. They did not receive any medical treatment before the assessment of initial CGM in the study. All these patients were recruited to receive CSII after informed consent was obtained. All patients were admitted as inpatients for Continuous Subcutaneous Insulin Infusion (CSII) therapy and CGM. After the baseline parameters were assessed, fasting blood serum was collected for insulin and C-peptide measurements. Enrolled subjects received intensive insulin treatment, without any oral antidiabetic drugs except metformin. Patients were divided into two groups based on their age: younger patient group: <60 years and older patient group: ≥60 years (the older population in China was above 60 years old). Patients in each group were also divided into two subgroups based on their gender (Table 1). The total daily insulin (human insulin, Novo Nordisk, Bagsværd, Denmark) dose was 0.5 IU/kg which was given in two modes: 50% of total daily dose was given as boluses with three meals at a fixed rate, and the remaining insulin was given over 24 hours (hrs). Insulin doses were then titrated on an individual-patient basis using the algorithm (if the fasting blood glucose level was less than 4.4 mmol/L, the basal insulin dose was reduced 0.2 units per hour from 1900 to 0500 by slowing the infusion speed; if the fasting blood glucose level was within 4.4 to 6.1 mmol/L, the basal insulin dose would be unchanged; if the fasting blood glucose level was from 6.2 to 7.8 and 7.9 to 10.0 and 10.0 mmol/L, the basal insulin dose would be increased subsequently by 0.2, 0.4, and 0.6 units per hour from 1900 to 0500 by increasing the infusion speed, resp., and if 2-hour postprandial blood glucose level was up, then the bolus insulin dose was titrated with the same algorithm as basal dose). When euglycemic control was achieved, treatments would be unchanged for another 3 weeks.

ItemsTotal patientsTotal patientsYounger (age < 60 years)Older (age 60 years)
Male (57)Female (47) valueYounger (69)Older (35) valueMale (41)Female (28) valueMale (16)Female (19) value

Age (years)0.96
BMI (kg/m2)0.50
HbA1c (%)0.51
2-h FC0.15

After log transformation for non-normally distributed data. Data are presented as means ± SD. , female patients versus male patients. FPG: fasting plasma glucose (mmol/L), LnFPG: Ln fasting plasma insulin (mU/L), Ln2-PPI:Ln 2-h postprandial insulin (mU/L), FC: fasting plasma C-peptide (pmol/L), 2-hFC: 2-h postprandial C-peptide (pmol/L), MI: Matsuda Index, II: Insulinogenic Index, TI: the total insulin doses per day (IU), Basal: basal insulin dose (IU), and Bolus: bolus insulin dose (IU).

All patients were subjected to 2 times’ 3-day retrospective CGM (Sof-sensor, CGMS-Gold, Medtronic Incorporated, Northridge, USA) in hospital by the specialist nurse during the study period. The first CGM was performed before therapy, and the second CGM was done after the completion of insulin treatment. Briefly, the CGM sensor was subcutaneously embedded at Day 0 around 1600–1700 PM. If CGM was performing well, subjects were instructed to keep the sensor fixed. The study nurse inputted at least 4 calibration readings every day. At Day 4, around 1600–1700 PM, subjects had the sensor removed, and the CGM data were saved by the investigator, as described previously [1012]. All patients received the same energy intake during the CGM periods. All subjects were instructed to maintain their usual physical activity and received meals consisting of a total daily caloric intake of 25 kcal/kg/day. The ratio of carbohydrate, proteins, and fats was 55%, 17% and 28%, respectively.

The 24-hrs mean glucose (MG), the standard deviation of the MG, the coefficient of variation (CV), the 24-hrs mean amplitude of glycemic excursions (MAGE), the percentage time duration (%) of hyperglycemia (glucose > 10.0 mmol/L), the incremental area under curve (AUC) of glucose above 10.0 mmol/L, and the hourly BG were recorded and calculated. The β-cell function and insulin resistance were assessed by the homoeostasis model assessment B (HOMA-B) and HOMA-IR [1, 13]. Matsuda Index [14] and Insulinogenic Index [15] were calculated as previously described.

Insulin, C-peptide, and HbA1c were measured centrally at the Department of Endocrinology, Nanjing First Hospital, Nanjing Medical University. Routine clinical laboratory tests were done in the central laboratory of the eight participating centers.

2.1. Statistical Analysis

Data were analyzed with the SPSS PASW Statistics 18 Package. Shapiro-Wilk test was used to assess the distribution of data. Normally distributed and continuous variables are presented as mean ± standard deviation (SD). Non-normally distributed variables were presented as median (IQR) and logarithmically transformed before analysis. The independent samples -test was used to compare the differences between two groups. A two-way ANOVA for repeated measurements was used in the comparison between groups. Bonferroni correction was followed. values were two-tailed with a significance level of 5%.

3. Results

Consecution of 106 newly diagnosed T2D patients met inclusion criteria (58 men and 48 women, age years, body-mass index  kg/m2,   %, and mean fasting plasma glucose  mmol/L) and were admitted to the study. We excluded a total of 2 younger patients (1 male and 1 female) who had glucose levels more than 22.2 mmol/L during the first CGM period as the CGM sensor used in this study is unable to monitor glucose concentrations > 22.2 mmol/L.

Patients were then divided into two groups. There were no differences in demographic characteristics between the 69 younger patients and the 35 older patients (Table 1). The younger female patients had higher 2-hr postprandial insulin concentrations, but all other baseline characteristics were similar between male and female patients in the younger patient group. The baseline characteristics were similar between male and female older patients.

There were no differences in the 24-hrs MG, the SD of 24-hrs MG, the CV of 4-hrs MG, the MAGE, the time spent in hyperglycemia (10 mmol/L) and the incremental AUC of hyperglycemia, and the percentage time duration (%) of hypoglycemia (glucose 10.0 mmol/L) within the two groups. CGM data showed that the hourly glucose concentrations (mmol/L) in older patients were lower than that in younger patients, especially from 0200 to 0700 o’clock (, , , , , and versus , , , , , and , , resp.) and 1100 to 1200 o’clock (, versus , , , resp.) (Figure 1).

The same standard weight based intensive insulin therapy treatment protocol was applied to all patients. CGM data showed that, as expected, all patients had significant improvement of MAGE, 24-hrs MG, and the incremental AUC of glucose above 10.0 mmol/L after treatment with intensive insulin therapy. No statistically significant differences in the abovementioned parameters were found when comparing between the groups before treatment. However, the female patients exhibited an increased 24-hrs MG levels after CSII treatment compared to the male patients using the same insulin therapy treatment protocol (Table 2). The younger male and female 24-hrs MG levels were almost the same after CSII treatment ( versus , ).

ItemsTotal patientsTotal patientsYounger (age < 60 years)Older (age 60 years)
Male (57)Female (47) valueYounger (69)Older (35) valueMale (41)Female (28) valueMale (16)Female (19) value

MAGE before CSII0.27
MAGE after CSII0.94
MG before CSII0.58
MG after CSII0.11
SD before CSII0.18
SD after CSII0.78
CV before CSII0.06
CV after CSII0.10
AUC before CSII0.53
AUC after CSII0.45
PT (%) before CSII0.34
PT (%) after CSII0.38

Data are presented as means ± SD. , female patients versus male patients. MAGE: mean amplitude of glycemic excursions (mmol/L), MG: mean glucose (mmol/L), SD: standard deviation (mmol/L), CV: coefficient of variation (%), AUC: area under curve above 10.0 mmol/L (mmol/L per day), PT: the percentage time duration of glucose above 10.0 mmol/L (%).

A stratified analysis comparing the older male and female groups revealed that male patients experienced lower glucose concentrations during intensive insulin therapy compared to female patients. In contrast, the younger male and female patient subgroups (<60 years) did not differ and had similar mean glucose concentrations at every hour at baseline before and after intensive insulin therapy (Figures 2(a) and 2(b)).

There was a tendency of lower glucose concentrations in older male subgroup as compared with that of old female subgroup at baseline, especially from 2200 to 0500 (Figure 2(c)), but this tendency was not statistically significant. After 3-week intensive insulin therapy, the hourly glucose concentrations, especially between 2300 and 2400 and from 0400 to 0600, in older male patient subgroup were significantly lower compared with that of the older female patients (, resp.) (Figure 2(d)). Furthermore, the 0000–0600 hours’ glucose concentrations in older male patients were significantly lower than that of older female patients after CSII treatment ( versus  mmol/L, ). In addition, we did not observe statistic differences in nocturnal glycemic variations (0000–0600 hours) between old male and female patient groups after treatment (SD: versus  mmol/L, ; and CV: versus ,