Background
Type 2 diabetes mellitus (T2DM), a chronic metabolic disease, has become a serious issue in China with increasing incidences over the past decades. Insulin resistance and impaired insulin secretion are considered as primary pathophysiological factors in the development of T2DM [
1]. The UK Prospective Diabetes Study has shown that the β cells function begins deteriorating before T2DM diagnosis and often years before the patients presenting clinical symptoms [
2,
3]. In most patients with T2DM, the metabolic control and β cell function progressively deteriorate as the duration of diabetes increases [
4,
5]. Because the β cell function declines with diabetic duration, patients with newly diagnosed drug naive T2DM would be suitable subjects of T2DM study. Hyperlipidemia, an increase of total cholesterol (TC) and/or triglycerides (TGs) in the serum, is one of the most common T2DM related comorbidities [
6]. Diabetic dyslipidemia is characterized by moderately increased TG levels and reduced high density lipoprotein-cholesterol (HDL-C), which is a well-recognized causes for atherosclerotic cardiovascular diseases [
7,
8]. In our previous studies, we found that the mice with heterozygous lipoprotein lipase (LPL) deficiency with a rising serum TG display a disorder of glucose metabolism and deterioration of β cells function [
9]. Therefore, it is important to investigate the role of lipid profiles in patients with newly diagnosed T2DM and whether the different TG levels influence the glucose control and insulin secretion. Several studies have reported the characteristics of newly diagnosed T2DM; however, very few focused on the relationship between TG and newly diagnosed T2DM. We hypothesized that newly diagnosed T2DM patients with high serum TG level might have worse clinical characteristics and more deteriorated β cells function than patients with normal TG level. Hence, in the present study, we examined the clinical characteristics and β cells function in patients with newly diagnosed drug naive T2DM with different levels of TG.
Methods
Patients
Patients with newly diagnosed T2DM (n = 624) were enrolled in the study between January 2008 and December 2009 in Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China. All patients had been diagnosed with T2DM within 5 months before the study enrollment and none of them have received drug treatment for T2DM. The diagnosis of T2DM was based on WHO diagnostic criteria established in 1998 [
10]. The patients were firstly divided into normal serum TG(newly diagnosed T2DM with TG up to 1.70 mmol/L, n = 348)and high serum TG (newly diagnosed T2DM with TG over 1.70 mmol/L, n = 276)and further divided into four sub-groups according to the quartile of serum TG (Group 1: newly diagnosed T2DM with TG up to 1.13 mmol/L, n = 152; Group 2: newly diagnosed T2DM with TG of 1.14 to 1.56 mmol/L, n = 158; Group 3: newly diagnosed T2DM with TG of 1.57 to 2.27 mmol/L, n = 158; and Group 4: newly diagnosed T2DM with TG of 2.28 to 11.65 mmol/L, n = 156). The study was carried out in compliance with the declaration of Helsinki. The study protocol was approved by the Ethical Committee of Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China (Number: Renjikls N026). Written informed consent for participation in the study was obtained from participants.
Data collection
The patients demographic data and clinical data were collected including age, sex, body height, weight, waist circumference (WC), systolic blood pressure (SBP), diastolic blood pressure (DBP), and levels of TG, TC, HDL-C, low density lipoprotein-cholesterol (LDL-C), fasting plasma glucose (FPG), 2 h postprandial glucose (2hPG), serum insulin concentrations at different time point, and hemoglobin A1c (HbA1c). Blood pressure was measured after 30 minutes of rest. The body mass index (BMI) was calculated as weight (kg) divided by the square of height (m2). Plasma lipid profiles were determined using fully automatic biochemistry analyzer (Hitachi 7020, Hitachi Co., Tokyo, Japan). A standard oral glucose tolerance test (75 g glucose load) and insulin releasing tests were performed after a 10-hour overnight fast. Plasma samples were obtained at 0, 30, 60, 120, and 180 minutes to measure glucose (Hitachi 7600–110, Hitachi Co.) and insulin (immunoradiometric assay kit, Dainabot, Tokyo, Japan) concentrations. The HbA1c levels were measured using a high-performance liquid chromatography.
The parameters including basic insulin secretion function index (homeostasis model assessment for β cell function index, HOMA-β), modified beta cell function index (MBCI), glucose disposition indices (DI), and early insulin secretion function index (insulinogenic index, IGI) were used to evaluate β cell function. Insulin sensitivity was estimated by homeostasis model assessment for insulin resistance (HOMA-IR) and insulin action index (IAI). The respective formulas for calculating the above mentioned parameters were as follows: HOMA-β = 20× I0/(G0-3.5); MBCI = I0 × G0/(G120 + G60-7); DI = IGI/HOMA-IR; IGI = △I30/△G30; HOMA-IR = I0× G0/22.5; and IAI = 1 / (I0 × G0), wherein, I0 (μU/mL) denotes fasting plasma insulin, I30 insulin level at 30 minutes after glucose load, G0(mmol/L) fasting plasma glucose, G30 plasma glucose level at 30 minutes after glucose load, G60 plasma glucose level at 60 minutes after glucose load, and G120 plasma glucose level at 120 minutes after glucose load.
Statistical analysis
Normality was tested using the one-sample Kolmogorov-Smirnov criterion. Non-normally distributed data were log transformed before analysis. Data were expressed as mean ± standard deviation for normally distributed variables and as median (Interquartile range was 25-75%) for skewed variables. Independent-samples t test and one-way analysis of variance test were used for normality distributed data. Mann–Whitney U test and Kruskal-Wallis H test were used for non-normal distributed data and alpha level was adjusted to reduce the error risk. A P value of <0.05 was considered statistically significant. All statistical analyses were performed using the SPSS statistical package (Version 17.0, SPSS Inc., USA)
Discussion
Patients with T2DM are common to have lipid disorders. In the present study, we found that patients of newly diagnosed T2DM with higher level of TG were younger and fatter. These patients had worse lipid profiles and glucose profiles than did patients with normal TG levels. Moreover, the basal β cell function initially increased along with rising TG levels and then decreased as the TG levels rose further. Insulin sensitivities were relatively high in patients with low TG levels and low in patients with higher TG levels.
Type 2 diabetes, a heterogeneous disorder characterized by impaired insulin secretion and insulin resistance, is closely related to obesity [
11]. BMI and WC usually serve as parameters to estimate the general and abdominal fat masses [
12]. Several studies have reported that BMI was positively associated with an endogenous insulin secretion as assessed by serum C-peptide response in T2DM [
13,
14]. In addition, BMI has been suggested to be positively associated with the decreased insulin sensitivity in T2DM [
15]. Although the BMI represents the degree of overweight and obesity, it fails to represent the body fat distribution. Visceral fat tissue is metabolically more active than non-visceral fat and secretes more hormones and cytokines, which promotes the development of insulin resistance and T2DM [
16]. WC measurement is a simple means assessing the levels of visceral fat. Increased WC is closely associated with the increased risk of diabetes [
17].
The findings in our present study are consistent with previous reports. We observed that the TG levels rise in patients as BMI and WC increase. Similarly, MBCI and HOMA-IR increase along with raising TG levels, which suggest that BMI and WC were positivity associated with insulin secretion and negativity associated with insulin sensitivity.
Several studies have demonstrated that the abnormalities in lipid profiles of patients with diabetes such as decreased levels of HDL-C, increased levels of the TC, TG, LDL-C, and very-low-density lipoprotein (VLDL)-C are associated with high insulin resistance [
7,
18]. Some mechanisms whereby insulin resistance could cause an alteration in lipid metabolism have been described [
19-
21]. Hyperinsulinemia is known to enhance the hepatic VLDL synthesis and thus may directly contribute to increased plasma TG and LDL-C levels [
19]. Resistance to the action of insulin on lipoprotein lipase in peripheral tissues may also contribute to the elevated TG and LDL-C levels [
21]. It has been suggested that insulin resistance may be responsible for low levels of HDL-C observed in patients with T2DM. Moreover, lipotoxicity could be one of the most important causes for T2DM. Hermans et al. [
22] reported that T2DM patients with a high ratio of log (TG)/HDL-C, used to evaluate the plasma atherogenic index, tend to have a high loss rate of insulin secretion and β cell function. Therefore, a lower ratio of log (TG)/HDL-C could be beneficial to glucose control. Imamura et al. [
23] have indicated that higher levels of TG (≥1.69 mmol/L) and FPG (5.5–7.0 mmol/L) are associated with a higher risk of DM preceded predominantly by β cell dysfunction. This may be attributed to that excessive plasma TG lead to elevated levels of circulating free fatty acids (FFAs) which causes the impairment of the β cell function. In our previous clinical studies, we found increased plasma triglyceride and free fatty acid levels are frequently associated with T2DM. LPL gene mutations contribute to the hypertriglyceridemia observed in T2DM patients [
24,
25]. In our animal experiments, we found LPL (+/−) mice with high serum TG level had worse glucose homeostasis and more serious insulin resistance in many insulin target tissues (liver, muscle, subcutaneous fat and ventral fat) than wild type mice with normal TG level[
9]. In agreement, our data showed that the patients of newly diagnosed T2DM with higher levels of TG had higher levels of TC and LDL-C and lower levels of HDL-C. In addition, HOMA-β was increased initially and then decreased with the rising TG levels, consisting with the symptoms of dysfunction of β cells.
The glucotoxicity generated by hyperglycaemia is commonly thought to be the fundamental acquired factor causing continuous decline of β cell function in T2DM [
2,
26]. Sustained hyperglycaemia reduces the β cell function through several ways, such as the increase of oxidative stress, activation of c-Jun N-terminal kinase pathway through activated p38 mitogen-activated protein kinase and protein kinase C, the reduction of the pancreatic and duodenal homeoboxfactor-1 function, and the reduction of ERp46 expression [
27-
29]. A previous study[
30] involving young adults (n = 223) with FPG < 126 mg/dL who underwent an evaluation of first and second phase insulin secretion during a 2 h hyperglycemic clamp found that the impairment in β cell function relative to insulin sensitivity was apparent even within the FPG range of those without diabetes; at the cutoff of FPG 100 mg/dL, there was an approximately 49% decline in the DI. In agreement, we observed that the patients with higher levels of TG had higher levels of TC, FPG, 2hPG, and HbA1c and significantly reduced levels of HOMA-β than other three groups. However, we did not observe significant differences in IGI and DI levels among all four groups of patients. This discrepancy may be due to differences in races of the patients and the limitations of study design.
Several studies have shown that the significance of insulin resistance and insulin secretion defect to diabetes development is linked to patients’ race. For example, the increased insulin resistance to diabetes development is a more prominent factor in Pima Indians, Mexican Americans and Caucasians; whereas the contribution of impaired insulin secretion is a more important factor in Japanese patients [
31-
33]. It is also reported that the β cell capacity is relatively lower in Asian than that in Western individuals [
34-
37]. Ma et al. [
23] indicated that the Chinese patients of newly diagnosed T2DM with hyperlipidemia were younger and had declined HOMA-β; however, there were no differences in HOMA-IR and quantitative insulin sensitivity check index. Qian et al. [
38] indicated that the early diabetes was more specifically characterized by declined insulin secretion rather than impaired insulin sensitivity. In the present study, though the insulin concentration curves indicate that patients with high TG level had a very obvious insulin resistance, a more detailed analysis with additional divisions of TG levels showed that the β cell function increases with the rising TG levels at the early phase, but later decreases as the TG levels further rise. Insulin resistance doesn’t deteriorate as the TG levels further rise. Taken together, therefore, we propose that insulin secretion dysfunction, rather than insulin resistance, may play an important role in the progression of T2DM in Chinese patients.
Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made.
The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder.
Competing interests
The authors declare that they have no competing interests.
Authors’ contributions
SZ and HZ collected, researched, and discussed the data and wrote, reviewed, and edited the manuscript. TTH and YXL contributed to discussion and reviewed and edited the manuscript. YZ researched the data, contributed to the discussion, and reviewed and edited the manuscript. WL contributed to the discussion, and reviewed and edited the manuscript. YMH collected and researched the data, contributed to the discussion, and reviewed and edited the manuscript. YMH is the guarantor of this work and, as such, had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. All authors read and approved the final manuscript.