Higher triglyceride is a risk factor for diabetes in adults with normal triglyceride in Chinese adults

doi:10.21203/rs.3.rs-1247925/v1

Purpose

Whether higher triglyceride is a risk factor for diabetes diagnosis in people with normal triglyceride is yet established. This study aimed to investigate this association in Chinese adults.

Methods

This cross-sectional study included 16,786 Chinese adults with triglyceride in the normal range, i.e., < 1.7 mmol/L. Associations between triglyceride and fasting plasma glucose and between triglyceride and diabetes diagnosis were analyzed using linear regression and binary logistic regression, respectively.

Results

Participants with higher triglyceride had higher fasting plasma glucose, higher prevalence of diabetes, and higher prevalence of use of anti-diabetic drugs. Triglyceride (natural log-transformed) was positively associated with fasting plasma glucose (natural log-transformed) after adjustment for all the tested confounders (β = 0.034, P < 0.001). A 1naturallogunit increase in triglyceride (e.g., from 0.50 to 1.36 mmol/L or from 44 to 120 mg/dL) was associated with a 61% higher multivariate-adjusted risk of diabetes diagnosis (odds ratio [OR], 1.61; 95% confidence interval [CI], 1.19-2.17). Participants with triglyceride in the highest quartile (1.26-1.69 mmol/L) had a 54% higher risk of diabetes diagnosis (OR, 1.54; 95% CI, 1.14-2.09) compared with those with triglyceride in the lowest quartile (< 0.73 mmol/L).

Conclusion

This study demonstrates that higher triglyceride is associated with higher risks of diabetes diagnosis in people with normal triglyceride. This suggests that patients with high “normal” triglyceride (e.g., 1.26-1.69 mmol/L) may need to be closely monitored for the risk of diabetes.

diabetes mellitus

triglyceride

association

risk factor

normal range

cut-off

Diabetes is one of the largest global public health concerns, imposing a heavy global burden on public health as well as socio-economic development [1]. In 2017, approximately 462 million individuals were affected by type 2 diabetes corresponding to 6.28% of the world’s population [2]. Over 1 million deaths per year can be attributed to diabetes alone [2]. Therefore, it is important to identify modifiable factors for the disease.

Epidemiological studies frequently showed that glyceride is higher in patients with diabetes [3, 4] and high triglyceride (≥ 1.7 mmol/L or 150 mg/dL) [5] is associated with a higher risk of diabetes diagnosis [6, 7]. In addition, high triglyceride was associated with a higher risk of diabetes incidence in longitudinal studies [8, 9]. However, the associations between triglyceride and fasting plasma glucose and between triglyceride and diabetes diagnosis in people with normal triglyceride (i.e. < 1.7 mmol/L) are not yet established. This study aimed to investigate these associations in Chinese adults with normal triglyceride.

Participants

A total of 22,571 participants underwent a routine health examination between January and May 2019 at the Health Physical Examination Centre of the First Affiliated Hospital of Shandong First Medical University, Jinan, Shandong Province, China. 5,771 were excluded as their triglyceride levels were ≥ 1.7 mmol/L, i.e., not in the normal range recommended by the US National Lipid Association Expert Panel [5]. Thirteen participants were further excluded due to being younger than 18 years and another one was excluded due to missing blood pressure data. The remaining 16,786 adult participants were included in this study. This retrospective study complied with the Declaration of Helsinki as revised in 2008 and was approved, and the requirement for obtaining patient informed consent was waived, by the Research Ethics Committee of the First Affiliated Hospital of Shandong First Medical University.

Measurements

Blood pressure was measured in all participants by trained professionals using Omron HBP-9020 Automated BP Monitors (Omron Healthcare Co. Ltd, Tokyo, Japan) in the seated position after the participant rested for 10 minutes. Blood pressure was measured 2 times at 2-min intervals and mean systolic and diastolic blood pressure were recorded [10, 11]. Body mass index (BMI) was calculated as weight in kilograms divided by height in meters squared. Venous blood samples were collected after an overnight fast. Fasting plasma glucose and serum concentrations of triglyceride, low-density lipoprotein (LDL) cholesterol, and high-density lipoprotein (HDL) cholesterol were measured using the Olympus AU2700 automatic biochemical analyzer [12].

Statistical analyses

All statistical analyses were performed using SPSS version 27.0 (IBM SPSS Statistics for Windows, Armonk, NY, International Business Machines Corporation). Data were expressed as mean and standard deviation (SD) for continuous variables or number and percentage for categorical variables. Statistical comparisons of continuous data among groups were performed using one-way ANOVA (for LDL cholesterol) or Kruskal-Wallis one-way ANOVA (for age, triglyceride, glucose, BMI, systolic blood pressure, and HDL cholesterol). Statistical comparisons of categorical data among groups were performed using Pearson’s Chi-square test. The associations between triglyceride and glucose and between triglyceride and diabetes diagnosis were analyzed by linear regression and binary logistic regression [13], respectively, with or without adjustment for confounding factors including age, sex, BMI, systolic blood pressure, HDL cholesterol, LDL cholesterol, and medications for treating diabetes or hyperlipidemia. Age, fasting plasma glucose, BMI, systolic blood pressure, triglyceride, and HDL cholesterol were natural log-transformed before putting into the regression models. All tests were two-sided and a P value of < 0.05 was regarded as statistically significant.

Clinical characteristics of the cohort

The study included 16,786 participants aged 18–95 years with a mean (SD) age of 45.0 (14.3) years. Participants with higher triglyceride had higher fasting plasma glucose, higher prevalence of diabetes, and higher prevalence of use of anti-diabetic drugs (Table 1). In addition, participants with higher triglyceride were older and had a higher percentage of males, higher BMI, higher systolic blood pressure, higher LDL cholesterol, and lower HDL cholesterol (Table 1).

Triglyceride was positively associated with fasting plasma glucose in participants with normal triglyceride

The increase in triglyceride was companied by an increase in fasting plasma glucose (Fig. 1). Linear regression analyses confirmed that triglyceride was positively associated with fasting plasma glucose after adjustment for all the tested confounders (β = 0.034, P < 0.001, Table 2).

Higher triglyceride was a risk factor for diabetes diagnosis in participants with normal triglyceride

Logistic regression analyses showed that higher triglyceride (continuous variable) was associated with higher risks of diabetes diagnosis, and a 1-natural-log-unit increase in triglyceride (e.g., from 0.50 to 1.36 mmol/L or from 44 to 120 mg/dL) was associated with a 61% higher multivariate-adjusted risk of diabetes diagnosis (odds ratio [OR], 1.61; 95% confidence interval [CI], 1.19-2.17; Table 3).

When triglyceride was treated as a categorical variable (i.e., quartiles), higher triglyceride was also associated with a higher risk of diabetes diagnosis (Table 4). Participants with triglyceride in the highest quartile (1.26-1.69 mmol/L) had a 54% higher risk of diabetes diagnosis (OR, 1.54; 95% CI, 1.14-2.09; Table 4) compared with those with triglyceride in the lowest quartile (< 0.73 mmol/L).

Sensitivity analyses showed that exclusion of those with anti-diabetic drugs (Supplemental Table 1) or those with either anti-diabetic or lipid-lowering drugs (Supplemental Table 2) did not materially change the results.

This study found that higher triglyceride was a risk factor for diabetes diagnosis in adults with normal triglyceride, and a triglyceride level between 1.26 and 1.69 mmol/L was associated with a 54% higher risk of diabetes diagnosis compared with those with triglyceride in the lowest quartile (<0.73 mmol/L).

This study found that in people with normal triglyceride, higher triglyceride was linearly associated higher fasting plasma glucose. The underlying mechanism is unclear. It has been hypothesized by Shulman [14] that high circulating triglyceride could lead to increased intracellular concentrations of fatty acid metabolites. These metabolites could activate a serine/threonine kinase cascade leading to phosphorylation of serine/ threonine sites on insulin receptor substrates (IRS-1 and IRS-2), which in turn reduces phosphoinositide 3-kinase (PI3K) activity. As a consequence, glucose transport activity decreases and circulating glucose rises. However, it cannot be ruled out that high blood glucose could increase circulating triglyceride levels.

The majority of relevant literature reports support a causal role of higher triglyceride in diabetes pathogenesis. For example, in people without diabetes at baseline, higher fasting triglyceride predicted impaired glucose tolerance [15], impaired fasting glucose, new-onset of diabetes [16–20], and diabetes-caused mortality [7]. In addition, some triglyceride-lowering drugs are frequently reported to be associated with better glycemic control; examples of these drugs include peroxisome proliferator-activated receptors (PPAR) alpha agonist fenofibrate [21], PPAR alpha/delta agonist GFT505 [22], and diacylglycerol acyltransferase 1 inhibitor pradigastat [23].

However, genetic studies showed inconsistent results. For example, triglyceride-enhancing alleles have been reported to be either positively associated with [24], or inversely associated with [18, 25, 26], or not associated with diabetes [27]. One of the genetic studies [18] revealed inconsistency between genetic and non-genetic results from the same cohort of participants: higher baseline circulating triglyceride levels were associated with higher new-onset of diabetes, whereas triglyceride-enhancing alleles were associated with lower new-onset of the disease. The reason underlying the observed inconsistency [18] is unknown; some of the selected genetic alleles might have other functions beyond regulating circulating triglyceride.

To the best of our knowledge, the current study was the first to investigate the association between triglyceride and plasma glucose and between triglyceride and diabetes diagnosis in people with normal triglyceride. This study, thus, expanded the positive association between triglyceride and diabetes diagnosis [6, 7] to people with “normal” triglyceride (< 1.7 mmol/L) and found that people with a triglyceride level between 1.26 and 1.69 mmol/L had a higher risk of diabetes diagnosis.

So far, there is only one study that investigated the association between triglyceride and diabetes in people with normal triglyceride [20]. However, that study [20] did not investigate the association between triglyceride and plasma glucose, nor the association between triglyceride and diabetes diagnosis. Rather, it investigated the association between baseline triglyceride and new-onset of diabetes [20], and found that higher triglyceride levels were associated with an increased risk for new-onset of diabetes in people with normal triglyceride [20], in particular, those with triglyceride at a concentration from 1.13 to 1.69 mmol/L (or from 100 to149 mg/dL). The results of that study [20] and the current study suggest that a triglyceride concentration near the high end of the current normal range may not be normal. More studies are needed to provide evidence on whether the current normal triglyceride cut-off value (i.e., 1.7 mmol/L) needs to be lowered.

This study had a number of strengths. First, the associations between triglyceride and plasma glucose and between triglyceride and diabetes diagnosis were adjusted for both HDL cholesterol and LDL cholesterol, as these two types of cholesterol are common confounding factors for triglyceride [22, 28, 29]. Second, this study had a large sample size (N = 16,786). This study also had several limitations. First, the cross-sectional nature of the study could not establish a causal relationship between triglyceride and plasma glucose and between triglyceride and diabetes diagnosis. Second, this study only adjusted for a limited number of confounders. Third, information on the type of diabetes was not available.

In conclusion, this study found that higher triglyceride was associated with a higher risk for diabetes diagnosis in adults with normal triglyceride.

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Table 1. Clinical characteristics of the 16,786 participants, stratified by quartiles of triglyceride

	1st quartile	2rd quartile	3rd quartile	4th quartile	Overall	P for trend
TG, mean (SD), mmol/L	0.58 (0.10)	0.84 (0.07)	1.10 (0.08)	1.46 (0.12)	1.00 (0.34)	< 0.001
Sample size, N	4,164	4,194	4,231	4,197	16,786	NA
Age, mean (SD), y	40.0 (13.0)	44.6 (14.2)	46.8 (14.3)	48.3 (14.2)	45.0 (14.3)	< 0.001
No. of males (%)	1,543 (37.1)	2,097 (50.0)	2,551 (60.3)	2,740 (65.3)	8931 (53.2)	< 0.001
FPG, mean (SD), mmol/L	4.97 (0.82)	5.18 (0.99)	5.35 (1.19)	5.51 (1.39)	5.25 (1.13)	< 0.001
BMI, mean (SD), kg/m²	22.4 (3.0)	23.7 (3.3)	24.8 (3.3)	25.8 (3.2)	24.2 (3.5)	< 0.001
SBP, mean (SD), mm Hg	121 (17)	127 (18)	131 (19)	133 (19)	128 (19)	< 0.001
LDL-C, mean (SD), mmol/L	2.36 (0.58)	2.65 (0.65)	2.84 (0.68)	2.96 (0.70)	2.70 (0.69)	< 0.001
HDL-C, mean (SD), mmol/L	1.47 (0.29)	1.38 (0.27)	1.29 (0.26)	1.22 (0.24)	1.34 (0.28)	< 0.001
Diabetes, N (%)	142 (3.4)	233 (5.6)	331 (7.8)	441 (10.5)	1,147 (6.8)	< 0.001
Number of people on anti-diabetic drugs, N (%)	75 (1.80)	99 (2.36)	137 (3.24)	162 (3.86)	473 (2.82)	< 0.001
Number of people on anti-dyslipidaemia drugs, N (%)	32 (0.77)	42 (1.00)	54 (1.28)	55 (1.31)	183 (1.09)	0.029

Abbreviations: BMI, body mass index; FPG, fasting plasma glucose; HDL-C, high-density lipoprotein cholesterol; LDL‑C: low-density lipoprotein cholesterol; N, number; NA, not applicable; No., number; SBP, systolic blood pressure; SD, standard deviation; TG, triglyceride.

Table 2. Association between fasting plasma glucose^a (dependent) and triglyceride^a (independent) in 16,786 participants with normal triglyceride

	β	P value
Model 1	0.211	< 0.001
Model 2	0.098	< 0.001
Model 3	0.035	< 0.001
Model 4	0.034	< 0.001

^a Natural log-transformed

Model 1: Not adjusted.

Model 2: Adjusted for age (natural log-transformed) and sex.

Model 3: Adjusted for factors in Model 2 plus body mass index, systolic blood pressure, LDL cholesterol, and HDL cholesterol. Body mass index, systolic blood pressure, and HDL cholesterol were natural log-transformed.

Model 4: Adjusted for factors in Model 3 plus number of lipid-lowering drugs prescribed and number of anti-diabetic drugs prescribed.

Table 3. Natural log-transformed triglyceride and risk for diabetes diagnosis in 16,786 participants with normal triglyceride

	Odds ratio	95% CI	P value
Model 1	3.79	3.14-4.58	< 0.001
Model 2	2.19	1.79-2.68	< 0.001
Model 3	1.45	1.16-1.83	0.001
Model 4	1.61	1.19-2.17	0.002

Abbreviations: CI, confidence interval

Model 1: Not adjusted.

Model 2: Adjusted for age (natural log-transformed) and sex.

Model 3: Adjusted for factors in Model 2 plus body mass index, systolic blood pressure, LDL cholesterol, and HDL cholesterol. Body mass index, systolic blood pressure, and HDL cholesterol were natural log-transformed.

Model 4: Adjusted for factors in Model 3 plus number of lipid-lowering drugs prescribed and number of anti-diabetic drugs prescribed.

Table 4. OR (95% CI) of risk for diabetes diagnosis according to triglyceride quartiles in 16,786 participants with normal triglyceride

	1st quartile (TG: range, < 0.73; mean, 0.58 mmol/L)	2rd quartile (TG: range, 0.73-0.96; mean, 0.84 mmol/L)	3rd quartile (TG: range, 0.97-1.25; mean, 1.10 mmol/L)	4th quartile (TG: range, 1.26-1.69; mean, 1.45 mmol/L)	P for trend
Model 1	1 (reference)	1.67 (1.35-2.06)	2.40 (1.97-2.94)	3.33 (2.74-4.04)	< 0.001
Model 2	1 (reference)	1.18 (0.95-1.48)	1.48 (1.20-1.83)	1.92 (1.57-2.35)	< 0.001
Model 3	1 (reference)	1.02 (0.81-1.28)	1.12 (0.89-1.39)	1.32 (1.06-1.65)	0.015
Model 4	1 (reference)	1.15 (0.84-1.58)	1.23 (0.91-1.67)	1.54 (1.14-2.09)	0.010

Abbreviations: CI, confidence interval; OR, odds ratio; TG, triglyceride.

Model 1: Not adjusted.

Model 2: Adjusted for age (natural log-transformed) and sex.

Model 3: Adjusted for factors in Model 2 plus body mass index, systolic blood pressure, LDL cholesterol, and HDL cholesterol. Body mass index, systolic blood pressure, and HDL cholesterol were natural log-transformed.

Model 4: Adjusted for factors in Model 3 plus number of lipid-lowering drugs prescribed and number of anti-diabetic drugs prescribed.

Funding. This work was funded by the Shandong Natural Fund (ZR2015HL008), Shandong Province, China. YW is supported by a grant from the National Health and Medical Research Council of Australia (1062671). The study funder was not involved in the design of the study; the collection, analysis, and interpretation of data; writing the report; and did not impose any restrictions regarding the publication of the report.

Conflict of interest. The authors declare no competing interests.

Data availability. All data from this article are available from the corresponding authors upon reasonable request.

Author Contributions. Conceptualization: Y.W., G.Y.; Methodology: H.L., S.M., T.Q., H.S., Q.X., X. H.; Formal analysis and investigation: Y.W., G.Y; Writing - original draft preparation: Y.W.; Writing - review and editing: G.Y., Y.F.; Funding acquisition: G.Y., Y.W.; Resources: X.H., W.H., G. Z.; Supervision: G.Y., Y.W.

Higher triglyceride is a risk factor for diabetes in adults with normal triglyceride in Chinese adults

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