The Influence of Family History Risk Levels of Diabetes on Disease Prevalence in a High-Risk Diabetic Chinese Population

Abstract

Background:

Diabetes is associated with genetic susceptibility, and family history is a risk factor. The study investigated the association between different family history risk levels and the prevalence of diabetes in a multi high-risk cohort and evaluated the impact of family history of diabetes on insulin secretion and insulin sensitivity.

Materials and Methods:

We analyzed data from 9754 adults who participated in the Shanghai High-Risk Diabetic Screen Project between 2002 and 2012. The association among three family history risk levels (mild, moderate, and high) with the prevalence of diabetes, insulin secretion, and insulin sensitivity was evaluated in the multi high-risk cohort.

Results:

Overall, 69.6%, 24.8%, and 5.6% of participants were categorized as having mild, moderate, and high familial risk, respectively. The standardized prevalence was higher in the high family history risk group (43.1%) than in the moderate group (37.3%) and in the mild group (23.5%) (P < 0.001). The odds ratios (ORs) were significantly increased in the moderate group (OR 1.27, 95% confidence interval [CI] 1.15–1.40, P < 0.05) and in the high group (OR 1.69, 95% CI 1.41–2.02, P < 0.05). Among the 3245 normal glucose tolerance participants, insulin secretion significantly declined with increasing levels of family history risk, but there were no significant differences in insulin sensitivity among the three groups.

Conclusion:

The prevalence of diabetes was independently associated with an increasing family history risk level among multi high-risk Chinese populations. Subjects with moderate and high familial history of diabetes displayed a significant decrease in insulin secretion.

Introduction

With an economic boom coupled with urbanization, industrialization, and changes of lifestyle (increased high-calorie, high-fat, and high-sugar diets and decreased physical activity), type 2 diabetes is becoming epidemic in China, with the prevalence ranging from 9.7% to 11.6% in adults.^1,2 As a multifactorial disease, diabetes is genetically susceptible,^3,4 and family history is a risk factor. Individuals with a positive family history of diabetes experience a significantly higher risk for diabetes than those without, for example, approximately two-fold to five-fold in the U.S. population, two-fold to seven-fold in the Korean population, two-fold to three-fold in the Dutch population, and two-fold to six-fold in the Chinese population.^5

–8 In addition, the prevalence of diabetes increases with higher levels of family history risk of diabetes. For example, in the U.S. population, the prevalence of diabetes increases from 2.2% among patients with mild family history risk to 8.2% among patients with high family history risk; in the Chinese population, the prevalence of diabetes increases from 8.4% among patients with FH0 (no first-degree relatives with diabetes) to 32.7% among patients with FH2 (at least two generations of first-degree relatives with diabetes).^5,8

Although the association between type 2 diabetes and family history has been confirmed in population-based studies, the contribution of family history risk levels to the prevalence of diabetes remains unclear in the multi high-risk cohort. The results of our previous study have shown that there are small differences in the prevalence of diabetes between subjects with a positive family history of diabetes (39.16%) and those without (35.93%).⁹ However, how the prevalence and risk of diabetes are associated with the stratification of a family history of diabetes in multi high-risk populations need to be further investigated.

On the contrary, the association of family history of diabetes with insulin secretion and insulin sensitivity is controversial. A survey conducted in a European population has reported that a positive familial history of diabetes is associated with both decreased insulin sensitivity and secretion.¹⁰ Nevertheless, another study of Chinese individuals with normal glucose tolerance (NGT) has shown decreased insulin sensitivity and increased insulin secretion in individuals with higher levels of familial history risk.⁸

We aim to investigate the association between the prevalence of diabetes and different stratifications of familial history risk of diabetes in a cohort in Shanghai and to evaluate insulin sensitivity and insulin secretion among different categories of family history of diabetes.

Materials and Methods

Study subjects and data collection

The study population was selected from the Shanghai High-Risk Diabetic Screen (SHiDS) project, a large annual clinic-based screening project that was implemented in the 11-year period from 2002 to 2012. Details on the methodology have previously been reported.⁹ In brief, we screened diabetes in subjects with known risk factors such as family history of diabetes, previously diagnosed impaired fasting glucose or impaired glucose tolerance, overweight or obesity, polycystic ovary syndrome, hypertension, dyslipidemia, and a medical history of gestational diabetes. Among the total (n = 10,043) Chinese subjects living in Shanghai older than 20 years of age who had been screened for diabetes, 9754 adults who provided detailed information about their family history of diabetes were included in this study. All participants were asked to complete a standard questionnaire, a physical examination, and measurements of anthropometric parameters administered and performed by trained nurses. All subjects underwent a 75-g oral glucose tolerance test (OGTT). Blood samples were collected for a series of laboratory examinations. The diagnosis of the glucose tolerance category was based on the 1999 World Health Organization (WHO) criteria as follows: NGT (fasting plasma glucose <6.1 mmol/L and 2 h postload glucose [PG] <7.8 mmol/L), prediabetes (fasting plasma glucose ≥6.1 mmol/L and <7.0 mmol/L, and/or 2 h PG ≥7.8 mmol/L and <11.1 mmol/L), and diabetes (fasting plasma glucose ≥7.0 mmol/L and/or a 2 h PG ≥11.1 mmol/L).¹¹ The definitions of overweight (body mass index [BMI] ≥24 kg/m²) and obesity (BMI ≥28 kg/m²) were based on the 2002 Working Group on Obesity in China (WGOC) criteria.¹² The study was approved by the Institutional Review Board of Shanghai Jiao Tong University Affiliated Sixth People's Hospital and conducted in accordance with the principles of the Declaration of Helsinki. Written informed consent was obtained from each participant.

Family history of diabetes

The family history of diabetes was defined as positive when a person recollected having any biological relatives living or deceased (parents, grandparents, brothers, and/or sisters) who had ever been diagnosed with diabetes by a health professional. On the basis of studies in the United States, we stratified the risk of diabetes into three levels based on family history as follows: (1) mild, no family history of diabetes or, at most, one second-degree relative with diabetes; (2) moderate, just one first-degree and one second-degree relative with diabetes, or only one first-degree relative with diabetes, or at least two second-degree relatives with diabetes from the same maternal or paternal line; or (3) high, at least two first-degree relatives or one first-degree and at least two second-degree relatives with diabetes from the same lineage.^5,13

Insulin clamp and OGTT-derived indices

In our previous study, we observed that the insulinogenic index (IGI) showed the highest correlation with the insulin secretion from the hyperglycemic clamp, and the modified Matsuda index showed the highest correlation with the M-value from the hyperinsulinemic–euglycemic clamp in the SHiDS study cohort.¹⁴ Therefore, IGI was used to estimate insulin secretion, and the modified Matsuda index was used to estimate insulin sensitivity in NGT subjects (n = 3245) in this study. IGI and the modified Matsuda index were calculated as follows: IGI = (Ins30 − Ins0)/(Glu30 − Glu0); modified Matsuda = 10,000/([Glu0*Ins0]*[meanGlu*meanIns])^0.5.^15,16

Statistical analyses

Statistical analyses were conducted using SPSS version 20.0 (SPSS, Inc., Chicago, IL). All statistical tests were two tailed, and P < 0.05 was considered statistically significant. For continuous variables, data were presented as the mean ± standard deviation for normal distribution and median (25th percentile) for skewed variables, whereas for categorical variables, data were presented as percentages. Variables with a non-normal distribution (the Shapiro–Wilk W-test) were logarithmically transformed before analysis. A direct standardization method based on the Chinese population structure in 2010 was used to adjust the prevalence of diabetes.¹⁷ Categorical variables were compared using the χ ² test. Continuous variables between groups were carried out using ANOVA and analysis of covariance. Post hoc analysis was performed with the Dunnett's test. Logistic regression was performed by standard methods and reported as odds ratio (OR) and 95% confidence interval (CI).

Results

Participant characteristics

A total of 9754 participants were included in the study. Among these participants, 6756 (69.6%) individuals were reported to be in the mild familial risk category, while the proportions in the moderate and high familial risk groups were 24.8% and 5.6%, respectively. The distribution of all participants according to the levels of familial risk of diabetes and demographic and anthropometric information was shown in Table 1. Participants were younger in the moderate family history risk group than in the mild and high family history risk groups (P < 0.001). There were more women than men in all three groups (P < 0.001). The BMI was similar, and there were no significant differences in blood pressure after adjustment for age and gender among participants in the three groups. Plasma glucose levels were the highest in the high family history risk group and the lowest in the mild group at 0, 30, 60, 120, and 180 min during OGTT (P < 0.001).

Table 1.

Characteristics and Prevalence of Diabetes in Study Participants According to the Familial Risk of Diabetes

Characteristics	Mild, n = 6756 (69.6%)	Moderate, n = 2443 (24.8%)	High, n = 555 (5.6%)	P^a	P-adjusted ^b
Age, years	53.2 (14.8)	50.6 (12.4)	53.4 (10.7)	<0.001
Age, n (%)
20–39	1284 (19.0)	499 (20.4)	60 (10.8)	<0.001
40–59	2995 (44.3)	1338 (54.8)	336 (60.5)
≥60	2477 (36.7)	606 (24.8)	159 (28.6)
Sex, n (%)
Male	3200 (47.4)	1058 (43.3)	230 (41.4)	<0.001
Female	3555 (52.6)	1385 (56.7)	325 (58.6)
BMI, kg/m²	24.5 (3.7)	24.5 (3.7)	24.5 (3.1)	0.94
BMI, n (%)				0.809
>24	3512 (52.0)	1302 (53.3)	291 (52.4)
≤24	3091 (45.8)	1111 (45.5)	255 (45.9)
Blood pressure, mmHg
Systolic	129.0 (18.0)	127.2 (17.5)	128.4 (17.5)	<0.001	0.125
Diastolic	81.5 (11.1)	80.8 (11.2)	81.3 (10.5)	0.014	0.179
OGTT, mmol/L
OGTT0	6.0 (1.4)	6.1 (1.5)	6.4 (1.6)	<0.001
OGTT30	9.9 (2.3)	10.1 (2.4)	10.5 (2.3)	<0.001
OGTT60	11.4 (3.6)	11.7 (3.6)	12.5 (3.5)	<0.001
OGTT120	10.0 (4.3)	10.3 (4.3)	11.0 (4.3)	<0.001
OGTT180	6.9 (3.5)	7.1 (3.6)	7.5 (3.8)	<0.001
Prevalence of diabetes (95% CI)
Crude	35.5 (34.4–36.6)	38.8 (36.9–40.7)	46.7 (42.5–50.9)	<0.001
Standardized
Overall (adjusted by age, sex)^c	23.5 (22.5–24.5)	37.3 (36.3–38.3)	43.1 (39.0–47.2)	<0.001
Male sex (adjusted by age)^c	36.6 (35.5–37.7)	47.0 (45.0–49.0)	52.7 (48.5–56.9)	<0.001
Female sex (adjusted by age)^c	25.7 (24.7–29.7)	27.7 (26.0–29.5)	33.5 (30.0–37.4)	<0.003

All participants were grouped according to the familial risk of diabetes; mild, moderate, high.

P-value for differences among mild, moderate, and high groups.

Adjusted P-value among mild, moderate, and high groups for age, sex, and BMI.

Adjusted by gender and age using a direct standardization method according to the Chinese population structure in 2010.

BMI, body mass index; CI, confidence interval; OGTT, oral glucose tolerance test.

Prevalence and risk of diabetes in participants

The prevalence of diabetes increased with higher levels of family history risk (Table 1). The standardized prevalence was higher in the high family history risk group (43.1%) than in the moderate group (37.3%) and in the mild group (23.5%) after adjusting for gender and age (P < 0.001, Table 1). This trend was similar in both men (P < 0.001) and women (P < 0.003) participants in the three groups (Table 1).

Next, we investigated whether the prevalence of diabetes was associated with family history risk in three different age groups (20–39, 40–59, and ≥60 years; Fig. 1). In each age group, the prevalence of diabetes significantly increased with higher family history risk levels after adjusting for gender and BMI (P < 0.05). In addition, the prevalence of diabetes increased with increasing age in all three levels of family history risk (Fig. 1).

FIG. 1.

Adjusted prevalence for the total population by age, controlling for BMI, gender (SHiDS, 2002–2012). ♦, mild familial risk; ■, moderate familial risk; ▲, high familial risk (statistical significance is shown in the text). BMI, body mass index; SHiDS, Shanghai High-Risk Diabetic Screen.

Binary logistic analysis showed that the ORs were significantly increased in the moderate and high familial risk groups compared with the mild familial risk group using three models (Table 2). In model 3, after adjusting for age, gender, and BMI, the ORs were increased by 27% in the moderate familial risk group and by 69% in the high familial risk group compared with the mild familial risk group (P < 0.05).

Table 2.

Odds Ratios (95% Confidence Interval) for Diabetic Subjects Grouped by Family History

	Mild	Moderate	High
Crude	1 (Ref)	1.17 (1.06–1.28)^a	1.64 (1.38–1.95)^a
Model 1	1 (Ref)	1.24 (1.12–1.36)^a	1.61 (1.35–1.92)^a
Model 2	1 (Ref)	1.27 (1.15–1.40)^a	1.68 (1.40–2.00)^a
Model 3	1 (Ref)	1.27 (1.15–1.40)^a	1.69 (1.41–2.02)^a

Model 1 was adjusted for age. Model 2 was adjusted for age and sex. Model 3 was adjusted for age, sex, and BMI.

P < 0.05 compared to mild risk.

Association of graded family history of diabetes with insulin secretion and sensitivity in NGT participants

Among the 9754 participants, 3245 were NGT participants. We found that insulin secretion significantly declined with increasing levels of family history risk among NGT participants (Table 3). The IGI, an index of insulin secretion, decreased by 17.1% in the moderate familial risk group and by 21.8% in the high familial risk group compared with the mild familial risk group (P = 0.001). In contrast, there were no significant differences in insulin sensitivity among the three groups of family history of diabetes, as indicated by the modified Matsuda index (Table 3).

Table 3.

Insulin Secretion and Sensitivity in Normal Glucose Tolerance Participants Grouped by Family History

NGT subjects	Mild	Moderate	High	P^a	P-adjusted ^b
IGI	19.3 (11.0)	16.0 (9.6)	15.1 (9.98)	0.001	<0.001
Modified Matsuda	80.8 (54.8)	81.3 (54.2)	77.3 (53.8)	0.598	0.298

Data were shown as the median (25th percentile). Variables with non-normal, right-skewed distribution were logarithmically transformed before analysis.

P-value for differences among mild, moderate, and high groups.

Adjusted P-value among mild, moderate, and high groups for age, sex, and BMI.

IGI, insulinogenic index; NGT, normal glucose tolerance.

Discussion

In the present study, we investigated the association of different levels of family history of diabetes with the prevalence of diabetes, insulin secretion, and insulin sensitivity in a large multi high-risk cohort. We found that the prevalence of diabetes increased with higher levels of family history risk, and that in NGT, participants' insulin secretion was significantly associated with family history risk levels, but not insulin sensitivity.

Our study showed that the prevalence of diabetes increased with increasing levels of family history risk of diabetes. We observed a gradual increase in the prevalence of diabetes from the mild family risk group to the high family risk group. This trend is similar to the results of previous studies in the United States and China.^5,8,13 In addition, we found that the proportion of subjects with high familial history risk (5.6%) was lower than that in the U.S. population (9.1%), indicating that high family history risk is less common in our patients than in the general population in the United States.⁵ Furthermore, our results showed that ORs increased by 27% in the moderate familial risk group and 69% in the high familial risk group compared to the mild familial risk group. Interestingly, the ORs in our study are lower than those of population-based studies.^5,8 In a U.S. population-based study, the ORs are increased by 1.3 times in the moderate familial risk group and 4.5 times in the high familial risk group.⁵ In another Chinese population-based study, ORs increased by 1.86 times in the moderate familial risk group and 5.16 times in the high familial risk group.⁸ One possible explanation for the findings is that in our study, participants may have other diabetes-related risk factors, although they do not have a family history.

Our results showed that insulin secretion significantly declined with increasing levels of family history risk in NGT participants. Compared to the mild family history risk group, insulin secretion decreased by 17.1% in the moderate familial risk group and 21.8% in the high familial risk group. This finding is to some extent consistent with a population-based study from Western Finland, which showed that insulin secretion declines by 8.4% in individuals with a family history of diabetes compared to those without.¹⁸ However, Zhang et al. showed that insulin secretion exhibits a significant increase with increasing levels of family history risk in Chinese NGT subjects.⁸ Another study has shown that there is no significant difference in insulin secretion between NGT subjects with family history of diabetes and those without.¹⁹ The possible reasons for the discrepancies between different studies could be as follows: (1) the definition and stratification of family history of diabetes are different among these studies and (2) our study was multi high-risk based, while other studies^8,18,19 are all population based.

There were no significant differences in insulin sensitivity among NGT participants with three different levels of family history risk. This is in agreement with a population-based study in Western Finland, which showed no significant difference between subjects with or without a family history of diabetes.¹⁸ However, Zhang et al. showed decreased insulin sensitivity in NGT subjects with increasing levels of familial history risk.⁸ Another study has reported that insulin sensitivity is decreased in subjects with a positive familial history of diabetes.²⁰ In these two studies, there are significant differences in BMI among different family history groups. Variation in BMI may cause differences in insulin sensitivity. Nevertheless, in our study, BMIs in the three groups were comparable. Our data suggest that in multi high-risk populations, a family history of diabetes may not contribute to insulin sensitivity if subjects have similar BMI.

In conclusion, our study showed that the prevalence of diabetes was independently associated with increasing family history risk level even in multi high-risk Chinese populations. Furthermore, subjects with moderate and high familial history of diabetes displayed a significant decrease in insulin secretion. Therefore, our study suggests that individuals with moderate and high family history risk of diabetes may need effective interventions for the prevention of diabetes.

Footnotes

Acknowledgments

The authors thank The Metabolic Diseases Biobank of Shanghai Jiao Tong University Affiliated Sixth People's Hospital for collecting data and offering help. The work was financially supported by grants from the National Natural Science Foundation of China (Grant No. 81570808), and The Innovation Foundation of Translational Medicine of Shanghai Jiao Tong University School of Medicine—Project of Precision Medicine (Grant No. 15ZH4006).

Author Disclosure Statement

No competing financial interests exist.

References

Yang

, Lu

, Weng

, et al.: Prevalence of diabetes among men and women in China. N Engl J Med, 2010; 362:1090–1101.

, Wang

, He

, et al.: Prevalence and control of diabetes in Chinese adults. JAMA, 2013; 310:948–959.

Mahajan

, Go

, Zhang

, et al.: Genome-wide trans-ancestry meta-analysis provides insight into the genetic architecture of type 2 diabetes susceptibility. Nat Genet, 2014; 46:234–244.

Kato

: Insights into the genetic basis of type 2 diabetes. J Diabetes Investig, 2013; 4:233–244.

Valdez

, Yoon

, Liu

, et al.: Family history and prevalence of diabetes in the U.S. population: the 6-year results from the National Health and Nutrition Examination Survey (1999–2004). Diabetes Care, 2007; 30:2517–2522.

Koo

, Kim

, Yi

, et al.: Changing relative contribution of abdominal obesity and a family history of diabetes on prevalence of diabetes mellitus in Korean men and women aged 30–49 years from 2001 to 2010. J Diabetes, 2015; 7:465–472.

Abbasi

, Corpeleijn

, van der Schouw

, et al.: Maternal and paternal transmission of type 2 diabetes: influence of diet, lifestyle and adiposity. J Intern Med, 2011; 270:388–396.

Zhang

, Yang

, Xiao

, et al.: Association between family history risk categories and prevalence of diabetes in Chinese population. PLoS One, 2015; 10:e0117044.

Wang

, Zhang

, et al.: Prevalence of type 2 diabetes among high-risk adults in Shanghai from 2002 to 2012. PLoS One, 2014; 9:e102926.

10.

Natali

, Muscelli

, Mari

, et al.: Insulin sensitivity and beta-cell function in the offspring of type 2 diabetic patients: impact of line of inheritance. J Clin Endocrinol Metab, 2010; 95:4703–4711.

11.

Alberti

, Zimmet

: Definition, diagnosis and classification of diabetes mellitus and its complications. Part 1: diagnosis and classification of diabetes mellitus provisional report of a WHO consultation. Diabet Med, 1998; 15:539–553.

12.

Zhou

: Predictive values of body mass index and waist circumference for risk factors of certain related diseases in Chinese adults—study on optimal cut-off points of body mass index and waist circumference in Chinese adults. Biomed Environ Sci, 2002; 15:83–96.

13.

Hariri

, Yoon

, Moonesinghe

, et al.: Evaluation of family history as a risk factor and screening tool for detecting undiagnosed diabetes in a nationally representative survey population. Genet Med, 2006; 8:752–759.

14.

Zhang

, Chen

, Lu

, et al.: Prevalence and risk of diabetes based on family history in the Shanghai High-Risk Diabetic Screen (SHiDS) study. Diabet Med, 2015 [Epub ahead of print]; DOI: 10.1111/dme.13013.

15.

Matsuda

, DeFronzo

: Insulin sensitivity indices obtained from oral glucose tolerance testing: comparison with the euglycemic insulin clamp. Diabetes Care, 1999; 22:1462–1470.

16.

Staimez

, Weber

, Ranjani

, et al.: Evidence of reduced beta-cell function in Asian Indians with mild dysglycemia. Diabetes Care, 2013; 36:2772–2778.

17.

National Bureau of Statistics of China. China Statistics Press. 2010. www.stats.gov.cn/tjsj/ndsj/2010/indexeh.htm. Accessed May 17, 2016 .

18.

Isomaa

, Forsen

, Lahti

, et al.: A family history of diabetes is associated with reduced physical fitness in the Prevalence, Prediction and Prevention of Diabetes (PPP)-Botnia study. Diabetologia, 2010; 53:1709–1713.

19.

Chen

, Li

, Xu

, et al.: Impact of family history of diabetes on beta-cell function and insulin resistance among Chinese with normal glucose tolerance. Diabetes Technol Ther, 2012; 14:463–468.

20.

Grill

, Persson

, Carlsson

, et al.: Family history of diabetes in middle-aged Swedish men is a gender unrelated factor which associates with insulinopenia in newly diagnosed diabetic subjects. Diabetologia, 1999; 42:15–23.