The impact of family history of type 2 diabetes on pancreatic b-cell function

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1 Contents lists available at ScienceDirect Diabetes Research and Clinical Practice journal homepage: The impact of family history of type 2 diabetes on pancreatic b-cell function Zhi-hong Wang, Su-Hua Zhang *, Li-lin Gong, Wei Ren, Rong Li, Rui-zhi Zheng, Yu-feng Zhang, Mao-rong Wang, Qi-fu Li Department of Endocrinology, The First Affiliated Hospital, Chongqing Medical University, Chongqing , China article info Article history: Received 4 April 2008 Received in revised form 3 March 2009 Accepted 2 April 2009 Published on line 11 August 2009 Keywords: Type 2 diabetes families First-degree relatives Spouses b-cell dysfunction Genetic factor abstract Aims: To study the impact of genetic factor on pancreatic b-cell function in the Chinese population. Methods: 233 first-degree relatives of patients with type 2 diabetes (T2D) with no history of blood glucose abnormalities and their 190 spouses, who did not have a family history of T2D, underwent a 75-g oral glucose tolerance test (OGTT). Based upon the OGTT, these two groups were further divided into three subgroups, including groups with normal glucose tolerance (NGT), impaired glucose regulation (IGR), and type 2 diabetes. Insulin resistance (IR) was evaluated usingthehomeostasismodelassessment IR (HOMA-IR), b-cell function indices of basal and first-phase were measured by DI1 (HOMA-b/HOMA-IR) and DI2 (DI30/DG30/HOMA- IR), respectively. Results: Among the first-degree relatives and their spouses, the HOMA-IR was highest in the T2D group and lowest in the NGT group. However, the HOMA-b, DI1 and DI2 declined significantly with progressive reductions in glucose tolerance (P < 0.01 or 0.05). DI1 and DI2 of the NGT group of first-degree relatives (FNGT) were significantly lower than those of the spouse NGT (SNGT) group (P < 0.05). DI1 and DI2 of the IGR of first-degree relatives (FIGR) group were significantly lower than those of the spouse IGR (SIGR) group. Conclusions: Defects in pancreatic b-cell function exist in the first-degree relatives, who have different glucose tolerance statuses, of T2D patients. These defects are more profound in FNGT and FIGR when compared to their spouses in corresponding glucose tolerance subgroups. However, there is no difference in IR between the corresponding glucose tolerance subgroups of the first-degree relatives and their spouses. It suggests that the genetic factor possibly aggravates b-cell lesion. # 2009 Published by Elsevier Ireland Ltd. 1. Introduction Insulin resistance (IR) and b-cell dysfunction are two major hallmarks in the pathogenesis of type 2 diabetes (T2D) [1], and which of these changes is responsible for initiating T2D and which contributes more in the development and progression of T2D is controversial [2]. Early studies suggested that IR was the predominant initiating factor of T2D; however, this concept has recently been revisited because these studies did not truly examine b-cell function by accounting for the now well-recognized effect of insulin resistance to increase insulin release, after adjusting for the effect of IR on the insulin secretion, many recent clinical studies indicated that functional defects in pancreatic b-cell contribute greatly to the development and progression of T2D [3 7]. Furthermore, among the novel T2D risk loci identified by genome-wide This work was supported by The National 863 Project of China (2004AA07) and The Chongqing Health Bureau Project (032080). * Corresponding author. Tel.: ; fax: addresses: towzh713@126.com (Z.-h. Wang), zhangsuhua0921@yahoo.com.cn (S.-H. Zhang) /$ see front matter # 2009 Published by Elsevier Ireland Ltd. doi: /j.diabres

2 62 association studies in recent 2 years, the transcription factor 7- like 2 (TCF7L2), the homeodomain protein HHEX, and the zinc transporter 8 (SLC30A8), et al. all appear to affect b-cell function but not IR [8]. It means that b-cell dysfunction seems to be more important in the pathogenesis of T2D whether by clinical investigation or by genetic study. In addition, it is well known that T2D results from the interaction of environmental factors with a combination of genetic factors [1]. However, the reported research results before did not exclude the impact of environmental factors on the b-cell function. The spouses of the first-degree relatives in T2D families who had no family history of diabetes shared similar environmental factors with the first-degree relatives, and they are mainly different from each other by hereditary factor. Thus, the current study analyzed and compared the functional defects of pancreatic b- cell and the alteration of IR in subgroups with different glucose tolerance, in first-degree relatives of T2D patients without a history of blood glucose abnormalities as well as their spouses, who did not have a family history of T2D, in Chinese population, and tried to understand the impact of genetic factor on pancreatic b-cell function. 2. Materials and methods 2.1. Subjects First-degree relatives (N = 233) of T2D patients without a history of glucose intolerance from 233 families with at least two T2D patients and their spouses (N = 190), who did not have a family history of T2D and glucose intolerance, living in Chongqing and its surrounding areas, aged years old, were selected for this study. The research project was approved by the medical ethics committee of The First Affiliated Hospital, Chongqing Medical University, and all subjects signed formal written informed consent. According to the 1999 WHO criteria [9], these subjects were subdivided into groups as follows: 72 belonged to the normal glucose tolerance group of spouses (SNGT); 63 belonged to the impaired glucose regulation [IGR: impaired fasting glucose (IFG) and/or impaired glucose tolerance (IGT)] group of spouses (SIGR); 54 belonged to the type 2 diabetes group of spouses (ST2D); 80 belonged to the normal glucose tolerance group of first-degree relatives (FNGT); 79 belonged to the impaired glucose regulation group of first-degree relatives (FIGR); and 74 belonged to the type 2 diabetes group of first-degree relatives (FT2D). Latent autoimmune diabetes in adults (LADA) was excluded in all subjects by assaying for antibodies specific for glutamic acid decarboxylase (GAD) and islet cell antibodies (ICA) in the serum, and maturity-onset diabetes of the young (MODY) was also excluded possibly according to the following clinical criteria [10]: (1) age of onset for at least one family member under 25 years, (2) correction of fasting hyperglycemia for at least 2 years without insulin, and (3) nonketotic diabetes Measurements Detailed histories were investigated in all the subjects according to the unified questionnaire for this study. Furthermore, physical parameters such as height, weight, waist circumference (WC), hip circumference, and blood pressure were measured during the fasting status. A 75-g oral glucose tolerance test (OGTT) was performed in all the subjects after 8 12 h of fasting. Biochemical indicators were measured after collecting the blood at fasting status and 30, 60, and 120 min after glucose loading. The glucose oxidase method was utilized for the measurement of plasma glucose, radioimmunoassays were used for the measurement of serum insulin (China Institute of Atomic Energy, Beijing, China), and an automatic biochemistry analyzer (OLYMPUS AU1000, OLYMPUS OPTICAL, LTD., Japan) measured the serum lipid profiles. The homeostasis model assessment for insulin resistance (HOMA-IR; fasting blood glucose fasting insulin/22.5) was applied for the evaluation of IR [11]. Two indices were utilized for the composite evaluation pancreatic b-cell secretory function [12,13], including (1) homeostasis model assessment for b-cell fuction [HOMA-b =20 fasting insulin/(fasting plasma glucose 3.5)]; (2) the ratio of the incremental insulin to glucose responses over the first 30 min during the OGTT, namely, DI30/DG30. In addition, according to the principle of the glucose disposition index (DI) proposed by Bergman et al. [14,15] and Kahn et al. [16], two indices, DI1 (HOMA-b/HOMA-IR) and DI2 (DI30/DG30/ HOMA-IR), were applied to reflect the compensatory alterations of pancreatic b-cells to IR and the maintenance of glucose homeostasis Statistical analysis Measurement data are expressed as mean standard deviation (s). Non-normal distribution data (insulin, HOMA-IR, HOMA-b, and DI) were transformed into normal distribution data with natural logarithms and then analyzed, and the x 2 - test was used for the comparison of ratios. Variance covariance analysis was used for the comparison of multiple groups. All the statistical analyses mentioned above were completed with SPSS version 11.5 for Windows. 3. Results The proportion of subjects in the six groups did not vary by sex (P > 0.05, Table 1). Among the first-degree relatives, the mean age of the FT2D group was significantly higher than that of FNGT group ( vs , Table 1). After adjusted for age, the waist circumference, body mass index (BMI), and waist-tohip ratio (WHR) of the FT2D and FIGR groups were significantly higher than those of the FNGT group (P < 0.01 and 0.05, respectively, Table 1). After adjusted for age, sex, and BMI using covariance analysis, HOMA-IR, Glu0, Glu30, Glu60, and Glu120 min were highest in the FT2D and lowest in the FNGT groups (Table 1). However, HOMA-b, DI1 and DI2 levels were statistically lower in the FT2D group and higher in the FNGT group. Ins30 and Ins120 of the FIGR group were significantly higher than those of the FNGT group; Ins30, Ins60, Ins120 and DI30/DG30 values of FT2D group were significantly lower than those of the FNGT and FIGR groups. There were no

3 63 Table 1 The clinical characteristics of the spouses and the first-degree relatives of T2D patients. Group Spouses First-degree relatives SNGT SIGR ST2D FNGT FIGR FT2D Case (n) Age (years) Sex (M/F) 30/43 33/30 26/28 36/44 33/46 35/49 WC (cm) BMI (kg/m 2 ) WHR SBP (mmhg) DBP (mmhg) Glu0 (mmol/l) Glu30 (mmol/l) Glu60 (mmol/l) Glu120 (mmol/l) Note: WC: waist circumference; BMI: body mass index; SBP: systolic blood pressure; 1 mmhg = kpa; DBP: diastolic blood pressure. Glu0: fasting plasma glucose; Glu30, Glu60, and Glu120: 30, 60, and 120 min plasma glucose during oral glucose tolerance test. In the spouses, compared to SNGT group: P < 0.05, P < 0.01; compared to SIGR group: P < 0.05, P < In the first-degree relatives, compared to the FNGT group: P < 0.05, P < 0.01; compared to FIGR group: P < 0.05, P < Comparison of FIGR group with SIGR group: P < 0.05, P < significantly differences in Ins0 between the three groups (Table 2). Among the spouses, the Ins60 and Ins120 values obtained from the OGTT for the SIGR group were significantly higher than those in SNGT group. Furthermore, the Ins30 and DI30/ DG30 values of the ST2D group were significantly lower than those of the SNGT group. Ins30, Ins60, Ins120 and DI30/DG30 values of ST2D were significantly lower than those of SIGR group (Table 2). After adjusted for age, sex, and BMI, the DI1 and DI2 values of the FNGT group was significantly lower when compared to the SNGT group (P < 0.05, Table 2 and Fig. 1). Although the mean age was younger in the FIGR group compared to the SIGR group, the DI30/DG30, DI1, and DI2 were significantly lower in the FIGR group (P < 0.05, Table 2 and Fig. 1). There were no significant differences in HOMA-IR, plasma glucose during OGTT, blood pressure, WC, WHR, and BMI measurements between subgroups of first-degree relatives and their corresponding subgroups of spouses (Tables 1 and 2). 4. Discussion Evaluating IR and pancreatic b-cell function comprises the basis for studying the pathogenesis of diabetes, anticipating the prognosis of diabetes, and formulating a rational treatment plan. Insulin-mediated glucose metabolic rate (M value) as measured by the hyperinsulinemic euglycemic clamp technique was the widely accepted gold standard for identifying the insulin sensitivity; however, its complicated, time-consuming nature makes it extremely difficult for the studies with large samples. HOMA-IR [11] correlate relatively well with the M value, and they are widely applied in the epidemiology and clinical research. However, evaluation of Table 2 The b-cell function and IR in the spouses and the first-degree relatives of T2D patients. Group Spouses First-degree relatives SNGT SIGR ST2D FNGT FIGR FT2D LNIns0 (mu/l) LNIns30 (mu/l) LNIns60 (mu/l) LNIns120 (mu/l) LNHOMA-IR LNHOMA-b LNDI30/DG LNDI LNDI Note: LNIns0: natural logarithm of fasting insulin; LNIns30, LNIns60, and LNIns120: natural logarithm of 30, 60, and 120 min serum insulin during oral glucose tolerance test; LNHoma-IR: natural logarithm of the homeostasis model assessment for insulin resistance; LNHoma-b: natural logarithm of the homeostasis model assessment of b-cell function; LNDI30/DG30: natural logarithm of the ratio of the differential value of 30 min insulin and fasting insulin (DI30) to the differential value of 30 min blood glucose and fasting glucose in the OGTT (DG30); and LNDI1, LNDI2: natural logarithm of the glucose disposition index. Comparison of FNGT group with SNGT group: P < 0.05, P < All other superscripts are indicated in Table 1.

4 64 Fig. 1 The indices of b-cell function and IR in the spouses and the first-degree relatives of T2D patients in corresponding glucose tolerance status. pancreatic b-cell function is more complicated, and at present, there is no index which can accurately reflect the b-cell function. For example, insulin secretion by b-cell not only includes changes of quality, quantity, and secretion phase, it is also regulated by glucose load and IR [17]. However, HOMA-b is a good index for evaluating basic insulin secretion [13], and DI30/DG30 is useful for evaluating the function of first-phase insulin secretion [12,13]. Hence, this study selected the two indices mentioned above to carry out the evaluation, and at the same time, to analyze any changes in insulin secretion at different phases. Insulin release is regulated by a feed-back loop, which includes both the insulin-sensitive tissues of the body and pancreatic b-cell. b-cell compensation for insulin sensitivity was calculated as the product of insulin sensitivity and insulin secretion, termed glucose disposition index. The DI describing the b-cell sensitivity secretion relationship as a rectangular hyperbola. Shifts in insulin sensitivity are accompanied by compensatory alterations in b-cell sensitivity to glucose. Insulin-sensitive subjects do not require a massive insulin response to exogenous glucose to maintain a normal blood glucose. But if their insulin sensitivity decreases by 80%, as in late pregnancy, they need a fivefold greater insulin response to achieve an identical disposition index. Women with gestational diabetes have an insulin response similar to that of normal volunteers; at first glance, this suggests similar islet function, but the utility of the DI is to normalize this response to the amplitude of third trimester insulin resistance, revealing severe b-cell deficiency. Therefore, this index is a constant, reflecting the compensatory ability of b-cells for the maintenance of glucose homeostasis in the body, and it is a quantitative, convenient, and accurate tool in analyzing b-cell function from epidemiologic data [14 16]. The present study applied the disposition indices composed of HOMA-IR and HOMA-b, HOMA-IR and DI30/DG30 further assess pancreatic b- cell function. In both first-degree relatives as well as their spouses, IR increased progressively (HOMA-IR gradually increased) from the NGT to the IGR and finally to the T2D subgroups, and at the same time, the pancreatic b-cell function decreased progressively (HOMA-b, DI1 and DI2 decreased gradually). These results were similar to those reported cross-sectional studies in groups of high risk subjects [3,12,18]. These findings demonstrated again that IR and b-cell dysfunction were characteristic features in both impaired glucose regulation and diabetes among the first-degree relatives and their spouses. Furthermore, as IR increased and b-cell function declined, glucose tolerance deteriorated. Therefore, the above result also strongly confirms that IR and b-cell dysfunction both are important contributors in the pathogenesis of T2D. Whether in groups of first-degree relatives or in their spouses, if the b-cell function was assessed singly by fasting insulin, there was no difference between the different glucose subgroups; if assessed singly by DI30/DG30, there was no difference between the SNGT and SIGR. However, when DI1 and DI2 were used to evaluate b-cell function, there were significant differences between the above subgroups. The finding was similar to that of Elbein et al. [19] who had found a heritability of b-cell function when it was assessed by DI, but no heritability when b-cell function was assessed by the insulin response to intravenous glucose in isolation. This result suggests that unless the loss of the insulin response is extremely large and already associated with frank diabetes, genetic defects will be difficult to identify unless the modulating effect of insulin sensitivity is considered. Also, it demonstrates that DI is sensitive index to identify early b- cell lesion. After adjusted for age, sex, and BMI, the DI1 and DI2 of the FNGT were significantly lower than those of the SNGT; however, the HOMA-IR, which estimates IR, increased but no significance. Considering the effect of IR on b-cell function, DI1 and DI2 indices reflect pancreatic b-cell function at the basal state and early phase more accurately, suggesting that the FNGT subgroup already had functional impairment of pancreatic b-cell without significant IR, which further confirms the results of most reports [3,6,18,20]. At the same time, it suggested that first-degree relatives with NGT were in a high risk group for developing T2D. Although the ages of the FIGR subgroup were younger than those of SIGR subgroup (the mean ages were and years, respectively), their DI30/DG30, DI1, and DI2 were significantly lower. At the same time, there was no significant difference between the two groups in HOMA-IR, plasma glucose, and insulin levels. These observations indicate that in the FIGR subgroup, insulin secretion defects

5 65 at both the basic state and first-phase were more serious than that in their spouses. Whether the DI1 and DI2 or the HOMA-b and DI30/DG30, which reflect pancreatic b-cell function at early stage, there are no difference significantly between the FT2D and ST2D subgroups. It suggests that when overt T2D was occurred, the b-cell dysfunction of basis and first-phase was not difference among first-relatives and their spouses. The result possibly correlated with the b-cell function indices were used here cannot estimate late stage b-cell dysfunction after glucose loading, thus it need further study to find other index to evaluate the late stage b-cell function. Functional defects in pancreatic b-cell exist in various glucose tolerance statuses in the first-degree relatives, and those defects were more serious than the accordant glucose tolerance status in their spouses except T2D subgroup. At the same time, there was no difference between first-degree relatives and their spouses of the accordant tolerance subgroups in IR. To date, this is the first report comparing relevant b-cell functions of impaired glucose tolerance subgroups in the first-degree relatives with corresponding people without a family history of diabetes. The spouses had no family history of diabetes, and they shared similar environmental factors with the first-degree relatives, suggests that the hereditary factors seemly aggravated the functional defect of b-cell in the first-degree relatives. The mechanism by which the hereditary factors affect the b-cell function is hitherto unknown. It is possibly related with the environmental factors, such as obesity and aging, acting on genetically susceptible virants of pancreatic b- cell and inducing the development of T2D. For example, TCF7L2 is the most important T2D susceptibility gene identified to date in all major racial groups, with the odds of developing T2D being increased by 30 50% for each allele inherited approximately double the odds ratio seen with most other diabetes susceptibility polymorphisms [21]. Lyssenko et al. [22] report on their human and isolated islet studies and suggest that the risk allele increases TCF7L2 expression in the pancreatic b-cell, reducing insulin secretion and hence predisposing the individual to diabetes. We would also like to mention potential limitations of the current report. Due to majority of participants were not obesity, which is the characteristic of Chinese, and the gene virants of MODY had not been examined in their DNA sample, some of them cannot fully excluded with MODY. But we indeedly had deleted a little diabetes families suspected with MODY according to the clinical features stated above. In addition, the prevalence of MODY in diabetes family is low (5 10%). Thus, the number of patients with MODY is theoretically little, and should not confound the result of this study. In summary, in the course of glucose tolerance from normal to impaired glucose regulation to diabetes, IR increases progressively, and pancreatic b-cell function also declines progressively. The functional defects in b-cell exist in all the glucose tolerance subgroups of the first-degree relatives of the family, and it is more serious in FNGT and FIGT than those of the corresponding glucose tolerance subgroups of their spouses without a family history of type 2 diabetes. However, there is no difference in IR between the corresponding glucose tolerance subgroups of the first-degree relatives and their spouses. These findings suggest that the genetic factor aggravates the b-cell deficiency. 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