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The Impact of a Family History of Type 2 Diabetes on Insulin Secretion and Insulin Sensitivity in Individuals With Varying Glucose Tolerance
CLINICAL INVESTIGATION
The Impact of a Family History of Type 2 Diabetes on Insulin Secretion and Insulin Sensitivity in Individuals With Varying Glucose Tolerance Ping Li, MD, Jing-Fan Zhang, MS, Ling Li, MD, PhD, Yu-Hui Liu, MD, Ying Shi, MD, Li-Wei Wang, MD, Jie-Qing Gao, MD and Cong Liu, MD, PhD
Abstract: Introduction: This study was performed to investigate the impact of a family history of type 2 diabetes (T2DM) on insulin resistance and beta-cell dysfunction in populations with varying glucose tolerance. Methods: Among the total of 142 participants, 73 subjects with no family history of T2DM (FH2) included 42 with normal glucose tolerance (NGT/FH2) and 31 with impaired glucose tolerance (IGT/FH2); and 69 first-degree relatives of patients with T2DM (FH+) included 36 with NGT (NGT/FH+) and 33 with IGT (IGT/FH+). Insulin resistance was evaluated by Insulin Sensitivity Index (ISI) based on the euglycemic hyperinsulinemic clamp. Islet betacell function was assessed by disposition index (DI) for the acute insulin response to glucose (AIRg) using intravenous glucose tolerance test. Metabolic data were compared between groups after adjustment for age, sex, body mass index and waist-to-hip ratio. Results: The NGT/FH+ group showed lower level of ISI (P 5 0.023) than the NGT/ FH2 group, whereas no difference was found in AIRg or DI between these 2 subgroups. In the FH2 individuals, both ISI and DI of the IGT/ FH2 group decreased compared with the NGT/FH2 group (both P , 0.05). In the FH+ individuals, no difference was found in ISI between the IGT/FH+ and NGT/FH+ groups, whereas the IGT/FH+ group had a lower level of AIRg and DI than the NGT/FH+ group (both P , 0.0001). Conclusions: This study showed that the pathophysiological changes were different between individuals with and without a family history of T2DM during the glucose tolerance aggravation. Key Indexing Terms: Type 2 diabetes; Family history; Impaired glucose tolerance; Insulin resistance; Beta-cell dysfunction. [Am J Med Sci 2013;345(1):22–27.]
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nsulin resistance and beta-cell dysfunction are 2 hallmarks of type 2 diabetes (T2DM). However, which of these is the major cause of initiation and damage during disease progression is still under debate. Extensive studies have found that there is an obvious heterogeneity among different ethnic populations.1–3 To address these questions, first-degree relatives with an inherited genetic background and high risk for T2DM were often chosen as suitable research subjects in many different countries. From the Department of Endocrinology (PL, J-FZ, LL, CL), Shengjing Hospital of China Medical University, Shenyang, Liaoning Province; The Second Department of Cadres (Y-HL), The General Hospital of Shenyang Military Region, Shenyang, Liaoning Province; Department of Endocrinology (YS), Shenyang Weikang Hospital, Shenyang, Liaoning Province; Department of Internal Medicine (L-WW), Beijing Nanyuan Hospital, Beijing; Department of Internal Medicine (J-QG), Beijing Xishan Hospital, Beijing; and The Liaoning Provincial Key Laboratory of Endocrine Diseases (LL), Shenyang, People’s Republic of China. Submitted November 25, 2011; accepted in revised form January 18, 2012. The study was supported by a grant (05L482) from the Education Department of Liaoning Province. Correspondence: Ling Li, MD, PhD, Department of Endocrinology, Shengjing Hospital of China Medical University, No. 39, Huaxiang Road, Tiexi District, Shenyang 110022, Liaoning Province, People’s Republic of China ( E-mail: [email protected]).
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For instance, a study in Japan revealed that an insulin secretion defect, rather than decreased insulin sensitivity, is the initial metabolic disorder in first-degree patients.4 This result was different from those obtained in other countries.5–10 Because of the differences among different populations, it would be interesting to know whether Chinese and Japanese people, 2 Asian populations, share the same physiological and pathological characteristics. Previous work has shown that, in individuals with the same level of glucose tolerance, insulin secretion function in first-degree relatives was significantly decreased compared with nonrelatives, with no observed difference in insulin sensitivity,11 which is very similar to results obtained from the Japanese population.4 Although much progress has been made regarding how genetic background affects the occurrence and development of T2DM, there are several issues that remain to be addressed. First, most studies have compared first-degree relatives with normal glucose tolerance (NGT) to NGT subjects with no family history of T2DM,4,8–10,12–14 whereas few studies have focused on firstdegree relatives with impaired glucose tolerance (IGT). Therefore, it is not clear how genetic background contributes to the conversion from NGT to IGT in the Chinese population with a family history of T2DM. Second, most studies on first-degree relatives with IGT have chosen nonrelative individuals with NGT as controls, instead of NGT relatives.7 Obviously, comparing pathophysiological characteristics under similar genetic backgrounds will shed more light on T2DM disease mechanisms. Last but not least, many studies have used oral glucose tolerance test (OGTT)derived formulas or the homeostatic model assessment (HOMA) index to assess insulin sensitivity and islet function.9–11,15,16 However, the gold standard for insulin sensitivity is hyperinsulinemic-euglycemic clamp, and intravenous glucose tolerance test (IVGTT) is considered to be better than the HOMA index for calculating the acute insulin response to glucose (AIRg).17 In this study, we used the hyperinsulinemic-euglycemic clamp and IVGTT to assess insulin resistance and beta-cell function, respectively. Our subjects were from the Han Chinese ethnic group living in Northeastern China and were divided into a first-degree group and 1 without a family history of T2DM. In each group, subjects were further divided into NGT and IGT subgroups based on their OGTT results. Our objective was to investigate how insulin resistance and beta-cell dysfunction develop with decreased glucose tolerance in people with or without a family history of T2DM. In addition, we sought to determine whether there was any pathophysiological difference in disease progression between these 2 groups of people.
METHODS Subjects A total of 142 Han Chinese subjects living in the northeast area were recruited from the outpatient department of our hospital. Of these, 73 were first-degree T2DM relatives
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(FH+) and were further divided into 2 subgroups by a 75-g OGTT with the measurement of fasting plasma glucose (FPG) concentration and 2-hour plasma glucose (2-hour PG) concentration according to the WHO 1999 diagnostic criteria. We selected 69 subjects without a family history of T2DM (FH2) who were of comparable age and gender with the FH+ group. The FH2 group was also divided into 2 subgroups (NGT/FH2, n 5 36; IGT/FH2, n 5 33) according to the OGTT results. All the subjects were aged between 20 and 70 years and were screened initially to confirm excellent health and the absence of any regular drug intake that may affect insulin sensitivity, blood pressure, circulating lipids or glucose. NGT (NGT/FH+, n 5 42) was defined as having an FPG level ,6.1 mmol/L and a 2-hour PG level ,7.8 mmol/L. IGT (IGT/FH+, n 5 31) was defined as having an FPG level ,6.1 mmol/L and a 2-hour PG level between 7.8 and 11.0 mmol/L. Individuals with IGT were diagnosed for the first time and had never been treated. There was no obvious difference in lifestyle among the subjects from the FH2 and FH+ groups. This study protocol was approved by the hospital ethics committee, and written informed consent was obtained from each person before participation. Methods and Assays All subjects received the euglycemic clamp and IVGTT, with at least 1 week between tests. During the 3 days before the study, the subjects consumed a weightmaintaining diet containing at least 200 g of carbohydrate per day. Before the study, an appointed researcher measured the subjects’ height, body weight, waist and hip circumstances and accordingly calculated the body mass index (BMI) 5 body weight/height2 (kg/m2) and waist-to-hip ratio (WHR) 5 waist circumstance/hip circumstance. The Hyperinsulin-Euglycemic Clamp At 8:00 am, after a 10- to 12-hour overnight fast, subjects underwent the hyperinsulin-euglycemic clamp. One polyethylene cannula was inserted into an antecubital vein for the infusion of glucose and insulin. A wrist vein on the dorsum of the other hand was cannulated retrogradely for blood sampling to measure PG and insulin concentration, and the arm was kept in a heated box in which the air temperature was maintained at 65°C to ensure arterialization of venous blood. After lying quietly for 15 to 20 minutes, the subjects were given a continuous infusion of insulin (Novolin R, Denmark) at a constant speed of 40 mU/m2 (body surface area) and a variable infusion rate of a 25% solution of glucose simultaneously adjusted according to the PG level. During the experiment, blood samples were taken at 5- to 10-minute intervals for immediate determination of glucose concentration by a glucose oxidase analyzer (BIOSEN 5030, Germany). The PG concentration was maintained at ;5 mmol/L by the periodic adjustment of glucose infusion according to the PG level until steady-state conditions of glucose infusion and constant euglycemia were achieved. The Intravenous Glucose Tolerance Test At 8:00 AM, after a 10- to 12-hour overnight fast, a 25% solution of glucose was infused intravenously at a precise rate of 0.5 g/kg (body weight) in 3 minutes. Blood samples for the determination of PG and serum insulin levels were taken before initiating the infusion and at 1, 3, 5, 10 and 30 minutes after the infusion was finished. PG level was measured by the same method as above. Serum insulin samples were stored at 220°C for later analysis by radioimmunoassay (China Institute of Atomic Energy, Beijing). Ó 2013 Lippincott Williams & Wilkins
Calculations Insulin sensitivity was expressed as the ratio between the average glucose infusion rate (GIR) during the final 40 minutes of the euglycemic clamp test and the average serum insulin concentration during the same interval, referred to as the Insulin Sensitivity Index (ISI). The mean of the incremental insulin response between 1 and 10 minutes after glucose injection was calculated as the AIRg. To evaluate whether AIR was adequate to compensate for insulin resistance, the disposition index (DI) was calculated as ISI 3 AIRg, based on the known hyperbolic relationship between these 2 variables,18 a relationship that is not affected by sex or differences in glucose tolerance.19 Statistical Analyses Statistical analysis was performed using SPSS version 17.0. Normally distributed variables are given as means 6 standard error. The nonnormally distributed data (GIR, ISI, AIRg and DI) were ln transformed to achieve a normal distribution and are expressed as geometric means with 95% confidence intervals given. Continuous variables were compared between groups using analysis of variance followed by the least significant difference test for variables for which the F test was significant. Metabolic data were compared between groups by analysis of covariance (ANCOVA) adjusted for age, sex, BMI and WHR. A 2-sided P , 0.05 was considered statistically significant.
RESULTS Demographic and Anthropometric Characteristics No substantial difference existed in age and sex between groups. Compared with the 2 groups with NGT, the IGT/FH2 and IGT/FH+ groups had significantly higher BMI and WHR (all P , 0.01). In comparison with the NGT/FH2 group, FPG and 2-hour PG during the OGTT were significantly increased in the IGT/FH+ and IGT/FH2 groups (all P , 0.01; Table 1). No subject who had impaired fasting glucose was included in the IGT/FH+ or IGT/FH2 groups. Euglycemic Clamp In the euglycemic clamp, the steady-state insulin levels were similar among all the 4 groups (Table 2). In the FH2 individuals, the IGT/FH2 subgroup with decreased glucose tolerance had lower levels of GIR and ISI than the NGT/FH2 subgroup (both P , 0.001) after adjustment for age, gender, BMI and WHR, indicating that insulin resistance was a major pathophysiological change along with decreasing glucose tolerance. However, in the FH+ subjects, no differences in GIR or ISI levels were found between the IGT/FH+ and NGT/FH+ subgroups (P 5 0.191 and 0.085, respectively), suggesting that insulin resistance did not contribute significantly to the decreasing glucose tolerance in the first-degree relatives. When we compared the subgroups with different genetic backgrounds, we found that GIR and ISI levels in the NGT/FH+ subgroup were clearly lower than those in the NGT/FH2 subgroup (P , 0.001 and P 5 0.023, respectively) (Figure 1), after adjustment for age, gender, BMI and WHR. In fact, ISI in the NGT/FH+ subgroup was as low as that in the IGT/FH2 subgroup, suggesting that although subjects in the NGT/FH+ subgroup had NGT, they already showed detectable insulin resistance as severe as that of IGT patients without a family history of T2DM.
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TABLE 1. Clinical characteristics of subjects and oral glucose tolerance test results NGT/FH2 IGT/FH2 NGT/FH+ n Age (yr) Gender (M/F) BMI (kg/m2) WHR OGTT FPG (mmol/L) 2-hr PG (mmol/L)
IGT/FH+
P for trend
42 43.9 6 13.5 19/23 24.0 6 2.6 0.82 6 0.05
31 49.3 6 12.3 12/19 26.3 6 1.4a 0.89 6 0.03a
36 44.1 6 15.2 18/18 24.6 6 2.0b 0.84 6 0.04a,b
33 49.5 6 9.3 14/19 25.5 6 1.9b 0.86 6 0.04a,b
— 0.110 0.819 ,0.0001 ,0.0001
4.7 6 0.4 5.4 6 1.0
5.1 6 0.5a 8.7 6 0.7a
4.9 6 0.4b 5.0 6 0.9a
5.2 6 0.4a,b 9.0 6 0.8a
,0.0001 ,0.0001
P , 0.0001 and b P , 0.05 vs. NGT/FH–. P , 0.0001 and b P , 0.05 vs. IGT/FH–. a P , 0.0001 and b P , 0.05 vs. NGT/FH+. NGT, normal glucose tolerance; FH, family history of T2DM; IGT, impaired glucose tolerance; BMI, body mass index; WHR, waist-to-hip ratio; OGTT, oral glucose tolerance test; FPG, fasting plasma glucose; 2-hr PG, 2-hr plasma glucose. a a
Intravenous Glucose Tolerance Test After adjustment for age and gender, fasting serum insulin level was higher in the IGT/FH2 and IGT/FH+ subgroups than in the 2 NGT subgroups (all P , 0.05). However, after adjustment for BMI and WHR, in addition to age and gender, there was no significant difference in fasting serum insulin level among groups, indicating that fasting serum insulin level was related to obesity (Table 3). In FH2 individuals, IVGTT showed that AIR was significantly decreased in the IGT/FH2 subgroup (P , 0.001), after adjusting for age, gender, BMI and WHR. Similarly, in FH+ individuals, AIR was obviously decreased in the IGT/FH+ subgroup (P , 0.001) in comparison with the NGT/FH+ subgroup (Figure 2). After adjusting for age, gender, BMI and WHR, we found that AIR and DI were at the same level between the 2 NGT subgroups and between the 2 IGT subgroups (Figure 2). We also found that AIR of the NGT/FH+ subgroup seemed to be higher than that of the NGT/FH2 subgroup (Figure 2). Although this difference was not statistically significant (P 5 0.584), it represents a compensation for insulin resistance present in NGT/FH+ individuals that maintained the DI of NGT/FH+ in the normal range, so that the NGT/FH+ individuals could still regulate their blood glucose adequately.
DISCUSSION Insulin sensitivity and insulin secretion are 2 interconnected functions that are crucial for maintaining stable blood
TABLE 2. Euglycemic clamp test results NGT/FH2 (n 5 42) Glucose infusion rate (mg$kg21$min21) Steady-state insulin (mU$L21) Insulin Sensitivity Index (mg$kg21$min21$mU21$L)
glucose levels. These processes have a hyperbolic relationship, as defined in Bergman’s model.20 In such a model, if 1 component deteriorates and the other 1 fails to compensate, blood glucose will increase. We are especially interested in finding out which component first fails to function properly and which contributes most to disease progression. In addition, we are interested in the potential differences among different ethnic populations. First-degree relatives of individuals with T2DM are particularly intriguing subjects for this research due to their inherited genetic background. In this study, we have chosen ethnic Han Chinese individuals living in Northeastern China and have selected subjects with and without a family history of T2DM. We found that first-degree relatives of T2DM already exhibited insulin resistance when they were euglycemic and that decreased insulin secretion played a key role in the development of glucose intolerance in these people. We also found that in individuals without a family history of T2DM, both insulin sensitivity and insulin secretion decreased significantly when glucose tolerance started to deteriorate. People with and without a family history of T2DM had different pathophysiological characteristics during the progression from NGT to IGT. Furthermore, these differences were independent of obesity or body fat distribution. In a study conducted in Poland, first-degree relatives of T2DM with NGT and BMI less than 25 were chosen as research subjects. Compared with the control group with no family history, the nonobese first-degree relatives had lower insulin sensitivity, but their insulin secretion function remained unchanged.13
IGT/FH2 (n 5 31)
NGT/FH+ (n 5 36)
IGT/FH+ (n 5 33)
P for trend
10.32 (9.56–11.08)
5.81 (4.14–7.48)a
7.17 (6.52–7.82)a
6.36 (5.65–7.07)a
,0.0001
93.5 (78.9–108.1)
100.7 (83.9–117.6)
90.3 (76.7–103.8)
105.7 (90.8–120.7)
0.689
0.070 (0.059–0.082)a
0.002
0.138 (0.116–0.161)
0.086 (0.054–0.118)b
0.100 (0.078–0.122)b
All data were adjusted for age, gender, BMI and WHR using ANCOVA. Nonnormally distributed data were ln transformed to achieve a normal distribution before comparison. a P , 0.0001 and b P , 0.05 vs. NGT/FH2. NGT, normal glucose tolerance; FH, family history of T2DM; IGT, impaired glucose tolerance; BMI, body mass index; WHR, waist-to-hip ratio; ANCOVA, analysis of covariance.
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FIGURE 1. Glucose infusion rate (GIR) and Insulin Sensitivity Index (ISI) in the euglycemic clamp test in 4 subgroups. All data were analyzed after adjustment for age, gender, body mass index (BMI) and waist-to-hip ratio (WHR). *P , 0.05 and **P , 0.0001 versus normal glucose tolerance with no family history of T2DM (NGT/FH2).
A large-scale study conducted in Australia also showed that insulin sensitivity was already decreased in first-degree relatives with NGT.8 Our data revealed that in ethnic Han people from Northeastern China, first-degree relatives of T2DM with NGT had significantly stronger insulin resistance but normal insulin secretion. This finding is similar to the studies conducted in Poland and Australia and demonstrates that inherited factors first influence insulin sensitivity but have no obvious effect on betacell function. However, these findings are opposite to those of the aforementioned results obtained by the Japanese researchers using the HOMA index.4 Some studies concluded that insulin resistance in euglycemic first-degree relatives of individuals with T2DM was secondary to obesity and increased abdominal fat.7,21 In this study, individuals in the NGT/FH+ and NGT/FH2 groups did not have significantly different BMI or WHR levels, and ANCOVA was used to control for small differences resulting from confounding factors. Therefore, we reasoned that the decrease in insulin sensitivity observed was independent of
TABLE 3. Intravenous glucose tolerance test results NGT/FH2 (n 5 42) Fasting serum insulin (mU$L21) Acute insulin response to glucose (mU$L21) Disposition index (mg$kg21$min21)
obesity and body fat distribution. This is consistent with results obtained from a multicenter study conducted in Europe.10 Other studies that support this conclusion include one in which phosphoprotein enriched in astrocytes 15 expression was found to be 2-fold higher in individuals with a family history of T2DM than in euglycemic individuals with no family history of diabetes, both at the protein and the messenger RNA level.22 This finding led to the conclusion that phosphoprotein enriched in astrocytes 15 overexpression represents a common defect in first-degree relatives of individuals with T2DM and is correlated with reduced insulin sensitivity in these individuals. In addition, a previous study performed hyperinsulin-euglycemic clamp analysis of 247 nondiabetic offspring of T2DM patients and found that adipose tissue sirtuin 1 (SIRT1) messenger RNA expression was clearly associated with insulin sensitivity.23 Together with our results, these studies illustrate that insulin resistance is under the influence of genetic factors, rather than secondary to environmental factors such as obesity.
IGT/FH2 (n 5 31)
NGT/FH+ (n 5 36)
IGT/FH+ (n 5 33)
P for trend
12.1 (10.3–13.8)
20.6 (12.9–28.2)
14.4 (9.8–19.1)
18.9 (13.9–23.9)
0.216
46.3 (41.2–51.4)
31.3 (26.2–36.5)a
53.7 (44.2–63.2)b
33.0 (26.4–39.6)a,c
,0.0001
6.79 (5.25–8.33)
2.32 (1.49–3.15)a
5.07 (3.77–6.37)b
2.30 (1.68–2.91)a,c
,0.0001
All data were adjusted for age, gender, BMI and WHR using ANCOVA. Nonnormally distributed data were ln transformed to achieve a normal distribution before comparison. a P , 0.0001 vs. NGT/FH–. b P , 0.0001 vs. IGT/FH–. c P , 0.0001 vs. NGT/FH+. NGT, normal glucose tolerance; FH, family history of T2DM; IGT, impaired glucose tolerance; ANCOVA, analysis of covariance.
Ó 2013 Lippincott Williams & Wilkins
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FIGURE 2. Acute insulin response to glucose (AIRg) and disposition index (DI) in the intravenous glucose tolerance test (IVGTT) for 4 subgroups. All data were analyzed after adjustment for age, gender, body mass index (BMI) and waist-to-hip ratio (WHR). **P , 0.0001 versus normal glucose tolerance with no family history of T2DM (NGT/FH2); ##P , 0.0001 versus IGT/FH2; DDP , 0.0001 versus NGT/FH+.
This study showed that in first-degree relatives, insulin resistance did not become more severe with worsening glucose tolerance, whereas insulin secretion function progressively decreased. It remains a question whether this impairment of beta-cell function is caused by inherited factors of first-degree relatives or whether beta cells are exhausted by long-term insulin resistance. A recent study in the Relationship Between Insulin Sensitivity and Cardiovascular Disease cohort investigating the associations between novel T2DM susceptibility gene loci found that the diabetes-risk alleles for CDK5 regulatory subunit associated protein 1-like 1, hemopoietically expressed homeobox, insulin degrading enzyme and transcription factor 7-like 2 were associated with a decrease in beta-cell function in nondiabetic individuals in an additive manner, providing evidence for the influence of inherited factors.24 However, whether environmental factors such as obesity still exert influence on the decreasing glucose tolerance of firstdegree relatives remains to be determined. A previous study followed up 33 first-degree relatives with NGT and found that dysfunction of insulin secretion, rather than insulin resistance, played an important role in progression from NGT to IGT and that this role was strengthened by obesity and abdominal fat.25 This finding partly confirmed our hypothesis that, in first-degree relatives, inherited factors tend to affect insulin sensitivity at the euglycemic stage with compensation from excessive insulin secretion, and glucose tolerance aggravation appears when inherited or environmental factors cause decreases in insulin secretion, so that the compensation effect is lost. Therefore, it is still important for first-degree relatives to control body weight and avoid central obesity to protect beta-cell function and prevent T2DM. For people without a family history of T2DM, our results showed that when they became glucose intolerant, both their insulin sensitivity and AIRg decreased, indicating that both insulin resistance and beta-cell dysfunction contributed to the development of the disease. The same results were obtained after adjusting for BMI and WHR, suggesting that both insulin resistance and beta-cell dysfunction were independent of obesity and abdominal fat. This is consistent with the study performed previously using similar methods as the euglycemic clamp and IVGTT.26 In theory, people without a family history have much lower risk for developing T2DM. So, what are the driving forces that cause insulin resistance and abnormal insulin secretion in these subjects? Do these 2 dysfunctions appear simultaneously or is one of them an initiator? These questions remain unclear. Taking NGT subjects with no family history as controls, our results showed that whether there was a family history of T2DM, ISI and DI were significantly lower in the IGT
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subgroups than in the 2 corresponding NGT subgroups (both P , 0.001), respectively. This suggests that people with IGT eventually exhibited decreased insulin sensitivity and defective insulin secretion, although the pathophysiological changing course was different in the 2 populations. There are several limitations in this study. First, it is a cross-sectional study with a relatively small sample size, which limits our conclusions regarding the temporality of the observed association. Second, because IGT individuals generally have higher BMI and WHR than NGT controls, we were not able to obtain 2 groups with matched BMI values. However, the ANCOVA method was used to eliminate the influence of BMI. In conclusion, our results point to pathophysiological differences in disease progression from euglycemia to IGT between people with a family history of T2DM and people with no family history. We found that in individuals with no family history of T2DM, decreased glucose tolerance was affected by both insulin resistance and insufficient insulin release. On the other hand, in first-degree relatives of individuals with T2DM, insulin resistance already existed when their glucose levels were normal, and dysfunction in insulin secretion was the key factor in determining the progression of glucose intolerance. REFERENCES 1. Haffner SM, D’Agostino R, Saad MF, et al. Increased insulin resistance and insulin secretion in nondiabetic African-Americans and Hispanics compared with non-Hispanic whites. The Insulin Resistance Atherosclerosis Study. Diabetes 1996;45:742–8. 2. Pimenta WP, Santos ML, Cruz NS, et al. Brazilian individuals with impaired glucose tolerance are characterized by impaired insulin secretion. Diabetes Metab 2002;28:468–76. 3. Mari A, Tura A, Natali A, et al; RISC Investigators. Impaired beta cell glucose sensitivity rather than inadequate compensation for insulin resistance is the dominant defect in glucose intolerance. Diabetologia 2010;53:749–56. 4. Matsumoto K, Sakamaki H, Izumino K, et al. Increased insulin sensitivity and decreased insulin secretion in offspring of insulin-sensitive type 2 diabetic patients. Metabolism 2000;49:1219–23. 5. Rasouli N, Spencer HJ, Rashidi AA, et al. Impact of family history of diabetes and ethnicity on -cell function in obese, glucose-tolerant individuals. J Clin Endocrinol Metab 2007;92:4656–63. 6. Pimenta WP, Santos ML, Cruz NS, et al. Insulin secretion, insulin sensitivity, and hepatic insulin extraction in first-degree relatives of type 2 diabetic patients. Braz J Med Biol Res 2003;36:301–8. 7. Emerson P, Van Haeften TW, Pimenta W, et al. Different pathophysiology of impaired glucose tolerance in first-degree relatives of individuals with type 2 diabetes mellitus. Metabolism 2009;58:602–7.
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8. Stadler M, Pacini G, Petrie J, et al; RISC Investigators. Beta cell (dys)function in non-diabetic offspring of diabetic patients. Diabetologia 2009;52:2435–44.
from an intravenous glucose tolerance test. Diabetes 2008;57: 1638–44.
9. Guerrer-Romer F, Rodríguez-Morán M, González-Ortiz M, et al. Insulin action and secretion in healthy Hispanic-Mexican first-degree relatives of subjects with type 2 diabetes. J Endocrinol Invest 2001;24:580–6.
18. Kahn SE, Prigeon RL, McCulloch DK, et al. Quantification of the relationship between insulin sensitivity and beta-cell function in human subjects. Evidence for a hyperbolic function. Diabetes 1993; 42:1663–72.
10. Vaag A, Lehtovirta M, Thye-Rönn P, et al; European Group of Insulin Resistance. Metabolic impact of a family history of type 2 diabetes. Results from a European multicentre study (EGIR). Diabet Med 2001;18:533–40.
19. Utzschneider KM, Prigeon RL, Carr DB, et al. Impact of differences in fasting glucose and glucose tolerance on the hyperbolic relationship between insulin sensitivity and insulin responses. Diabetes Care 2006; 29:356–62.
11. Wang ZH, Zhang SH, Gong LL, et al. The impact of family history of type 2 diabetes on pancreatic beta-cell function. Diabetes Res Clin Pract 2009;86:61–6.
20. Bergman RN, Ader M, Huecking K, et al. Accurate assessment of beta-cell function: the hyperbolic correction. Diabetes 2002;51(suppl 1): S212–20.
12. Mari A, Gastaldelli A, Natali A, et al. Characterization of beta-cell function impairment in first-degree relatives of type 2 diabetic subjects: modeling analysis of 24-h triple-meal tests. Am J Physiol Endocrinol Metab 2005;288:E541–6.
21. Osei K, Cottrell DA, Orabella MM. Insulin sensitivity, glucose effectiveness, and body fat distribution pattern in nondiabetic offspring of patients with NIDDM. Diabetes Care 1991;14:890–6.
13. Straczkowski M, Kowalska I, Stepie n A, et al. Insulin resistance in the first-degree relatives of persons with type 2 diabetes. Med Sci Monit 2003;9:CR186–90. 14. Nyholm B, Pørksen N, Juhl CB, et al. Assessment of insulin secretion in relatives of patients with type 2 (non-insulin-dependent) diabetes mellitus: evidence of early beta-cell dysfunction. Metabolism 2000; 49:896–905. 15. Jensen CC, Cnop M, Hull RL, et al; American Diabetes Association GENNID Study Group. Beta-cell function is a major contributor to oral glucose tolerance in high-risk relatives of four ethnic groups in the U.S. Diabetes 2002;51:2170–8. 16. DeFronzo RA, Tobin JD, Andres R. Glucose clamp technique: a method for quantifying insulin secretion and resistance. Am J Physiol 1979;237:E214–23. 17. Festa A, Williams K, Hanley AJ, et al. Beta-cell dysfunction in subjects with impaired glucose tolerance and early type 2 diabetes: comparison of surrogate markers with first-phase insulin secretion
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22. Valentino R, Lupoli GA, Raciti GA, et al. The PEA15 gene is overexpressed and related to insulin resistance in healthy first-degree relatives of patients with type 2 diabetes. Diabetologia 2006;49: 3058–66. 23. Rutanen J, Yaluri N, Modi S, et al. SIRT1 mRNA expression may be associated with energy expenditure and insulin sensitivity. Diabetes 2010;59:829–35. 24. Pascoe L, Frayling TM, Weedon MN, et al; RISC Consortium. Beta cell glucose sensitivity is decreased by 39% in non-diabetic individuals carrying multiple diabetes-risk alleles compared with those with no risk alleles. Diabetologia 2008;51:1989–92. 25. Cnop M, Vidal J, Hull RL, et al. Progressive loss of beta-cell function leads to worsening glucose tolerance in first-degree relatives of subjects with type 2 diabetes. Diabetes care 2007;30:677–82. 26. Weyer C, Tataranni PA, Bogardus C, et al. Insulin resistance and insulin secretory dysfunction are independent predictors of worsening of glucose tolerance during each stage of type 2 diabetes development. Diabetes Care 2001;24:89–94.
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The Impact of a Family History of Type 2 Diabetes on Insulin Secretion and Insulin Sensitivity in Individuals With Varying Glucose Tolerance Ping Li, MD, Jing-Fan Zhang, MS, Ling Li, MD, PhD, Yu-Hui Liu, MD, Ying Shi, MD, Li-Wei Wang, MD, Jie-Qing Gao, MD and Cong Liu, MD, PhD
Abstract: Introduction: This study was performed to investigate the impact of a family history of type 2 diabetes (T2DM) on insulin resistance and beta-cell dysfunction in populations with varying glucose tolerance. Methods: Among the total of 142 participants, 73 subjects with no family history of T2DM (FH2) included 42 with normal glucose tolerance (NGT/FH2) and 31 with impaired glucose tolerance (IGT/FH2); and 69 first-degree relatives of patients with T2DM (FH+) included 36 with NGT (NGT/FH+) and 33 with IGT (IGT/FH+). Insulin resistance was evaluated by Insulin Sensitivity Index (ISI) based on the euglycemic hyperinsulinemic clamp. Islet betacell function was assessed by disposition index (DI) for the acute insulin response to glucose (AIRg) using intravenous glucose tolerance test. Metabolic data were compared between groups after adjustment for age, sex, body mass index and waist-to-hip ratio. Results: The NGT/FH+ group showed lower level of ISI (P 5 0.023) than the NGT/ FH2 group, whereas no difference was found in AIRg or DI between these 2 subgroups. In the FH2 individuals, both ISI and DI of the IGT/ FH2 group decreased compared with the NGT/FH2 group (both P , 0.05). In the FH+ individuals, no difference was found in ISI between the IGT/FH+ and NGT/FH+ groups, whereas the IGT/FH+ group had a lower level of AIRg and DI than the NGT/FH+ group (both P , 0.0001). Conclusions: This study showed that the pathophysiological changes were different between individuals with and without a family history of T2DM during the glucose tolerance aggravation. Key Indexing Terms: Type 2 diabetes; Family history; Impaired glucose tolerance; Insulin resistance; Beta-cell dysfunction. [Am J Med Sci 2013;345(1):22–27.]
I
nsulin resistance and beta-cell dysfunction are 2 hallmarks of type 2 diabetes (T2DM). However, which of these is the major cause of initiation and damage during disease progression is still under debate. Extensive studies have found that there is an obvious heterogeneity among different ethnic populations.1–3 To address these questions, first-degree relatives with an inherited genetic background and high risk for T2DM were often chosen as suitable research subjects in many different countries. From the Department of Endocrinology (PL, J-FZ, LL, CL), Shengjing Hospital of China Medical University, Shenyang, Liaoning Province; The Second Department of Cadres (Y-HL), The General Hospital of Shenyang Military Region, Shenyang, Liaoning Province; Department of Endocrinology (YS), Shenyang Weikang Hospital, Shenyang, Liaoning Province; Department of Internal Medicine (L-WW), Beijing Nanyuan Hospital, Beijing; Department of Internal Medicine (J-QG), Beijing Xishan Hospital, Beijing; and The Liaoning Provincial Key Laboratory of Endocrine Diseases (LL), Shenyang, People’s Republic of China. Submitted November 25, 2011; accepted in revised form January 18, 2012. The study was supported by a grant (05L482) from the Education Department of Liaoning Province. Correspondence: Ling Li, MD, PhD, Department of Endocrinology, Shengjing Hospital of China Medical University, No. 39, Huaxiang Road, Tiexi District, Shenyang 110022, Liaoning Province, People’s Republic of China ( E-mail: [email protected]).
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For instance, a study in Japan revealed that an insulin secretion defect, rather than decreased insulin sensitivity, is the initial metabolic disorder in first-degree patients.4 This result was different from those obtained in other countries.5–10 Because of the differences among different populations, it would be interesting to know whether Chinese and Japanese people, 2 Asian populations, share the same physiological and pathological characteristics. Previous work has shown that, in individuals with the same level of glucose tolerance, insulin secretion function in first-degree relatives was significantly decreased compared with nonrelatives, with no observed difference in insulin sensitivity,11 which is very similar to results obtained from the Japanese population.4 Although much progress has been made regarding how genetic background affects the occurrence and development of T2DM, there are several issues that remain to be addressed. First, most studies have compared first-degree relatives with normal glucose tolerance (NGT) to NGT subjects with no family history of T2DM,4,8–10,12–14 whereas few studies have focused on firstdegree relatives with impaired glucose tolerance (IGT). Therefore, it is not clear how genetic background contributes to the conversion from NGT to IGT in the Chinese population with a family history of T2DM. Second, most studies on first-degree relatives with IGT have chosen nonrelative individuals with NGT as controls, instead of NGT relatives.7 Obviously, comparing pathophysiological characteristics under similar genetic backgrounds will shed more light on T2DM disease mechanisms. Last but not least, many studies have used oral glucose tolerance test (OGTT)derived formulas or the homeostatic model assessment (HOMA) index to assess insulin sensitivity and islet function.9–11,15,16 However, the gold standard for insulin sensitivity is hyperinsulinemic-euglycemic clamp, and intravenous glucose tolerance test (IVGTT) is considered to be better than the HOMA index for calculating the acute insulin response to glucose (AIRg).17 In this study, we used the hyperinsulinemic-euglycemic clamp and IVGTT to assess insulin resistance and beta-cell function, respectively. Our subjects were from the Han Chinese ethnic group living in Northeastern China and were divided into a first-degree group and 1 without a family history of T2DM. In each group, subjects were further divided into NGT and IGT subgroups based on their OGTT results. Our objective was to investigate how insulin resistance and beta-cell dysfunction develop with decreased glucose tolerance in people with or without a family history of T2DM. In addition, we sought to determine whether there was any pathophysiological difference in disease progression between these 2 groups of people.
METHODS Subjects A total of 142 Han Chinese subjects living in the northeast area were recruited from the outpatient department of our hospital. Of these, 73 were first-degree T2DM relatives
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(FH+) and were further divided into 2 subgroups by a 75-g OGTT with the measurement of fasting plasma glucose (FPG) concentration and 2-hour plasma glucose (2-hour PG) concentration according to the WHO 1999 diagnostic criteria. We selected 69 subjects without a family history of T2DM (FH2) who were of comparable age and gender with the FH+ group. The FH2 group was also divided into 2 subgroups (NGT/FH2, n 5 36; IGT/FH2, n 5 33) according to the OGTT results. All the subjects were aged between 20 and 70 years and were screened initially to confirm excellent health and the absence of any regular drug intake that may affect insulin sensitivity, blood pressure, circulating lipids or glucose. NGT (NGT/FH+, n 5 42) was defined as having an FPG level ,6.1 mmol/L and a 2-hour PG level ,7.8 mmol/L. IGT (IGT/FH+, n 5 31) was defined as having an FPG level ,6.1 mmol/L and a 2-hour PG level between 7.8 and 11.0 mmol/L. Individuals with IGT were diagnosed for the first time and had never been treated. There was no obvious difference in lifestyle among the subjects from the FH2 and FH+ groups. This study protocol was approved by the hospital ethics committee, and written informed consent was obtained from each person before participation. Methods and Assays All subjects received the euglycemic clamp and IVGTT, with at least 1 week between tests. During the 3 days before the study, the subjects consumed a weightmaintaining diet containing at least 200 g of carbohydrate per day. Before the study, an appointed researcher measured the subjects’ height, body weight, waist and hip circumstances and accordingly calculated the body mass index (BMI) 5 body weight/height2 (kg/m2) and waist-to-hip ratio (WHR) 5 waist circumstance/hip circumstance. The Hyperinsulin-Euglycemic Clamp At 8:00 am, after a 10- to 12-hour overnight fast, subjects underwent the hyperinsulin-euglycemic clamp. One polyethylene cannula was inserted into an antecubital vein for the infusion of glucose and insulin. A wrist vein on the dorsum of the other hand was cannulated retrogradely for blood sampling to measure PG and insulin concentration, and the arm was kept in a heated box in which the air temperature was maintained at 65°C to ensure arterialization of venous blood. After lying quietly for 15 to 20 minutes, the subjects were given a continuous infusion of insulin (Novolin R, Denmark) at a constant speed of 40 mU/m2 (body surface area) and a variable infusion rate of a 25% solution of glucose simultaneously adjusted according to the PG level. During the experiment, blood samples were taken at 5- to 10-minute intervals for immediate determination of glucose concentration by a glucose oxidase analyzer (BIOSEN 5030, Germany). The PG concentration was maintained at ;5 mmol/L by the periodic adjustment of glucose infusion according to the PG level until steady-state conditions of glucose infusion and constant euglycemia were achieved. The Intravenous Glucose Tolerance Test At 8:00 AM, after a 10- to 12-hour overnight fast, a 25% solution of glucose was infused intravenously at a precise rate of 0.5 g/kg (body weight) in 3 minutes. Blood samples for the determination of PG and serum insulin levels were taken before initiating the infusion and at 1, 3, 5, 10 and 30 minutes after the infusion was finished. PG level was measured by the same method as above. Serum insulin samples were stored at 220°C for later analysis by radioimmunoassay (China Institute of Atomic Energy, Beijing). Ó 2013 Lippincott Williams & Wilkins
Calculations Insulin sensitivity was expressed as the ratio between the average glucose infusion rate (GIR) during the final 40 minutes of the euglycemic clamp test and the average serum insulin concentration during the same interval, referred to as the Insulin Sensitivity Index (ISI). The mean of the incremental insulin response between 1 and 10 minutes after glucose injection was calculated as the AIRg. To evaluate whether AIR was adequate to compensate for insulin resistance, the disposition index (DI) was calculated as ISI 3 AIRg, based on the known hyperbolic relationship between these 2 variables,18 a relationship that is not affected by sex or differences in glucose tolerance.19 Statistical Analyses Statistical analysis was performed using SPSS version 17.0. Normally distributed variables are given as means 6 standard error. The nonnormally distributed data (GIR, ISI, AIRg and DI) were ln transformed to achieve a normal distribution and are expressed as geometric means with 95% confidence intervals given. Continuous variables were compared between groups using analysis of variance followed by the least significant difference test for variables for which the F test was significant. Metabolic data were compared between groups by analysis of covariance (ANCOVA) adjusted for age, sex, BMI and WHR. A 2-sided P , 0.05 was considered statistically significant.
RESULTS Demographic and Anthropometric Characteristics No substantial difference existed in age and sex between groups. Compared with the 2 groups with NGT, the IGT/FH2 and IGT/FH+ groups had significantly higher BMI and WHR (all P , 0.01). In comparison with the NGT/FH2 group, FPG and 2-hour PG during the OGTT were significantly increased in the IGT/FH+ and IGT/FH2 groups (all P , 0.01; Table 1). No subject who had impaired fasting glucose was included in the IGT/FH+ or IGT/FH2 groups. Euglycemic Clamp In the euglycemic clamp, the steady-state insulin levels were similar among all the 4 groups (Table 2). In the FH2 individuals, the IGT/FH2 subgroup with decreased glucose tolerance had lower levels of GIR and ISI than the NGT/FH2 subgroup (both P , 0.001) after adjustment for age, gender, BMI and WHR, indicating that insulin resistance was a major pathophysiological change along with decreasing glucose tolerance. However, in the FH+ subjects, no differences in GIR or ISI levels were found between the IGT/FH+ and NGT/FH+ subgroups (P 5 0.191 and 0.085, respectively), suggesting that insulin resistance did not contribute significantly to the decreasing glucose tolerance in the first-degree relatives. When we compared the subgroups with different genetic backgrounds, we found that GIR and ISI levels in the NGT/FH+ subgroup were clearly lower than those in the NGT/FH2 subgroup (P , 0.001 and P 5 0.023, respectively) (Figure 1), after adjustment for age, gender, BMI and WHR. In fact, ISI in the NGT/FH+ subgroup was as low as that in the IGT/FH2 subgroup, suggesting that although subjects in the NGT/FH+ subgroup had NGT, they already showed detectable insulin resistance as severe as that of IGT patients without a family history of T2DM.
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TABLE 1. Clinical characteristics of subjects and oral glucose tolerance test results NGT/FH2 IGT/FH2 NGT/FH+ n Age (yr) Gender (M/F) BMI (kg/m2) WHR OGTT FPG (mmol/L) 2-hr PG (mmol/L)
IGT/FH+
P for trend
42 43.9 6 13.5 19/23 24.0 6 2.6 0.82 6 0.05
31 49.3 6 12.3 12/19 26.3 6 1.4a 0.89 6 0.03a
36 44.1 6 15.2 18/18 24.6 6 2.0b 0.84 6 0.04a,b
33 49.5 6 9.3 14/19 25.5 6 1.9b 0.86 6 0.04a,b
— 0.110 0.819 ,0.0001 ,0.0001
4.7 6 0.4 5.4 6 1.0
5.1 6 0.5a 8.7 6 0.7a
4.9 6 0.4b 5.0 6 0.9a
5.2 6 0.4a,b 9.0 6 0.8a
,0.0001 ,0.0001
P , 0.0001 and b P , 0.05 vs. NGT/FH–. P , 0.0001 and b P , 0.05 vs. IGT/FH–. a P , 0.0001 and b P , 0.05 vs. NGT/FH+. NGT, normal glucose tolerance; FH, family history of T2DM; IGT, impaired glucose tolerance; BMI, body mass index; WHR, waist-to-hip ratio; OGTT, oral glucose tolerance test; FPG, fasting plasma glucose; 2-hr PG, 2-hr plasma glucose. a a
Intravenous Glucose Tolerance Test After adjustment for age and gender, fasting serum insulin level was higher in the IGT/FH2 and IGT/FH+ subgroups than in the 2 NGT subgroups (all P , 0.05). However, after adjustment for BMI and WHR, in addition to age and gender, there was no significant difference in fasting serum insulin level among groups, indicating that fasting serum insulin level was related to obesity (Table 3). In FH2 individuals, IVGTT showed that AIR was significantly decreased in the IGT/FH2 subgroup (P , 0.001), after adjusting for age, gender, BMI and WHR. Similarly, in FH+ individuals, AIR was obviously decreased in the IGT/FH+ subgroup (P , 0.001) in comparison with the NGT/FH+ subgroup (Figure 2). After adjusting for age, gender, BMI and WHR, we found that AIR and DI were at the same level between the 2 NGT subgroups and between the 2 IGT subgroups (Figure 2). We also found that AIR of the NGT/FH+ subgroup seemed to be higher than that of the NGT/FH2 subgroup (Figure 2). Although this difference was not statistically significant (P 5 0.584), it represents a compensation for insulin resistance present in NGT/FH+ individuals that maintained the DI of NGT/FH+ in the normal range, so that the NGT/FH+ individuals could still regulate their blood glucose adequately.
DISCUSSION Insulin sensitivity and insulin secretion are 2 interconnected functions that are crucial for maintaining stable blood
TABLE 2. Euglycemic clamp test results NGT/FH2 (n 5 42) Glucose infusion rate (mg$kg21$min21) Steady-state insulin (mU$L21) Insulin Sensitivity Index (mg$kg21$min21$mU21$L)
glucose levels. These processes have a hyperbolic relationship, as defined in Bergman’s model.20 In such a model, if 1 component deteriorates and the other 1 fails to compensate, blood glucose will increase. We are especially interested in finding out which component first fails to function properly and which contributes most to disease progression. In addition, we are interested in the potential differences among different ethnic populations. First-degree relatives of individuals with T2DM are particularly intriguing subjects for this research due to their inherited genetic background. In this study, we have chosen ethnic Han Chinese individuals living in Northeastern China and have selected subjects with and without a family history of T2DM. We found that first-degree relatives of T2DM already exhibited insulin resistance when they were euglycemic and that decreased insulin secretion played a key role in the development of glucose intolerance in these people. We also found that in individuals without a family history of T2DM, both insulin sensitivity and insulin secretion decreased significantly when glucose tolerance started to deteriorate. People with and without a family history of T2DM had different pathophysiological characteristics during the progression from NGT to IGT. Furthermore, these differences were independent of obesity or body fat distribution. In a study conducted in Poland, first-degree relatives of T2DM with NGT and BMI less than 25 were chosen as research subjects. Compared with the control group with no family history, the nonobese first-degree relatives had lower insulin sensitivity, but their insulin secretion function remained unchanged.13
IGT/FH2 (n 5 31)
NGT/FH+ (n 5 36)
IGT/FH+ (n 5 33)
P for trend
10.32 (9.56–11.08)
5.81 (4.14–7.48)a
7.17 (6.52–7.82)a
6.36 (5.65–7.07)a
,0.0001
93.5 (78.9–108.1)
100.7 (83.9–117.6)
90.3 (76.7–103.8)
105.7 (90.8–120.7)
0.689
0.070 (0.059–0.082)a
0.002
0.138 (0.116–0.161)
0.086 (0.054–0.118)b
0.100 (0.078–0.122)b
All data were adjusted for age, gender, BMI and WHR using ANCOVA. Nonnormally distributed data were ln transformed to achieve a normal distribution before comparison. a P , 0.0001 and b P , 0.05 vs. NGT/FH2. NGT, normal glucose tolerance; FH, family history of T2DM; IGT, impaired glucose tolerance; BMI, body mass index; WHR, waist-to-hip ratio; ANCOVA, analysis of covariance.
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FIGURE 1. Glucose infusion rate (GIR) and Insulin Sensitivity Index (ISI) in the euglycemic clamp test in 4 subgroups. All data were analyzed after adjustment for age, gender, body mass index (BMI) and waist-to-hip ratio (WHR). *P , 0.05 and **P , 0.0001 versus normal glucose tolerance with no family history of T2DM (NGT/FH2).
A large-scale study conducted in Australia also showed that insulin sensitivity was already decreased in first-degree relatives with NGT.8 Our data revealed that in ethnic Han people from Northeastern China, first-degree relatives of T2DM with NGT had significantly stronger insulin resistance but normal insulin secretion. This finding is similar to the studies conducted in Poland and Australia and demonstrates that inherited factors first influence insulin sensitivity but have no obvious effect on betacell function. However, these findings are opposite to those of the aforementioned results obtained by the Japanese researchers using the HOMA index.4 Some studies concluded that insulin resistance in euglycemic first-degree relatives of individuals with T2DM was secondary to obesity and increased abdominal fat.7,21 In this study, individuals in the NGT/FH+ and NGT/FH2 groups did not have significantly different BMI or WHR levels, and ANCOVA was used to control for small differences resulting from confounding factors. Therefore, we reasoned that the decrease in insulin sensitivity observed was independent of
TABLE 3. Intravenous glucose tolerance test results NGT/FH2 (n 5 42) Fasting serum insulin (mU$L21) Acute insulin response to glucose (mU$L21) Disposition index (mg$kg21$min21)
obesity and body fat distribution. This is consistent with results obtained from a multicenter study conducted in Europe.10 Other studies that support this conclusion include one in which phosphoprotein enriched in astrocytes 15 expression was found to be 2-fold higher in individuals with a family history of T2DM than in euglycemic individuals with no family history of diabetes, both at the protein and the messenger RNA level.22 This finding led to the conclusion that phosphoprotein enriched in astrocytes 15 overexpression represents a common defect in first-degree relatives of individuals with T2DM and is correlated with reduced insulin sensitivity in these individuals. In addition, a previous study performed hyperinsulin-euglycemic clamp analysis of 247 nondiabetic offspring of T2DM patients and found that adipose tissue sirtuin 1 (SIRT1) messenger RNA expression was clearly associated with insulin sensitivity.23 Together with our results, these studies illustrate that insulin resistance is under the influence of genetic factors, rather than secondary to environmental factors such as obesity.
IGT/FH2 (n 5 31)
NGT/FH+ (n 5 36)
IGT/FH+ (n 5 33)
P for trend
12.1 (10.3–13.8)
20.6 (12.9–28.2)
14.4 (9.8–19.1)
18.9 (13.9–23.9)
0.216
46.3 (41.2–51.4)
31.3 (26.2–36.5)a
53.7 (44.2–63.2)b
33.0 (26.4–39.6)a,c
,0.0001
6.79 (5.25–8.33)
2.32 (1.49–3.15)a
5.07 (3.77–6.37)b
2.30 (1.68–2.91)a,c
,0.0001
All data were adjusted for age, gender, BMI and WHR using ANCOVA. Nonnormally distributed data were ln transformed to achieve a normal distribution before comparison. a P , 0.0001 vs. NGT/FH–. b P , 0.0001 vs. IGT/FH–. c P , 0.0001 vs. NGT/FH+. NGT, normal glucose tolerance; FH, family history of T2DM; IGT, impaired glucose tolerance; ANCOVA, analysis of covariance.
Ó 2013 Lippincott Williams & Wilkins
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FIGURE 2. Acute insulin response to glucose (AIRg) and disposition index (DI) in the intravenous glucose tolerance test (IVGTT) for 4 subgroups. All data were analyzed after adjustment for age, gender, body mass index (BMI) and waist-to-hip ratio (WHR). **P , 0.0001 versus normal glucose tolerance with no family history of T2DM (NGT/FH2); ##P , 0.0001 versus IGT/FH2; DDP , 0.0001 versus NGT/FH+.
This study showed that in first-degree relatives, insulin resistance did not become more severe with worsening glucose tolerance, whereas insulin secretion function progressively decreased. It remains a question whether this impairment of beta-cell function is caused by inherited factors of first-degree relatives or whether beta cells are exhausted by long-term insulin resistance. A recent study in the Relationship Between Insulin Sensitivity and Cardiovascular Disease cohort investigating the associations between novel T2DM susceptibility gene loci found that the diabetes-risk alleles for CDK5 regulatory subunit associated protein 1-like 1, hemopoietically expressed homeobox, insulin degrading enzyme and transcription factor 7-like 2 were associated with a decrease in beta-cell function in nondiabetic individuals in an additive manner, providing evidence for the influence of inherited factors.24 However, whether environmental factors such as obesity still exert influence on the decreasing glucose tolerance of firstdegree relatives remains to be determined. A previous study followed up 33 first-degree relatives with NGT and found that dysfunction of insulin secretion, rather than insulin resistance, played an important role in progression from NGT to IGT and that this role was strengthened by obesity and abdominal fat.25 This finding partly confirmed our hypothesis that, in first-degree relatives, inherited factors tend to affect insulin sensitivity at the euglycemic stage with compensation from excessive insulin secretion, and glucose tolerance aggravation appears when inherited or environmental factors cause decreases in insulin secretion, so that the compensation effect is lost. Therefore, it is still important for first-degree relatives to control body weight and avoid central obesity to protect beta-cell function and prevent T2DM. For people without a family history of T2DM, our results showed that when they became glucose intolerant, both their insulin sensitivity and AIRg decreased, indicating that both insulin resistance and beta-cell dysfunction contributed to the development of the disease. The same results were obtained after adjusting for BMI and WHR, suggesting that both insulin resistance and beta-cell dysfunction were independent of obesity and abdominal fat. This is consistent with the study performed previously using similar methods as the euglycemic clamp and IVGTT.26 In theory, people without a family history have much lower risk for developing T2DM. So, what are the driving forces that cause insulin resistance and abnormal insulin secretion in these subjects? Do these 2 dysfunctions appear simultaneously or is one of them an initiator? These questions remain unclear. Taking NGT subjects with no family history as controls, our results showed that whether there was a family history of T2DM, ISI and DI were significantly lower in the IGT
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subgroups than in the 2 corresponding NGT subgroups (both P , 0.001), respectively. This suggests that people with IGT eventually exhibited decreased insulin sensitivity and defective insulin secretion, although the pathophysiological changing course was different in the 2 populations. There are several limitations in this study. First, it is a cross-sectional study with a relatively small sample size, which limits our conclusions regarding the temporality of the observed association. Second, because IGT individuals generally have higher BMI and WHR than NGT controls, we were not able to obtain 2 groups with matched BMI values. However, the ANCOVA method was used to eliminate the influence of BMI. In conclusion, our results point to pathophysiological differences in disease progression from euglycemia to IGT between people with a family history of T2DM and people with no family history. We found that in individuals with no family history of T2DM, decreased glucose tolerance was affected by both insulin resistance and insufficient insulin release. On the other hand, in first-degree relatives of individuals with T2DM, insulin resistance already existed when their glucose levels were normal, and dysfunction in insulin secretion was the key factor in determining the progression of glucose intolerance. REFERENCES 1. Haffner SM, D’Agostino R, Saad MF, et al. Increased insulin resistance and insulin secretion in nondiabetic African-Americans and Hispanics compared with non-Hispanic whites. The Insulin Resistance Atherosclerosis Study. Diabetes 1996;45:742–8. 2. Pimenta WP, Santos ML, Cruz NS, et al. Brazilian individuals with impaired glucose tolerance are characterized by impaired insulin secretion. Diabetes Metab 2002;28:468–76. 3. Mari A, Tura A, Natali A, et al; RISC Investigators. Impaired beta cell glucose sensitivity rather than inadequate compensation for insulin resistance is the dominant defect in glucose intolerance. Diabetologia 2010;53:749–56. 4. Matsumoto K, Sakamaki H, Izumino K, et al. Increased insulin sensitivity and decreased insulin secretion in offspring of insulin-sensitive type 2 diabetic patients. Metabolism 2000;49:1219–23. 5. Rasouli N, Spencer HJ, Rashidi AA, et al. Impact of family history of diabetes and ethnicity on -cell function in obese, glucose-tolerant individuals. J Clin Endocrinol Metab 2007;92:4656–63. 6. Pimenta WP, Santos ML, Cruz NS, et al. Insulin secretion, insulin sensitivity, and hepatic insulin extraction in first-degree relatives of type 2 diabetic patients. Braz J Med Biol Res 2003;36:301–8. 7. Emerson P, Van Haeften TW, Pimenta W, et al. Different pathophysiology of impaired glucose tolerance in first-degree relatives of individuals with type 2 diabetes mellitus. Metabolism 2009;58:602–7.
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8. Stadler M, Pacini G, Petrie J, et al; RISC Investigators. Beta cell (dys)function in non-diabetic offspring of diabetic patients. Diabetologia 2009;52:2435–44.
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9. Guerrer-Romer F, Rodríguez-Morán M, González-Ortiz M, et al. Insulin action and secretion in healthy Hispanic-Mexican first-degree relatives of subjects with type 2 diabetes. J Endocrinol Invest 2001;24:580–6.
18. Kahn SE, Prigeon RL, McCulloch DK, et al. Quantification of the relationship between insulin sensitivity and beta-cell function in human subjects. Evidence for a hyperbolic function. Diabetes 1993; 42:1663–72.
10. Vaag A, Lehtovirta M, Thye-Rönn P, et al; European Group of Insulin Resistance. Metabolic impact of a family history of type 2 diabetes. Results from a European multicentre study (EGIR). Diabet Med 2001;18:533–40.
19. Utzschneider KM, Prigeon RL, Carr DB, et al. Impact of differences in fasting glucose and glucose tolerance on the hyperbolic relationship between insulin sensitivity and insulin responses. Diabetes Care 2006; 29:356–62.
11. Wang ZH, Zhang SH, Gong LL, et al. The impact of family history of type 2 diabetes on pancreatic beta-cell function. Diabetes Res Clin Pract 2009;86:61–6.
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12. Mari A, Gastaldelli A, Natali A, et al. Characterization of beta-cell function impairment in first-degree relatives of type 2 diabetic subjects: modeling analysis of 24-h triple-meal tests. Am J Physiol Endocrinol Metab 2005;288:E541–6.
21. Osei K, Cottrell DA, Orabella MM. Insulin sensitivity, glucose effectiveness, and body fat distribution pattern in nondiabetic offspring of patients with NIDDM. Diabetes Care 1991;14:890–6.
13. Straczkowski M, Kowalska I, Stepie n A, et al. Insulin resistance in the first-degree relatives of persons with type 2 diabetes. Med Sci Monit 2003;9:CR186–90. 14. Nyholm B, Pørksen N, Juhl CB, et al. Assessment of insulin secretion in relatives of patients with type 2 (non-insulin-dependent) diabetes mellitus: evidence of early beta-cell dysfunction. Metabolism 2000; 49:896–905. 15. Jensen CC, Cnop M, Hull RL, et al; American Diabetes Association GENNID Study Group. Beta-cell function is a major contributor to oral glucose tolerance in high-risk relatives of four ethnic groups in the U.S. Diabetes 2002;51:2170–8. 16. DeFronzo RA, Tobin JD, Andres R. Glucose clamp technique: a method for quantifying insulin secretion and resistance. Am J Physiol 1979;237:E214–23. 17. Festa A, Williams K, Hanley AJ, et al. Beta-cell dysfunction in subjects with impaired glucose tolerance and early type 2 diabetes: comparison of surrogate markers with first-phase insulin secretion
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22. Valentino R, Lupoli GA, Raciti GA, et al. The PEA15 gene is overexpressed and related to insulin resistance in healthy first-degree relatives of patients with type 2 diabetes. Diabetologia 2006;49: 3058–66. 23. Rutanen J, Yaluri N, Modi S, et al. SIRT1 mRNA expression may be associated with energy expenditure and insulin sensitivity. Diabetes 2010;59:829–35. 24. Pascoe L, Frayling TM, Weedon MN, et al; RISC Consortium. Beta cell glucose sensitivity is decreased by 39% in non-diabetic individuals carrying multiple diabetes-risk alleles compared with those with no risk alleles. Diabetologia 2008;51:1989–92. 25. Cnop M, Vidal J, Hull RL, et al. Progressive loss of beta-cell function leads to worsening glucose tolerance in first-degree relatives of subjects with type 2 diabetes. Diabetes care 2007;30:677–82. 26. Weyer C, Tataranni PA, Bogardus C, et al. Insulin resistance and insulin secretory dysfunction are independent predictors of worsening of glucose tolerance during each stage of type 2 diabetes development. Diabetes Care 2001;24:89–94.
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