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Short communication *Corresponding author Nanette Steinle, Baltimore Veterans Affairs Medical Center, 10 North, Greene Street Room 5D 142, Baltimore, MD 21201, USA, Tel: 1 (410)605-7432; Eating Behavior Disinhibition Fax: 1 (410) 605-7849; Email:

Submitted: 24 May 2017 Predicts Insulin Resistance in Accepted: 30 June 2017 Published: 30 June 2017 the Old Order Amish ISSN: 2333-6706 Copyright 1 2 1 Sara Schwab , Timothy Xu , Kathleen Ryan , and Nanette © 2017 Steinle et al. Steinle1,3* OPEN ACCESS 1Division of Endocrinology, Diabetes & Nutrition, University of Maryland School of Medicine, USA Keywords 2Emory University, USA • Disinhibition 3Baltimore Veteran Affairs Medical Center, USA • Insulin sensitivity

Abstract Background: Eating behavior is influenced by genetics and environment, and is associated with many obesity related conditions. Objective: We assessed the relationship between self-reported disinhibition scores and insulin resistance assessed during an oral glucose tolerance test (OGTT). Design: The study included 779 volunteers from the Amish Family Diabetes Study; 77 with Type 2 Diabetes Mellitus, 133 with Impaired Glucose Tolerance [IGT] and 569 with Normal Glucose Tolerance [NGT]. All patients with IGT and NGT completed oral glucose tolerance tests [OGTT], and had insulin levels measured during the OGTT. Volunteers completed the Three-Factor Eating Questionnaire to quantify self-perceived disinhibition. Conclusions: Higher disinhibition scores are associated with higher fasting insulin levels and insulin area under the curve during an OGTT. These results suggest a highly significant, positive correlation between the eating behavior disinhibition and insulin insensitivity. Treatments aimed at modifying eating behavior may be helpful in mitigating insulin resistance.

ABBREVIATIONS by others who overeat. It is a predictor of weight gain and body mass index [BMI], particularly in women [2-8]. Prior studies AFDS: Amish Family Diabetes Study; OOA: Old Order Amish; have shown higher disinhibition to be associated with metabolic GAD: Glutamic Acid Decarboxylase; GABA: Gamma-Aminobutyric syndrome and T2DM [4,5]. Acid; TFQ: Three-Factor Questionnaire; OGTT: Oral Glucose Tolerance Tests; T2DM: Type 2 Diabetes; IGT: Impaired Glucose Tolerance; NGT: Normal Glucose Tolerance; HFD: High Fat Diet; environmental factors [3,9-12]. With respect to disinhibition, heritabilityEating behavior was estimated is influenced to be 0.40 by in both the Amish genetic Family and WAT: White Adipose Tissue Diabetes Study (AFDS) [3]; while in the Quebec Family Study INTRODUCTION the heritability of disinhibition was estimated to be 0.19 [10].

Eating behavior encompasses an individual’s food preferences, disinhibition, including a common variant in TAS2R38, belonging toSpecific the TAS2R gene gene variants family have of bitter been taste associated receptors, with while increased other psychological, social, as well as genetic factors. Uncontrolled TAS2R gene variants have been associated with altered glucose meal selection, and food intake. It is influenced by physiological, eating behavior impacts dietary intake and contributes to the and insulin homeostasis in AFDS [9]. Another gene, neuromedin-β, increasing prevalence of obesity-related conditions such as which encodes aneuropeptide that mediatessatiety, has been diabetes, hypertension, and coronary artery disease, and related shown to be associated with disinhibited eating behavior in the metabolic conditions including insulin resistance. Quebec Family Study [10]. Additionally, gene variants coding for glutamic acid decarboxylase [GAD], which is involved in gamma-aminobutyric acid [GABA] synthesis, are also linked to hunger, and disinhibition. As measured by the Three Factor Eating Quantifiable components of eating behavior include restraint, disinhibition and increased carbohydrate intake [11]. Due to disinhibition’s association with genetic factors and measuresQuestionnaire an individual’s [TFEQ], restraint subjective is defineddesire to as eat the [1]. intentional Here, we its potential role in the development of obesity and metabolic focusavoidance on disinhibition: of specific foods characterized to control body by overeating, weight and impaired hunger dysregulation, we hypothesized that self-reported disinhibition satiety, and the counter-regulation of restraint. Disinhibition attributes could predict insulin resistance, an archetypal diabetes is also thought of as the tendency to overeat when surrounded characteristic.

Cite this article: Schwab S, Xu T, Ryan K, Steinle N (2017) Eating Behavior Disinhibition Predicts Insulin Resistance in the Old Order Amish. J Hum Nutr Food Sci 5(2): 1109. Steinle et al. (2017) Email:

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Central Bringing Excellence in Open Access METHODS in all subjects or just age and sex in non-diabetes subjects. ANOVA models were used to measure the relationship between Subjects were participants in the AFDS, which began in disinhibition scores and diabetes. All analyses were carried out in 1995 as previously described [13]. They are members of the SAS 9.3 [Carey, NC]. Old Order Amish of Lancaster, Pennsylvania and have similar socioeconomic status, a common lifestyle, a genetically well- RESULTS Of the 779 participants who completed the TFQ, 77 [10%] were characterized as diagnosed with Type 2 Diabetes [T2DM] defined founder population with large families, and extensive the Amish Research Clinic [ARC] in Strasburg, PA. Individuals with [18 probands and 59 with newly diagnosed T2D]; 133 [17%] genealogical records. Briefly, participants were enrolled through had impaired glucose tolerance [IGT] and 569 [73%] had normal glucose tolerance [NGT]. The mean age of participants with T2DM type 2 diabetes were identified through door-to-door interviews with previously diagnosed diabetes with an age at diagnosis of was 62+/- 11.4 years, those with IGT were 52+/- 14.9 years and and by word of mouth. Probands were defined as individuals those with NGT were 42+/- 13.9 years [p<0.0001] Characteristics y were recruited around the probands. If another individual with of the cohort are further described in Table 1. Fasting insulin 35–65 y. All first- and second-degree family members aged ≥18 levels were positively correlated with mean disinhibition scores. Participants with fasting insulin levels <8.025mU/ml [n=208] diabetes was identified in the family [eg, aunt or uncle], the family had mean disinhibition scores of 4.7 ± 0.2, those with fasting was expanded further to include the first- and second-degree oral glucose tolerance test at the ARC as well as the Three Factor insulin levels >8.025 mU/ml and <= 10.085 mU/ml [n=195] relatives aged ≥18 y of that individual. Participants completed an Questionnaire [TFQ]. had mean disinhibition scores of 4.9 ± 0.2, those with fasting The TFQ is commonly used to quantify dimensions of insulin levels >10.085 mU/ml but <=12.95 mU/ml [n=187] had eating behavior and was devised by Stunkard and Messick [1]. mean disinhibition scores of 5.2 ± 0.2, and those with fasting Participants were administered the TFQ to quantify their self- insulin levels >12.945mU/ml [n=189] had mean disinhibition perceived disinhibition, as well as restraint and hunger attributes. scores of 6.1 ± 0.2 [p=0.0001]. Insulin AUC during the OGTT was Subjects evaluated numerous disinhibition statements such as, “I also associated with disinhibition [beta = 0.00575, p=0.0003]. usually eat too much at social occasions, like parties and picnics” However, disinhibition was not associated with fasting glucose and “Sometimes when I start eating, I just can’t seem to stop.” [p=0.62], glucose AUC [p=0.50], or insulin secretion [p=0.91]

Oral glucose tolerance tests [OGTT] were administered to by diabetes status, disinhibition scores for participants with participants who had no prior diagnosis of T2DM to determine newlywhen adjusted diagnosed for age, diabetes sex, and compared diabetes status. to those When with stratified NGT glucose and insulin response. Glucose and insulin were measured diabetes [n=59] had a mean disinhibition score of 5.8 ± 0.3; IGT and insulin curves [glucose AUC and insulin AUC] were calculated participantstrended toward [n=133] being had significant; a mean disinhibition those with score newly of diagnosed 5.7 ± 0.3, toat five assess time glycemic points during response the OGTT. to oral The glucose areas administrationunder the glucose as while NGT participants [n=569] had a mean disinhibition score of previously described [13]. Standard glucose cut off parameters 5.0 ± 0.1[p=0.05]. This trend was not observed when comparing participants with diabetes who previously knew of their diabetes consent. The study was approved by the University of Maryland status and participants without diabetes [mean disinhibition Baltimorewere used Institutionalto define diabetes. Review All Board. participants provided informed score 5.9 ± 0.6 vs. 5.2 ± 0.1, p=0.21]. Pearson correlation factor for disinhibition score vs sex was 0.19 [p<0.0001], as women STATISTICAL ANALYSES tended to have higher disinhibition scores compared to men. No Disinhibition scores were measured using the TFEQ [3]. Mean correlation was seen for disinhibition score vs age [p=0.13]. The ± standard errors and frequencies and univariate correlations analysis also showed a difference in hunger scores when data between disinhibition scores and age and sex were calculated. was analyzed by newly diagnosed vs non diabetes status [mean Linear regression was used to investigate the relationship hunger score 6.1 ± 0.6 vs. 4.6 ± 0.1, p=0.001].No differences were between disinhibition scores and insulin/glucose traits. The observed for the eating behavior restraint when analyzed vs linear regressions were adjusted for age, sex, and diabetic status insulin, glucose or diabetes status.

Table 1: Characteristics of study participants. Characteristic T2DM IGT NGT P-values N=77 N=133 N=569 Age (years) 61.89 +/- 11.42 51.96 +/- 14.92 41.87 +/- 13.91 <0.0001 Sex – No. (%) Male 28 (7.7) 44 (12.0) 294 (80.3) <0.0001 Female 49 (11.9) 89 (21.6) 275 (66.6) BMI (kg/m2) 29.25 +/- 4.53 28.72 +/- 5.32 26.44 +/- 4.37 <0.0001 Fasting Glucose (mg/dl) 135.82 +/- 60.21 93.33 +/- 8.49 89.53 +/- 8.07 <0.0001 Fasting insulin (mg/dl) 17.31 +/- 32.63 12.25 +/- 7.48 10.69 +/- 5.82 <0.0001 *Plus-minus values are means +/- SD

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Central Bringing Excellence in Open Access DISCUSSION population of European ancestry [26.9 kg/m2] vs. [26.5 kg/m2] Prior studies have shown higher disinhibition to be associated with poor metabolic health. A cross sectional study by Straub insulinrespectively sensitivity. [13]. WeWith recognize respect to that how both these modifiable traits may [lifestyle] impact et al. [4], found that those with T2DM and a high disinhibition and non modifiable factors [genetics] impact eating behavior and score were more likely to have poor glycemic control. Hainer et behavior and insulin resistance observed in this adult cohort al., found that individuals with higher disinhibition scores were areor be likely modified to be by generalizable BMI, we believe to thethat general the links population between eating given more likely to have metabolic syndrome, including increased similarities in BMI. BMI, weight circumference, hypercholesterolemia, hypertension Although weight gain and obesity measures correlate with disinhibition as measured by the TFQ, to our knowledge, no other and cardiovascular disease [5]. Although Hainer et al., did not find reports have shown direct correlation between disinhibition as restraint,an association and diabetes. between Chearskul disinhibition et al., and found T2DM; that obese they didwomen find measured by the TFQ and insulin resistance assessed with an hadsignificant higher correlations disinhibition between scores, the plasma eating glucose, behaviors and hunger, insulin when compared to non-obese Thai women [14]. These trends is associated with insulin resistance, insulin area under the curve, andOGT. aOur trend findings toward suggest diabetes that higher status self-reported in the OOA. disinhibition Participants a positive correlation between insulin levels during an OGT and in our cohort with newly diagnosed diabetes also tended to disinhibitionare consistent scores. with findings in the current study, as we observed report higher hunger scores. In the future, development of clinical assessment of disinhibited eating behavior may be a In other studies, higher disinhibition scores have also been associated with increased liking and use of sweets, pastries, early interventions aimed at changing eating behavior with the butter and margarine, foods high in carbohydrates and fats goaluseful of in achieving helping and identify maintaining individuals healthy who eating may benefitpatterns from and [15,16] which, if consumed in excess could promote insulin preserving cellular function to prevent insulin resistance and the resistance. Although disinhibition is only a crude measure of development of type 2 diabetes. Traditional dietary assessments one’s propensity to consume surplus nutrients, our results are include questions with respect to food intake, but typically do consistent with contemporary literature linking nutrient surplus not probe eating behaviors. Future research should focus on with changes in molecular physiology that contribute to insulin developing an easily administered tool to identify disinhibited resistance. eating behavior, along with strategies to promote and sustain At the molecular level, high fat diet [HFD] and overfeeding prudent eating behavior practices. have been linked to inhibition of sirtuins, a family of proteins that are primarily NAD-dependent deacetylases that modulate ACKNOWLEDGEMENTS mitochondrial function and metabolism [17-19]. Decreased SIRT3 Sources of support expression leads to mitochondrial protein hyperacetylation [19-21]; byproducts of mitochondrial-derived acetyl-CoA Mid Atlantic Nutrition and Obesity Center NIH/ accumulate in liver and muscle cells, and have been proposed NIDDKP30DK072488. to epigenetically alter gene expression by increasing nuclear The original AFDS study was supported by grants from Glaxo histone acetyltransferase activity and inhibiting nuclear histone WellcomeInc, Sequana Therapeutics, the NIH [R01 DK54261 deacetylase [22,23]. HFD has also been implicated in inhibiting and K24 DK02673], the American Diabetes Association, and the SIRT1, which is involved in liver gluconeogenesis, white adipose Hopkins Bayview General Clinical Research Center. tissue fat mobilization, and pancreatic insulin signaling [24,25]. SIRT1 promotes browning of white adipose tissue [WAT], Short running head which is important for repressing insulin resistance associated Disinhibited eating behavior is associated with insulin with visceral WAT [25]. HFD has also been shown to activate resistance. in adipose tissue and leads to metabolic dysfunction [26]. Thus Conflict of Interest [COI] Statement overfeeding,inflammation-activated represented caspase-1, by disinhibited which induces eating SIRT1 behavior, cleavage may contribute to subsequent changes in molecular physiology that with the company or organization sponsoring the research at leads to insulin resistance, possibly by disrupting sirtuin activity the Authorstime the must research disclose was anydone. financial Such relationships or personal relationships may include and/or through other mechanisms. employment, sharing in a patent, serving on an advisory board or Physical activity improves insulin sensitivity. Although speakers’ panel, or owning shares in the company. If an author or physical activity has been measured in a separate cohort of OOA [27], assessment of physical activity was not performed in the The COI Statement must include all authors. authors have no potential conflicts of interest, please state this. current study. We have, however measured physical activity in a Authors’Contributions cohort of OOA children, and found activity among children to be higher than a comparable cohort of rural living children [27]. In NS designed research; NS conducted research; KR analyzed future studies, it would be interesting to investigate the potential data and performed statistical analysis; SS and TX wrote the for interaction between physical activity and eating behavior. We paper and provided background literature research for the have reported, however, that in spite of lower rates of diabetes, introduction and discussion; NS had primary responsibility for this cohort of adult OOA has similar BMI as the general US

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Cite this article Schwab S, Xu T, Ryan K, Steinle N (2017) Eating Behavior Disinhibition Predicts Insulin Resistance in the Old Order Amish. J Hum Nutr Food Sci 5(2): 1109.

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