Associations between relative grip strength and type 2 diabetes mellitus: The Yangpyeong cohort of the Korean genome and epidemiology study.

OBJECTIVE: To investigate the association between relative grip strength and the prevalence of type 2 diabetes mellitus (T2DM) independently and in combination with body mass index (BMI) in Korean adults.
METHODS: The cross-sectional study includes 2,811 men and women (age 40 to 92 years old) with no history of heart disease, stroke, or cancer. Relative grip strength was measured by a handheld dynamometer and calculated by dividing absolute grip strength by body weight. Logistic regression analysis was used to calculate the odds ratios (ORs) and 95% confidence intervals (CIs) of T2DM by sex-specific quintiles of relative grip strength. In a joint analysis, participants were classified into 4 groups: "weak (lowest 20% quintile one) and normal weight (BMI <25.0 kg/m2)", "weak and overweight/obese (BMI ≥25.0 kg/m2)", "strong (upper 80% four quintiles) and normal weight" or "strong and overweight/obese".
RESULTS: Among the 2,811 participants, 371 were identified as having T2DM. Compared with the lowest quintile of relative grip strength (weakest), the ORs (95% CIs) of T2DM were 0.73 (0.53-1.02), 0.68 (0.48-0.97), 0.72 (0.50-1.03), and 0.48 (0.32-0.74) in upper quintiles two, three, four, and five, respectively, after adjusting for BMI and other potential confounders. In the joint analysis, compared with the "weak and overweight/obese" reference group, the odds of T2DM [ORs (95% CIs)] was lower in the "strong and overweight/obese" group [0.65 (0.46-0.92)] and the "strong and normal weight" group [0.49 (0.35-0.67)], after adjusting for potential confounders.
CONCLUSION: In this cross-sectional study, greater relative grip strength was associated with a lower prevalence of T2DM independent of BMI in Korean adults. Additional prospective studies are needed to determine whether a causal association exists between relative grip strength and T2DM prevalence considering BMI.

Introduction

Type 2 diabetes mellitus (T2DM) is a growing global health concern, which is associated with a greater risk of mortality [1]. Individuals with T2DM present with insulin resistance and have high blood glucose levels, as tissue no longer effectively uptakes glucose [2]. Skeletal muscle is a major organ for glucose uptake [3], and indeed, lower muscle mass is associated with a greater risk of developing T2DM [4].

Grip strength is a simple, common measure of overall muscular strength and is well known as a prognostic indicator of mortality and various chronic diseases [5, 6]. Previous studies have shown that individuals with low grip strength are at a greater risk of developing T2DM [7-9]. However, grip strength is related to body size, with larger individuals being stronger in general [10, 11]. Studies have shown that relative grip strength, which is grip strength divided by body weight or BMI, may be more strongly associated with metabolic syndrome and cardiometabolic risk factors (e.g., blood pressure, triglyceride, fasting glucose) than absolute grip strength [12-14]. Thus, relative grip strength may have a stronger association with T2DM than absolute grip strength.

Obesity is attributed to insulin resistance by permanently increasing free fatty acids in plasma and reducing glucose uptake by muscle [15]. Many previous studies have elucidated the importance of obesity, assessed by body mass index (BMI) ≥30 kg/m2, as a prominent risk factor for T2DM [16, 17]. Thus, the association between grip strength and T2DM may depend on BMI status. Previous studies investigating the relationship between grip strength and T2DM have controlled for BMI [18], however, few have investigated how the association between relative grip strength and T2DM is varied with BMI status.

It is important to examine the combined effects of muscular strength and overweight/obesity since both are important to develop public health recommendations and policies. For example, if people with overweight/obesity can reduce the risk of T2DM by improving muscular strength, this has a large clinical and public health impact since overweight/obesity is prevalent in most mid- and high-income countries [19]. Further, there is still limited data on the relative contributions of muscular strength versus overweight/obesity to T2DM. Therefore, the purpose of this study is to investigate the relationship of relative grip strength with T2DM using data from the Yangpyeong cohort of Korean Genome and Epidemiology Study. We aim to 1) evaluate the relationship between relative grip strength and the prevalence of T2DM independent of BMI and 2) investigate the combined association of relative grip strength and BMI with T2DM.

Materials and methods

Study population

Study participants were from the Yangpyeong cohort, one of the Multi-Rural Community cohorts within the Korean Genome and Epidemiology Study, which is being conducted by the Korea Centers for Disease Control and Prevention to identify risk factors for cardiovascular disease in Koreans (KoGES_CAVAS) [20]. A total 3,351 men and women (aged ≥ 40 years) were enrolled from centers located in Yangpyeong County and completed questionnaires, blood analysis, physical measurements, and fitness tests between 2007 to 2016.

Among the 3,351 participants who participated in the examination, 540 participants were excluded for the following reasons: history of cancer, stroke, and/or heart disease (n = 312); not fasting over 8 hours (n = 20); or missing data on covariates (n = 39) or grip strength (n = 169). In total, 2,811 participants were included in this study. The study was approved by the Institutional Review Board of Hanyang University (IRB No: HYUN IRB 2005–15). The study was conducted in accordance with the Declaration of Helsinki. All patients provided written informed consent, and all data were fully anonymized prior to analysis.

Grip strength assessment

Grip strength was measured using a handheld dynamometer T.K.K.5401 (Takei, Tokyo, Japan) which has demonstrated both good test-retest reliability and criterion-related validity [21]. Participants experiencing hand or wrist pain or who had previous surgery were excluded from the measurement. Participants were instructed to stand upright with their arm fully extended, slightly away from the side of their body, and to squeeze the dynamometer for 3 seconds as hard as they could, alternating two times per hand with 30 seconds rest between measurements. The highest values from each hand were averaged together and used as the absolute grip strength (kg) [22].

Relative grip strength was calculated by dividing absolute grip strength (kg) by body weight (kg) following earlier studies [11, 12, 23, 24]. Participants were then categorized into sex-specific quintiles of relative grip strength.

Diagnosis of T2DM

T2DM was defined according to the following criteria: (1) self-reported diagnosis of T2DM by a physician; (2) current use of hyperglycemic medication or insulin; and/or (3) fasting blood glucose over 126 mg/dL [2]. Fasting blood glucose and lipid profile were analyzed using an ADVIA1650 Automatic Analyzer (Siemens, New York, USA) [25].

Covariates

Participants underwent a clinical examination following an ≥8 hour fast. Weight and height were measured using a standard clinical scale and stadiometer, respectively, and BMI was calculated as weight (kg) divided by height squared (m2). Participants were classified as normal weight, overweight, or obese using the World Health Organization cut-points of <25.0 kg/m2, 25.0–29.9 kg/m2, and ≥30.0 kg/m2, respectively [26].

Resting blood pressure was measured using a sphygmomanometer. After resting for five minutes in the seated position, systolic and diastolic blood pressure were measured at least twice at intervals of one minute. If the two systolic or diastolic blood pressure differed by more than 5 mmHg, additional measures were taken until the last two blood pressure were within 5 mmHg, and the average of the last two blood pressure values was used. Hypertension was defined by combining the questionnaire and blood pressure examination results. A participant was considered to have hypertension if they indicated a previous physician diagnosis, were currently taking anti-hypertensive medication, or their systolic blood pressure was ≥ 130 mmHg or diastolic blood pressure ≥ 80 mmHg [27].

Dyslipidemia was classified by combining the questionnaire and clinical examination results. A participant was considered to have dyslipidemia if they indicated a previous physician diagnosis, were currently using anti-lipidemic medications, or if their serum low-density lipoprotein ≥ 130 mg/dL, total cholesterol ≥ 200 mg/dL, high-density lipoprotein ≤ 40 mg/dL, or triglyceride level ≥ 150 mg/dL [28].

Participants completed an interview-based questionnaire on demographic characteristics (e.g. age, sex, smoking status, current alcohol drinking, living with family, education level, regular exercise participation), medical conditions (e.g. hypertension, dyslipidemia, T2DM), and family history of diabetes. Smoking status was classified into three categories: never smoker, former smoker, or current smoker. Current alcohol drinking was classified into “yes” or “no”. Living with family was indicated as “yes” if the participant had lived with family for the last year, or “no” if the participant had lived alone for the last year. Education level was classified as high school graduate (12 years of education) or not. Regular exercise participation was indicated as “yes” or “no” based on the reported answer to the question, “Do you regularly participate in exercise that elicits sweat?”. Participants were classified as having a family history of diabetes if the parents, siblings, or children had been diagnosed or died from diabetes.

Statistical analysis

Participant characteristics at baseline are expressed as means and standard deviations (SD) for continuous variables and percentages for categorical variables. Baseline characteristics between sex-specific relative grip strength quintiles and T2DM status were compared using ANOVA tests for continuous variables and Chi-squared tests for categorical variables. Logistic regression analysis was used to estimate the odds ratios (OR) and 95% confidence intervals (CI) of T2DM according to the relative grip strength quintiles. The lowest quintile was used as the reference group. Logistic regression was also used to determine linear trends of T2DM by quintiles of relative grip strength. In addition, the ORs for the prevalence of T2DM per SD change were also calculated. All analyses were completed adjusting for sex and age (model 1). In Model 2, we further adjusted for smoking status (never, former, current), current alcohol drinking (yes or no), regular exercise (yes or no), living with family (yes or no), ≥high school graduate (yes or no), family history of diabetes (yes or no), hypertension (yes or no), and dyslipidemia (yes or no). Model 3 was additionally adjusted for BMI as a continuous variable. Stratified analyses were conducted to assess whether the association of relative grip strength and T2DM differs for sex, age, smoking status, current alcohol drinking, and regular exercise. Associations between relative grip strength and the OR of T2DM revealed consistent trends across all strata with no significant interaction effects observed (p>0.05).

A joint analysis was conducted by dichotomizing relative grip strength (“weak” [lowest 20%] or “strong” [upper 80%]) and BMI (“overweight/obese” [BMI ≥ 25.0] or “normal weight” [BMI < 25.0]) and categorizing participants into ‘weak and overweight/obese’, ‘strong and overweight/obese’, ‘weak and normal weight’, or ‘strong and normal weight’ groups. The weak and overweight/obese group was used as the reference group. This categorization was based on the recommendation of the Asian Working Group for Sarcopenia (AWGS) [29]. AWGS recommended using the lower 20th percentile of grip strength of the study population as the cutoff value for low muscle strength before if outcome-based data is unavailable. Although AWGS suggested being defined low grip strength as <26 kg for men and <18kg for women, we cannot use this absolute cutoff value because we used relative grip strength. The method using the cutoff at the 20th percentile was reported in previous studies [30-32]. A sensitivity analysis was conducted to assess the robustness of the original statistical model by altering exposure categories and covariate definitions. 1) Relative grip strength was categorized into quartiles, and then again into tertiles, to explore exposure-outcome relationships (S1 Table). 2) Absolute grip strength was used instead of relative grip strength. 3) BMI was re-categorized using the cut-off points for the Asian population (normal weight: < 23.0 kg/m2, overweight: 23.0–25.0 kg/m2, and obesity ≥ 25.0 kg/m2) [33]. All analyses were conducted using SAS software version 9.4 (SAS Institute, Inc., Cary, NC), and 2-sided p values <0.05 were considered significant.

Results

Among the 2,811 participants, 371 were identified as having T2DM. Table 1 shows the baseline characteristics of the participants by quintiles of relative grip strength and T2DM status. Compared to other groups, participants in the highest relative grip strength group were more likely to be younger, have lower BMIs, participate in more exercise, live alone, and have less hypertension and dyslipidemia.

Table 1

Baseline characteristics of the participants by quintiles of relative grip strength.

Characteristics	All	Quintiles of relative grip strength					P value	T2DMa		P value
		Q1 (Weakest)	Q2	Q3	Q4	Q5 (Strongest)		Cases	Non-cases
N	2,811	563	562	562	562	562		371	2,440
Women, n (%)	1,755 (62.4)	351 (62.3)	351 (62.5)	351 (62.5)	351 (62.5)	351 (62.5)		204 (55.0)	1,551 (63.6)
Age (years)	60.5 (10.4)	65.4 (9.6)	61.9 (9.7)	60.4 (10.1)	58.7 (9.8)	56.4 (10.4)	< .001	62.5 (9.4)	60.3 (10.5)	< .001
Weight (kg)	61.1 (10.0)	64.1 (10.0)	63.2 (10.3)	62.2 (9.6)	59.9 (9.2)	55.9 (8.7)	< .001	63.4 (10.4)	60.7 (9.9)	< .001
BMI (kg/m2)b	24.5 (3.2)	26.1 (3.4)	25.3 (3.2)	24.9 (2.7)	23.8 (2.6)	22.2 (2.5)	< .001	25.0 (3.3)	24.4 (3.2)	< .001
Absolute grip strength (kg)c	27.1 (8.7)	20.8 (6.6)	25.3 (7.3)	27.9 (8.0)	29.5 (8.1)	32.0 (8.9)	< .001	27.3 (8.8)	27.1 (8.7)	0.621
Smoking status, n(%)							0.079			0.219
Never smoked	2,261 (80.4)	462 (82.1)	461 (82.0)	454 (80.8)	448 (79.7)	436 (77.6)		286 (77.1)	1,975 (80.9)
Former Smoker	251 (8.9)	50 (8.9)	42 (7.5)	58 (10.3)	55 (9.8)	46 (8.2)		39 (10.5)	212 (8.7)
Current smoker	299 (10.6)	51 (9.1)	59 (10.5)	50 (8.9)	59 (10.5)	80 (14.2)		46 (12.4)	253 (10.4)
Current alcohol drinking, n (%)d	1445 (51.4)	274 (48.7)	281 (50.0)	301 (53.6)	305 (54.3)	285 (50.7)	0.274	208 (56.1)	1238 (50.7)	0.056
Regular exercise, n (%)e	919 (32.7)	154 (27.4)	184 (32.7)	178 (31.7)	200 (35.6)	203 (36.1)	0.013	146 (39.4)	773 (31.7)	0.003
Living with family, n (%)f	2,491 (88.6)	486 (86.3)	504 (89.7)	485 (86.3)	501 (89.2)	515 (91.6)	0.019	336 (90.6)	2,155 (88.3)	0.204
≥High school graduate (%)g	884 (31.5)	117 (20.8)	166 (29.5)	204 (36.3)	224 (39.9)	224 (39.9)	< .001	94 (25.3)	790 (32.4)	0.007
Family history of diabetes, n (%)	511 (18.2)	90 (16.0)	115 (20.5)	100 (17.8)	121 (21.5)	85 (15.1)	0.020	125 (33.7)	386 (15.8)	< .001
Hypertension, n (%)h	1,621 (57.7)	371 (65.9)	332 (59.1)	325 (57.8)	312 (55.5)	281 (50.0)	< .001	254 (68.5)	1,367 (56.0)	< .001
Dyslipidemia, n (%)i	2,175 (77.4)	462 (82.1)	460 (81.9)	451 (80.3)	436 (77.6)	366 (65.1)	< .001	318 (85.7)	1,857 (76.1)	< .001

Data are presented as mean (SD) unless indicated otherwise.

a T2DM was defined as the presence of T2DM (history of physician diagnosis, use of hyperglycemic medication or insulin, or measured fasting glucose ≥126 mg/dL [7.0 mmol/L]).

b Weight in kilograms divided by height in meters squared.

c Absolute grip strength (kg) was assessed using average value (out of 2 trials of each hand).

d Current alcohol drinking was defined as a current drinker and non-current drinker.

e Participant regularly participates in exercise enough to initiate sweating.

f Participant had lived with family during the last year.

h Defined as systolic/diastolic blood pressure ≥ 130/80mmHg, self-reported diagnosed hypertension, and/or taking blood pressure medication.

i Defined as if a serum low-density lipoprotein ≥ 130 mg/dL, if a serum total cholesterol ≥ 200 mg/dL, if a serum high-density lipoprotein ≤ 40 mg/dL, or if a serum triglyceride level ≥ 150 mg/dL., self-reported diagnosed dyslipidemia, and/or taking anti-lipidemic medication.

Compared to the lowest quintile of relative grip strength (weakest), the odds of T2DM were reduced in the upper four relative grip strength quintiles with ORs (95% CIs) of 0.75 (0.54–1.02), 0.64 (0.46–0.89), 0.68 (0.48–0.95) and 0.37 (0.25–0.55), respectively, after controlling for age and sex in model 1 (Table 2). After further adjustment for potential confounders in model 2, the odds of T2DM were similar and quintiles two to five showed significantly lower odds ratios. In Model 3, however, the addition of BMI weakened the association between relative grip strength and T2DM although a significant linear trend was still observed (p = 0.002). Moreover, the ORs for T2DM per SD increase in relative grip strength was 0.76 (0.64–0.91), after adjustment for potential confounders in model 3.

Table 2

Odds ratios of T2DM by quintiles of relative grip strength.

Relative grip strength	N	Cases	OR (95% CI)
			Model 1	Model 2	Model 3
Q1 (weakest)	563	107	1.00 (reference)	1.00 (reference)	1.00 (reference)
Q2	562	81	0.75 (0.54–1.02)	0.71 (0.51–0.99)	0.73 (0.53–1.02)
Q3	562	70	0.64 (0.46–0.89)	0.65 (0.46–0.91)	0.68 (0.48–0.97)
Q4	562	72	0.68 (0.48–0.95)	0.66 (0.46–0.93)	0.72 (0.50–1.03)
Q5 (strongest)	562	41	0.37 (0.25–0.55)	0.42 (0.28–0.63)	0.48 (0.32–0.74)
P for linear trend			< .001	< .001	0.002
Per SD in relative grip strengtha			0.69 (0.59–0.81)	0.72 (0.61–0.84)	0.76 (0.64–0.91)

a A 1 SD in relative grip strength is equivalent to 0.11kg.

Model 1 was adjusted for sex and age (years).

Model 2 was adjusted for Model 1 plus smoking status (never, former, current), current alcohol drinking status (yes or no), regular exercise (yes or no), living with family (yes or no), ≥high school graduate (yes or no), family history of diabetes (yes or no), hypertension (yes or no), dyslipidemia (yes or no).

Model 3 was adjusted for Model 2 plus body mass index (kg/m2).

Our sensitivity analyses using sex-specific tertiles and quartiles of relative grip strength showed similar trends as our presented quintiles. When using quintiles of absolute grip strength, the ORs (95% CIs) of T2DM for the second, third, fourth, and fifth absolute grip strength quintiles in the fully adjusted model were 0.79 (0.56–1.12), 0.95 (0.67–1.34), 0.71 (0.48–1.05), and 0.64 (0.42–0.97), respectively.

Fig 1 shows the odds of T2DM across relative grip strength quintiles, stratified by major confounders. Associations between relative grip strength and the odds of T2DM revealed consistent trends across all strata with no significant interaction effects observed (p>0.05); however, results appeared to be stronger among men, those less than 65 years old, those who ever or currently smoke or currently drink alcohol, and those not participating in regular exercise.

Fig 1

Odds ratios of T2DM by relative grip strength in stratified subgroup analyses.

Data presented as adjusted odds ratios (95% confidence intervals) across the quintiles of relative grip strength. Analyses were adjusted for sex (not in sex-stratified analyses), age (years, not in age-stratified analyses), smoking status (never, former, or current, not in smoking-stratified analyses), current alcohol drinking (yes or no, not in alcohol-stratified analyses), regular exercise (yes or no, not in regular exercise-stratified analyses), living with family (yes or no), ≥high school graduate (yes or no), family history of diabetes (yes or no), hypertension (yes or no), dyslipidemia (yes or no), and body mass index (kg/m2).

Fig 2 demonstrates the combined association between BMI and relative grip strength on the odds of T2DM. Compared to the ‘weak and overweight/obese’ group, the ‘weak and normal weight’, ‘strong and overweight/obese’, and ‘strong and normal weight’ groups had lower odds of T2DM with ORs (95% CIs) of 0.68 (0.43–1.09), 0.65 (0.46–0.92) and 0.49 (0.35–0.67), respectively. When the joint association analysis was performed using the BMI cut-off points for the Asian population, similar results were observed. Compared to the ‘weak and overweight/obese’ group, the ‘strong and overweight/obese’, ‘weak and normal weight’, and ‘strong and normal weight’ groups had ORs (95% CIs) of 0.62 (0.46–0.83), 0.80 (0.41–1.56), and 0.58 (0.42–0.81), respectively.

Fig 2

Joint associations of relative grip strength and body mass index with T2DM.

Participants were divided into four groups based on combined categories of relative grip strength (weak or strong) and body mass index (normal weight, overweight/obese), respectively. "Weak" was the lower 20% of relative grip strength and "strong" was the upper 80% of relative grip strength. Normal weight was BMI < 25.0kg/m2, overweight/obese was BMI ≥ 25.0 kg/m2. The model was adjusted for sex, age (years), smoking status (never, former, current), current alcohol drinking (yes or no), regular exercise (yes or no), living with family (yes or no), ≥high school graduate (yes or no), family history of diabetes (yes or no), hypertension (yes or no), dyslipidemia (yes or no), The number of participants (cases of T2DM) in the “overweight/obese and weak,” “overweight/obese and strong,” “normal weight and weak,”, and “normal weight and strong” groups were 352 (73), 824 (120), 211 (34), and 1,424 (144), respectively.

Discussion

This study examined the association between relative grip strength and the prevalence of T2DM independent of and combined with BMI. The main findings were: 1) higher relative grip strength is associated with the lower prevalence of T2DM independent of BMI (Table 2); 2) the associations between relative grip strength and T2DM were generally consistent across different sex, age groups, and the status of smoking, alcohol drinking, and regular exercise although many subgroups showed no significance partially due to the smaller T2DM cases (Fig 1); and 3) in the joint analysis, stronger relative grip strength was associated with a low prevalence of T2DM regardless of BMI (Fig 2).

The inverse relationship observed between relative grip strength and the prevalence of T2DM in the Korean adult population in the current study is in line with previous studies in other populations [24, 30, 34]. Furthermore, a significant association between relative grip strength and incidence of diabetes has also been shown in prospective studies. In a study of over 21,000 Japanese aged 20 to 92 individuals in the lowest quartile of relative grip strength had 56% greater risk of developing diabetes compared to the highest relative grip strength group [23]. Similarly, following 16-years of follow-up in 440 women, greater relative grip strength was associated with a lower risk of incident diabetes [7]. These results support our findings of greater relative grip strength and lower odds of T2DM.

BMI is commonly used to define obesity [26], with higher BMI associated with increased risk of mortality [35], cardiovascular disease [36], and diabetes [37]. About 90% of T2DM is related to excessive weight [38], so it was expected that the association between relative grip strength with T2DM would be affected by BMI. In several previous studies, higher relative grip strength was associated with a lower prevalence of hypertension [39] and cardiometabolic risk factors [40], but the associations disappeared after controlling for BMI. In our study, however, the association between relative grip strength and T2DM remained even after controlling for BMI. Interestingly, in the prospective studies previously discussed, after adjustment for BMI and waist-to-hip ratio, respectively, relative grip strength remained associated with the incidence of T2DM [7, 23]. These results in combination with ours suggest there is a significant relationship between muscle strength and T2DM independent of BMI.

In our joint analysis (Fig 2), stronger relative grip strength was associated with a lower prevalence of T2DM regardless of BMI. Conversely, when relative grip strength was weak even with normal weight, the prevalence of T2DM was not significantly attenuated. The results of this study are inconsistent with previous studies that analyzed the joint association between relative grip strength and BMI. A cross-sectional study in Korean adults found that lower absolute grip strength was associated with a higher prevalence of diabetes only in the non-obese population [41]. Furthermore, as a result of a 10-year follow-up of 394 Japanese-American adults, high baseline absolute grip strength significantly lowered diabetes risk but only in leaner individuals [18]. These studies suggest the association between absolute grip strength and diabetes risk is significantly modified by BMI, but this contrasts our findings that higher relative grip strength lowers the prevalence of T2DM in both normal and overweight/obese individuals. One possible explanation of the contradicting findings may be that both prior studies used absolute grip strength without considering the strong association between body weight and grip strength.

In the present study, we relativized grip strength to body weight, as has been done in many previous studies involving muscular strength [8, 42]. As expected, when absolute grip strength was used, the association with T2DM in Model 3 was weaker than when using relative grip strength. This may be due to the increased confounding effect of body weight on both the exposure (absolute grip strength) and the outcome (T2DM) whereas relative grip strength reduces one source of confounding through the exposure. Previous studies have shown that relative grip strength predicted metabolic syndrome better than absolute grip strength [8, 12]. Thus, relative grip strength may be more strongly associated with the prevalence of T2DM prevalence than absolute grip strength.

Relative grip strength may be more closely related to the ratio of muscle mass and fat mass that make up body weight. Muscle strength is highly associated with muscle mass rather than fat mass [43]. Therefore, someone with high relative grip strength adjusted by body weight may have a high proportion of muscle mass that constitutes their body mass and may have less fat mass, whereas someone with low relative grip strength may have a relatively small proportion of muscle mass and a relatively large proportion of fat mass. In our data, high relative grip strength was associated with low body weight and BMI. In other words, the association between high relative grip strength and low body fat may be a factor that explains the association with T2DM. However, there was a difference in the results of analysis when using the relative grip strength normalized by body weight or BMI. In our results, the associations were attenuated when using BMI-normalized grip strength (S2 Table) compared to body weight-normalized grip strength on the prevalence of T2DM. One previous study has reported that weight-normalized grip strength has a greater association with metabolic syndrome than BMI-normalized grip strength [12]. There is no study comparing weight and BMI normalized grip strength on the prevalence of T2DM. Therefore, further studies are clearly warranted to examine the difference between relative grip strength normalized by body weight or BMI.

The mechanistic evidence for the relationship between grip strength and T2DM is still limited, but it can be partially explained by the following evidence. Strength training improves the glycemic control process. Repetitive strength exercise increases the expression of GLUT4, which is a glucose transporter playing an important role in glucose uptake [44]. Additionally, as glucose is used as the main fuel for skeletal muscle, some evidence indicates that it is related to skeletal muscle mass. Muscle strength is highly associated with muscle mass [43], and loss of muscle mass due to physical inactivity or aging causes an inflammatory reaction and increases insulin resistance, leading to diabetes [45]. Conversely, diabetes induces muscle protein degradation and attenuates the mitochondrial function in muscles, accelerating the loss of muscle mass and strength due to aging. Indeed, a bi-directional Mendelian randomization study to investigate the effects of markers of grip strength on T2DM showed that higher grip strength was associated with lower T2DM risk and conversely showed that T2DM was associated with lower grip strength [46]. As several studies have reported a significant association between grip strength and whole-body strength [47-49], it is possible to partially explain the relationship between grip strength and T2DM based on this evidence. But further studies are needed to explain a clear mechanism.

We performed a subgroup analysis to determine whether the association between relative grip strength and T2DM varies according to each confounder (S3 Table). Although there were no interaction effects in all strata, all subgroups showed some differences in association according to classification, especially when stratified by sex, there was a significant trend only in men. These differences are difficult to explain clearly. One possible explanation is that the different glycaemic profiles between men and women. Impaired fasting glucose more common in men than women, and impaired glucose tolerance are more common in women [50, 51]. So, differences in the association between men and women may be affected by the diagnostic criteria for T2DM used in our study. However, further studies, especially prospective studies, with larger samples are clearly warranted to examine the sex-specific difference relationship between relative grip strength and T2DM.

A strength of our study is that, to our knowledge, it is the first to examine the association between relative grip strength and T2DM, independently of BMI, in a large-scale cohort for the Korean population. This study also utilized comprehensive data analyses including stratified analyses to explore effect modification (Fig 1), joint stratification based on both relative grip strength and BMI (Fig 2), and several important sensitivity analyses. Further, grip strength is an emerging easy, safe, and well validated assessment. However, the study presents some limitations. First, this study is cross-sectional in design, therefore it is not possible to establish a causal relationship between relative grip strength and the prevalence of T2DM, and reverse causality (e.g., T2DM could induce the loss of muscle mass and strength) is possible. Second, our study was limited to Korean adults who lived in Yangpyeong City. Therefore, the results of our study may only be generalizable to adults living in rural areas in Korea or other Asian population, especially Northeast Asians such as Chinese or Japanese people [52]. Third, major covariates that could affect diabetes prevalence, such as socioeconomic status and caloric intake, were not available in this study. Finally, many confounders were collected through a self-report questionnaire thus introducing the potential for information bias and bias due to social desirability, which could subsequently lead to misclassification. This potential bias should be considered when interpreting the results from this study. However, we tried to potentially counter the limitation by setting that the main exposure was measured and that T2DM was determined not only based on self-report of the disease, but also medications and fasting glucose.

In conclusion, relative grip strength was inversely associated with T2DM among Korean adults, independent of BMI, and stronger relative grip strength was associated with a low prevalence of T2DM even with obesity. This suggests that greater muscle strength may be an important factor underlying T2DM regardless of BMI. Prospective studies are needed to examine whether strength training can be an effective method for T2DM prevention and treatment.

Odds ratios of T2DM by tertiles of relative grip strength.

(DOCX)

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Odds ratios of T2DM by quintiles of grip strength divided by body mass index.

(DOCX)

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Odds ratio of prevalence of type 2 diabetes mellitus, stratified by relative grip strength in subgroup.

(DOCX)

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5 May 2021

PONE-D-21-08378

Associations between relative grip strength and type 2 diabetes mellitus: The Yangpyeong cohort of the Korean genome and epidemiology study

PLOS ONE

Dear Dr. Song,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

It is an interesting study, but as both reviewers pointed out, there are some limitations in the current statistical analysis, the presentation of the paper in the introduction and discussion. Please revise the manuscript accordingly.

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We look forward to receiving your revised manuscript.

Kind regards,

Jie V Zhao

Academic Editor

PLOS ONE

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This work was partly supported by the Research Program funded by the Korea Centers for Disease Control and Prevention (2007-E71002-00, 2008-E71004-00, 2009-E71006-00, 2010-E71003-00, 2011-E71002-00, 2012-E71007-00, 2013-E71008-00, 2014-E71006-00, 2014-E71006-01, 2016-E71001-00).

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Additional Editor Comments:

This is an interesting study, but as the reviewers pointed out, some concerns over the statistical analysis and presentation of this paper exist. Please address these concerns accordingly.

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Partly

Reviewer #2: Partly

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2. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: No

Reviewer #2: N/A

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3. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: No

Reviewer #2: No

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4. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: No

Reviewer #2: Yes

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5. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: Review of the manuscript (PONE-D-21-08378)

This is a cross sectional study exploring the relation of relative grip strength and type 2 diabetes risk in a Korean population. The study is straightforward although the Introduction and Discussion could be enhanced for better readability. I have some concerns over the statistical analyses and the way how the exposures were being categorized in the analyses. Please see below for my comments.

Major comments

The Introduction should be revised to capture the key points the study is trying to address. I think the issue with previous studies is the lack of consideration of body mass index which is related to grip strength. It would be helpful for authors to explain why considering relative grip strength and BMI altogether with type 2 diabetes is helpful, especially when relative grip strength takes into account the effect of BMI in the calculation.

Have the authors considered using other body composition metrics as the BMI to calculate relative grip strength? If the authors preferred to use body weight, please also provide justifications (PMID: 20191251; 27559733). This would also have implications for all downstream analyses.

It would be good for the authors to repeat the analyses using the actual values of the relative grip strength to assess robustness of findings by different ways of categorization. This will maximize the use of data rather than categorizing them into tertiles or quartiles.

It would be more preferable to assess potential interactions using formal interaction analyses such as the significance of the interaction term. The low number of diabetes case may also make particular subgroup analyses lack sufficient statistical power. The way how grip strength is being dichotomized appears arbitrary (20%) and require further justification.

It is unclear why the authors considered the use of absolute grip strength given the issue with confounding by BMI or other body composition. To me, that would be inferior to the main analyses. The same applies to the BMI cutoff where I think it would be better to use Asian specific cutoffs in the main analyses. The use of different cutoffs probably would not provide much insight since the differences reflect the varying % of fat and lean mass in Asians and Europeans.

The Discussion is a bit long and I think it is not necessary to describe in details the studies the author compared their findings with.

Minor comments

A previous genetic study suggested a causal role of grip strength in risk of type 2 diabetes and can be discussed in the manuscript (PMID: 30798333).

Line 230: The number of participants in reference 23 should be 0.42 million

Line 303-304: Stratified analyses by major confounders: This appears confusing as I think the main purpose is to use stratified analyses to explore effect modification rather than controlling for confounding?

Line 309-310: Would be good to elaborate more on why there are issues with generalisability.

Reviewer #2: Thank you very much for the opportunity to review the study entitled “Associations between relative grip strength and type 2 diabetes mellitus: The Yangpyeong cohort of the Korean genome and epidemiology study”. The manuscript under review assesses whether relative grip strength is associated with type 2 diabetes mellitus (T2DM) prevalence independently of BMI among Korean elderly.

A major strength of this study is acknowledging the use of relative handgrip strength as a safe and convenient assessment for diabetes risk prediction in a representative ethnic-homogenous population.

However, I have some major concerns as follow:

1. In the introduction, the underlying rationale to explore the association of relative grip strength and T2DM independent of and combined with BMI is not clearly addressed by simply stating that “Previous studies investigating the relationship between grip strength and T2DM have controlled for BMI, however, few have investigated relative grip strength and T2DM independent of and combined with BMI.” Previous studies regard BMI as a potential confounder to adjust for because grip strength is known to be correlated with body size (weight, height and BMI) and BMI is a risk factor for diabetes. Can the authors elaborate why examining the association of interest independent of BMI? What is the rationale behind employing a combined association of RELATIVE GRIP STRENGTH and T2DM with BMI?

2. In the logistic regression model 3, the authors controlled for BMI along with other potential confounders but hastily concluded that the association of interest was independent of BMI. These points need clarification along with solid evidence. Other strategies such as automatic variable selection can be used to support or refute whether adjustment for BMI is required (1). In addition, in line 244-246 "however, the association between grip strength and T2DM remained even after controlling for BMI. This suggests that there is a significant relationship between muscle strength and T2DM independent of BMI.", the sentence lacks reasoning. I think the association remain significant after adjustment for a third variable is not enough to say the relationship is independent of the third variable.

3. In line 43, please be more specific in the sentence “may be more strongly associated with various diseases” as of what diseases were RELATIVE GRIP STRENGTH associated with? Are these diseases also correlated to the outcome of interest, which is necessary to address?

4. Lack of justification for the underlying rationale subsequently leads to a few arguable points in the methods and statistical analysis part. In the logistic regression analysis to estimate the odds ratios (OR) of T2DM with the relative grip strength quintiles, important confounders such as socioeconomic position, nutritional intake were not controlled because they were not available. Additionally, is there a need to adjust for “living status” in Model 2?

Also, I wonder if glycaemic status is another important confounder to consider within the association of interest. As suggested in the reference 12, “relative HGS has stronger associations with metabolic syndrome and its component parameters, including high-density lipoprotein cholesterol (HDLC), TG, fasting glucose, and blood pressure”.

Without considering important confounders can lead to confounding bias while accounting for a non-confounder may introduce spurious associations within the association. Both affect the validity of the study that mask the true association and lead to incorrect results and interpretation. However, even after adjusting for potential confounders, residual confounding remains.

5. In Figure 1, why choose 70 as a cut-off age in stratification analysis? The >70 age group has a small sample size, especially among the strongest RELATIVE GRIP STRENGTH quintile, which may lack statistical power to detect the strength of associations. Also, it would be good to report the sex-specific difference in the association between RELATIVE GRIP STRENGTH and T2DM, like the strength of association in female was not significant as in male.

6. In line 195, “Fig 2 demonstrates the additive effects of combining BMI and relative grip strength on the odds of T2DM.” What do you mean by "additive effects"? The analysis in Figure 2 seems to examine the statistical interaction of BMI on RELATIVE GRIP STRENGTH by stratification among subgroups. Is this an appropriate analysis? I doubt about it to treat BMI as an effect modifier as from the Figure 1 results, it is not certain to claim the association between RELATIVE GRIP STRENGTH and T2DM is independent of BMI. I might have missed this, but what do the stratum-specific ORs by BMI look like?

7. Information bias is another issue not addressed in the discussion. This can occur in measuring and classifying covariates, exposure and outcomes and may lead to misclassification. For example, “Do you regularly participate in exercise that elicits sweat” is a qualitative question with a "Yes/No" answer to define “regular exercise”. Furthermore, inaccuracy in classifying self-reported lifestyle variables on smoking, alcohol drinking status, and medical conditions (e.g. hypertension, dyslipidemia, T2DM) can exist. Social desirability bias, as a form of information bias, cannot be ruled out here.

8. In the discussion, the authors acknowledge that it is not possible to establish a causal relationship in this cross-sectional study and stated that T2DM can induce loss of muscle mass and muscle strength in line 299-301. Therefore, reverse causality bias is possible(2).

9. A complete case analysis is based on the assumption that variables were missing completely at random. This may not be valid sometimes if the missing data is dependent on a variable affecting both T2DM risks and missingness of data. Is there a valid assumption in this study to utilize complete case analysis? To validate the assumption, are there sensitivity analyses using different methods such as inverse probability weight to simulate the missing data?

10. For generalizability, the sentence in line 310-311, “the participants were limited to only one ethnic group and living only in one area, so it is difficult to generalize our findings to the population” needs clarification. What does “the population” refer to?

11. Please provide the results of sensitivity analyses that assess the robustness of statistical models in detail if possible, to substantiate the findings.

Minor comments on the manuscript:

1. In line 167, “The addition of BMI in Model 3..”, please be clearer in the description to additionally adjust for BMI based on Model 2 confounders.

2. For the study population, a reference to the cohort profile of the study population would be helpful when discussing generalizability.

3. The subsection "clinical examination" under the "Material and Methods" section describes not only clinical examination. "covariates" would be a better word.

4. Fig2. The 3D graph does not add values to the visual aids but may be quite confusing. A simple 2-by-2 table would be good for results presentation.

5. Causal language was used sometimes within the text. For example, in line 195 when describing Figure 2, “…the additive effects of combining BMI and relative grip strength…” and line 269, the word “effects” would convey causal connotation.

6. Please be consistent when referring to relative grip strength or absolute grip strength throughout the manuscript to avoid confusion. For instance, (line 242-247) “In our study, however, the association between grip strength and T2DM remained even after controlling for BMI.”

References

1. Causal knowledge as a prerequisite for confounding evaluation: an application to birth defects epidemiology. Am J Epidemiol. 2002 155: 176-184

2. Yeung CHC, Au Yeung SL, Fong SSM, Schooling CM. Lean mass, grip strength and risk of type 2 diabetes: a bi-directional Mendelian randomisation study. Diabetologia. 2019;62(5):789-99.

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Reviewer #1: No

Reviewer #2: No

[NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files.]

While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email PLOS at figures@plos.org. Please note that Supporting Information files do not need this step.

25 Jun 2021

We thank the editor and reviewers for their helpful edits and comments, which have improved the manuscript, and we are grateful for the opportunity to provide a revised version for consideration. We have carefully considered, discussed, and responded to each comment below, with direct references to the locations (page and line numbers) of changes in the revised manuscript by using track changes. We have submitted our manuscript with the following three file names: ‘Response to Reviewers’. ‘Revised Manuscript with Track Changes’, ‘Manuscript’.

Submitted filename: Response to Reviewers Comments.docx

Click here for additional data file.

14 Jul 2021

PONE-D-21-08378R1

Associations between relative grip strength and type 2 diabetes mellitus: The Yangpyeong cohort of the Korean genome and epidemiology study

PLOS ONE

Dear Dr. Song,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

Please submit your revised manuscript by 12 August. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

Please include the following items when submitting your revised manuscript:

A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'.

A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'.

An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'.

If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter. Guidelines for resubmitting your figure files are available below the reviewer comments at the end of this letter.

If applicable, we recommend that you deposit your laboratory protocols in protocols.io to enhance the reproducibility of your results. Protocols.io assigns your protocol its own identifier (DOI) so that it can be cited independently in the future. For instructions see: http://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols. Additionally, PLOS ONE offers an option for publishing peer-reviewed Lab Protocol articles, which describe protocols hosted on protocols.io. Read more information on sharing protocols at https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols.

We look forward to receiving your revised manuscript.

Kind regards,

Jie V Zhao

Academic Editor

PLOS ONE

Journal Requirements:

Please review your reference list to ensure that it is complete and correct. If you have cited papers that have been retracted, please include the rationale for doing so in the manuscript text, or remove these references and replace them with relevant current references. Any changes to the reference list should be mentioned in the rebuttal letter that accompanies your revised manuscript. If you need to cite a retracted article, indicate the article’s retracted status in the References list and also include a citation and full reference for the retraction notice.

Additional Editor Comments (if provided):

[Note: HTML markup is below. Please do not edit.]

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #1: (No Response)

Reviewer #2: All comments have been addressed

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2. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Yes

Reviewer #2: Yes

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3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #2: Yes

**********

4. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

Reviewer #2: Yes

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5. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

Reviewer #2: Yes

**********

6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: Thank you for addressing my comments. Please see below for some minor points

- I think it would deserve more description to explain possible differences in association when BMI was used to normalize grip strength instead of body weight alone, where the associations were attenuated (in terms of effect size) when BMI was used.

- Regarding generalizability, I think the key thing is whether studies in Koreans can be applied to other populations, such as Chinese.

Reviewer #2: Thank you very much for addressing all comments and questions raised in my previous review. The revised manuscript is much clearer to me now, along with the supplementary material to further expand on sensitivity analyses.

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7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: No

Reviewer #2: No

[NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files.]

While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email PLOS at figures@plos.org. Please note that Supporting Information files do not need this step.

7 Aug 2021

We thank the editor and reviewers for their helpful edits and comments, which have improved the manuscript, and we are grateful for the opportunity to provide a revised version for consideration. We have carefully considered, discussed, and responded to each comment below, with direct references to the locations (page and line numbers) of changes in the revised manuscript by using track changes. We have submitted our manuscript with the following three file names: ‘Response to Reviewers’. ‘Revised Manuscript with Track Changes’, ‘Manuscript’.

Submitted filename: Response to Reviewers.docx

Click here for additional data file.

10 Aug 2021

Associations between relative grip strength and type 2 diabetes mellitus: The Yangpyeong cohort of the Korean genome and epidemiology study

PONE-D-21-08378R2

Dear Dr. Song,

We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.

Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication.

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Kind regards,

Jie V Zhao

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Reviewers' comments:

12 Aug 2021

PONE-D-21-08378R2

Associations between relative grip strength and type 2 diabetes mellitus: The Yangpyeong cohort of the Korean genome and epidemiology study

Dear Dr. Song:

I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production department.

If your institution or institutions have a press office, please let them know about your upcoming paper now to help maximize its impact. If they'll be preparing press materials, please inform our press team within the next 48 hours. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information please contact onepress@plos.org.

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on behalf of

Dr. Jie V Zhao

Academic Editor

PLOS ONE