Gastric emptying in newly diagnosed, treatment-naïve Han Chinese with type 2 diabetes and the impact of 4-week insulin pump therapy.

AIM: To evaluate gastric emptying (GE) and the glycaemic response to a 75-g oral glucose load in newly diagnosed, treatment-naïve Han Chinese with type 2 diabetes (T2D) before insulin pump therapy, after 4 weeks of insulin pump therapy, and 12-15 months after insulin pump therapy. MATERIALS AND METHODS: Twenty participants with T2D (baseline glycated haemoglobin [± SD] 10.7% [± 1.2%] 93 [± 10] mmol/mol) ingested a 75-g glucose drink containing 150 mg 13C-acetate, to determine the gastric half-emptying time, and underwent assessment of plasma glucose and serum insulin, C-peptide and glucagon-like peptide-1 (GLP-1) over 180 min before and after 4 weeks of insulin pump therapy (discontinued for 48 h before re-assessment). Data were compared to those in 19 healthy participants matched for sex and age. After 12-15 months, GE was re-measured in 14 of the T2D participants. RESULTS: At baseline, participants with T2D exhibited substantially augmented fasting and post-glucose glycaemia, diminished insulin secretion, and more rapid GE (p < 0.05 each), but comparable GLP-1, compared to healthy participants. Following insulin pump therapy, insulin secretion increased, GLP-1 secretion was attenuated, fasting and post-glucose glycaemia were lower, and GE was slowed (p < 0.05 each). The slowing of GE in T2D participants was sustained over 12-15 months of follow-up. CONCLUSIONS: In newly diagnosed Han Chinese with T2D, GE is often accelerated despite poor glycaemic control and is slowed by short-term insulin pump therapy. The effect on GE is maintained for at least 12 months.

Gastric emptying is slower in women than men with type 2 diabetes and impacts on postprandial glycaemia.

AIM: To evaluate sex differences in gastric emptying and the glycaemic response to a glucose drink and a high carbohydrate meal in type 2 diabetes (T2D). METHODS: In cohort 1, 70 newly diagnosed, treatment-naïve Chinese patients with T2D (44 men) recruited from a diabetes outpatient clinic ingested a 75-g glucose drink containing 150 mg 13C-acetate. In cohort 2, 101 Australian patients with T2D (67 male) recruited from the community, managed by diet and/or metformin monotherapy, ingested a semi-solid mashed potato meal, labelled with 100 µl 13C-octanoic acid. Breath samples were collected over 3 and 4 h, respectively, for assessment of gastric emptying, and venous blood was sampled for evaluation of glycaemia (with and without adjustment for each participant's estimated total blood volume). RESULTS: Gastric emptying was slower in female than male subjects in both cohorts (both p < .01). Multiple linear regression analyses revealed that gastric emptying was independently associated with sex (both p < .05). Without adjustment for blood volume, the glycaemic responses to oral glucose and the mixed meal were greater in female subjects (both p < .001). However, after adjustment for blood volume, the glycaemic responses were greater in men (both p < .05). CONCLUSIONS: Gastric emptying is slower in women than men with T2D, associated with a reduced blood volume-adjusted glycaemic response to oral glucose and a mixed meal in women. These observations highlight the sex difference in postprandial glucose handling, which is relevant to the personalized management of postprandial glycaemia in T2D.

Gastric emptying of a glucose drink is predictive of the glycaemic response to oral glucose and mixed meals, but unrelated to antecedent glycaemic control, in type 2 diabetes.

BACKGROUND: Gastric emptying (GE), with wide inter-individual but lesser intra-individual variations, is a major determinant of postprandial glycaemia in health and type 2 diabetes (T2D). However, it is uncertain whether GE of a carbohydrate-containing liquid meal is predictive of the glycaemic response to physiological meals, and whether antecedent hyperglycaemia influences GE in T2D. We evaluated the relationships of (i) the glycaemic response to both a glucose drink and mixed meals with GE of a 75 g glucose drink, and (ii) GE of a glucose drink with antecedent glycaemic control, in T2D. METHODS: Fifty-five treatment-naive Chinese adults with newly diagnosed T2D consumed standardised meals at breakfast, lunch and dinner with continuous interstitial glucose monitoring. On the subsequent day, a 75 g glucose drink containing 150 mg 13C-acetate was ingested to assess GE (breath test) and plasma glucose response. Serum fructosamine and HbA1c were also measured. RESULTS: Plasma glucose incremental area under the curve (iAUC) within 2 hours after oral glucose was related inversely to the gastric half-emptying time (T50) (r = -0.34, P = 0.012). The iAUCs for interstitial glucose within 2 hours after breakfast (r = -0.34, P = 0.012) and dinner (r = -0.28, P = 0.040) were also related inversely to the T50 of oral glucose. The latter, however, was unrelated to antecedent fasting plasma glucose, 24-hour mean interstitial glucose, serum fructosamine, or HbA1c. CONCLUSIONS: In newly diagnosed, treatment-naive, Chinese with T2D, GE of a 75 g glucose drink predicts the glycaemic response to both a glucose drink and mixed meals, but is not influenced by spontaneous short-, medium- or longer-term elevation in glycaemia.

Impact of the timing of metformin administration on glycaemic and glucagon-like peptide-1 responses to intraduodenal glucose infusion in type 2 diabetes: a double-blind, randomised, placebo-controlled, crossover study.

AIMS/HYPOTHESIS: Metformin lowers postprandial glycaemic excursions in individuals with type 2 diabetes by modulating gastrointestinal function, including the stimulation of glucagon-like peptide-1 (GLP-1). The impact of varying the timing of metformin administration on postprandial glucose metabolism is poorly defined. We evaluated the effects of metformin, administered at different intervals before an intraduodenal glucose infusion, on the subsequent glycaemic, insulinaemic and GLP-1 responses in metformin-treated type 2 diabetes. METHODS: Sixteen participants with type 2 diabetes that was relatively well-controlled by metformin monotherapy were studied on four separate days in a crossover design. On each day, participants were randomised to receive a bolus infusion of metformin (1000 mg in 50 ml 0.9% saline) via a nasoduodenal catheter at t = -60, -30 or 0 min (and saline at the other timepoints) or saline at all timepoints (control), followed by an intraduodenal glucose infusion of 12.56 kJ/min (3 kcal/min) at t = 0-60 min. The treatments were blinded to both participants and investigators involved in the study procedures. Plasma glucose, insulin and total GLP-1 levels were measured every 30 min between t = -60 min and t = 120 min. RESULTS: There was a treatment-by-time interaction for metformin in reducing plasma glucose levels and increasing plasma GLP-1 and insulin levels (p<0.05 for each). The reduction in plasma glucose levels was greater when metformin was administered at t = -60 or -30 min vs t = 0 min (p<0.05 for each), and the increases in plasma GLP-1 levels were evident only when metformin was administered at t = -60 or -30 min (p<0.05 for each). Although metformin did not influence insulin sensitivity, it enhanced glucose-induced insulin secretion (p<0.05), and the increases in plasma insulin levels were comparable on the 3 days when metformin was given. CONCLUSIONS/INTERPRETATION: In well-controlled metformin-treated type 2 diabetes, glucose-lowering by metformin is greater when it is given before, rather than with, enteral glucose, and this is associated with a greater GLP-1 response. These observations suggest that administration of metformin before meals may optimise its effect in improving postprandial glycaemic control. TRIAL REGISTRATION: www.anzctr.org.au ACTRN12621000878875 FUNDING: The study was not funded by a specific research grant.

Effects of a bitter substance, denatonium benzoate, on pancreatic hormone secretion.

There is increasing evidence linking bitter taste receptor (BTR) signaling to gut hormone secretion and glucose homeostasis. However, its effect on islet hormone secretion has been poorly characterized. This study investigated the effect of the bitter substance, denatonium benzoate (DB), on hormone secretion from mouse pancreatic islets and INS-1 832/13 cells. DB (0.5-1 mM) augmented insulin secretion at both 2.8 mM and 16.7 mM glucose. This effect was no longer present at 5 mM DB likely due to the greater levels of cellular apoptosis. DB-stimulated insulin secretion involved closure of the KATP channel, activation of T2R signaling in beta-cells, and intraislet glucagon-like peptide-1 (GLP-1) release. DB also enhanced glucagon and somatostatin secretion, but the underlying mechanism was less clear. Together, this study demonstrates that the bitter substance, DB, is a strong potentiator of islet hormone secretion independent of glucose. This observation highlights the potential for widespread off-target effects associated with the clinical use of bitter-tasting substances.NEW & NOTEWORTHY We show that the bitter substance, denatonium benzoate (DB), stimulates insulin, glucagon, somatostatin, and GLP-1 secretion from pancreatic islets, independent of glucose, and that DB augments insulin release via the KATP channel, bitter taste receptor signaling, and intraislet GLP-1 secretion. Exposure to a high dose of DB (5 mM) induces cellular apoptosis in pancreatic islets. Therefore, clinical use of bitter substances to improve glucose homeostasis may have unintended negative impacts beyond the gut.

Muscle Quality in Relation to Prediabetes Phenotypes: A Population-Based Study With Mediation Analysis.

CONTEXT: Prediabetes is associated with an increased risk of physical disability, yet no studies have assessed the extent to which muscle quality, a measure reflecting muscle functionality, was altered in prediabetes and its specific phenotype. OBJECTIVE: We evaluated their associations in a general US population with mediation analysis. METHODS: This was a cross-sectional study based on the National Health and Nutrition Examination Survey 2011-2014. Participants with prediabetes were stratified as having an isolated defect (impaired fasting glucose [IFG], impaired glucose tolerance [IGT], or impaired hemoglobin A1c [IA1c]), 2 defects (IFG + IGT, IFG + IA1c, or IGT + IA1c), or all defects (IFG + IGT + IA1c). Muscle quality was calculated as dominant grip strength divided by dominant arm muscle mass measured by dual-energy X-ray absorptiometry. RESULTS: We included 2351 participants (938 with prediabetes and 1413 with normoglycemia). Despite higher grip strength and larger arm muscle mass, arm muscle quality was lower in prediabetes and all prediabetes phenotypes (except for IGT) than normoglycemia (all P < .04), and was unrelated to prediabetes awareness. Arm muscle quality was decreased and the odds of low arm muscle quality was increased in prediabetes with increasing numbers of glucometabolic defects (both P < .001), with insulin resistance being the predominant mediator. HbA1c-defined prediabetes (IA1c) had lower arm muscle quality and higher odds of low arm muscle quality than blood glucose-defined prediabetes (IFG, IGT, or IFG + IGT). CONCLUSION: Muscle quality was impaired in prediabetes and its specific phenotype. Relative to blood glucose, elevated HbA1c might be a better predictor of reduced muscle quality.

Prediabetes Progression and Regression on Objectively- Measured Physical Function: A Prospective Cohort Study.

BACKGRUOUND: Prediabetes leads to declines in physical function in older adults, but the impact of prediabetes progression or regression on physical function is unknown. This study assessed this longitudinal association, with physical function objectivelymeasured by grip strength, walking speed, and standing balance, based on the Health and Retirement Study enrolling United States adults aged >50 years. METHODS: Participants with prediabetes were followed-up for 4-year to ascertain prediabetes status alteration (maintained, regressed, or progressed), and another 4-year to assess their impacts on physical function. Weak grip strength was defined as <26 kg for men and <16 kg for women, slow walking speed was as <0.8 m/sec, and poor standing balance was as an uncompleted fulltandem standing testing. Logistic and linear regression analyses were performed. RESULTS: Of the included 1,511 participants with prediabetes, 700 maintained as prediabetes, 306 progressed to diabetes, and 505 regressed to normoglycemia over 4 years. Grip strength and walking speed were declined from baseline during the 4-year followup, regardless of prediabetes status alteration. Compared with prediabetes maintenance, prediabetes progression increased the odds of developing weak grip strength by 89% (95% confidence interval [CI], 0.04 to 2.44) and exhibited larger declines in grip strength by 0.85 kg (95% CI, -1.65 to -0.04). However, prediabetes progression was not related to impairments in walking speed or standing balance. Prediabetes regression also did not affect any measures of physical function. CONCLUSION: Prediabetes progression accelerates grip strength decline in aging population, while prediabetes regression may not prevent physical function decline due to aging.

Serum alanine transaminase is predictive of fasting and postprandial insulin and glucagon concentrations in type 2 diabetes.

The liver plays a key role in glucose homeostasis. Serum liver enzyme levels, including alanine transaminase (ALT), aspartate transaminase (AST) and gamma-glutamyl transferase (GGT), are reportedly predictive of the risk of type 2 diabetes (T2D). However, the link between the liver enzyme profile and metabolic derangements in T2D, particularly the secretion of both insulin and glucagon, is not clear. This study evaluated its relationships with glycemia, insulin and glucagon both during fasting and after an oral glucose load or a mixed meal in T2D. 15 healthy and 43 T2D subjects ingested a 75 g glucose drink. 86 T2D subjects consumed a mixed meal. Venous blood was sampled for measurements of blood glucose and plasma insulin, C-peptide and glucagon. Blood glucose, plasma insulin, C-peptide and glucagon concentrations, both fasting and after oral glucose, correlated directly with ALT, while fewer and weaker correlations were observed with GGT or AST. Subgroup analysis in T2D subjects ascertained that plasma insulin, C-peptide and glucagon concentrations after oral glucose were higher with increasing ALT. Similar findings were observed in the T2D subjects who received a mixed meal. In conclusion, serum liver enzyme profile, particularly ALT, reflects dysregulated fasting and nutrient-stimulated plasma insulin and glucagon concentrations in T2D.

Impaired antibody response to inactivated COVID-19 vaccines in hospitalized patients with type 2 diabetes.

Patients with type 2 diabetes (T2D) are at an increased risk of morbidity and mortality of coronavirus disease 2019 (COVID-19). Data on the antibody response to COVID-19 vaccines in T2D patients are less studied. This study aimed to evaluate IgG antibody response to inactivated COVID-19 vaccines in hospitalized T2D patients. Hospitalized patients with no history of COVID-19 and received two doses of inactivated COVID-19 vaccines (Sinopharm or CoronaVac) were included in this study from March to October 2021. SARS-CoV-2 specific IgG antibodies were measured 14-60 days after the second vaccine dose. A total of 209 participants, 96 with T2D and 113 non-diabetes patients, were included. The positive rate and median titer of IgG antibody against receptor-binding domain (anti-RBD) of spike (S) protein of SARS-CoV-2 in T2D group were lower than in control group (67.7% vs 83.2%, p = .009; 12.93 vs 17.42 AU/ml, p = .014) respectively. Similarly, seropositivity and median titers of IgG antibody against the nucleocapsid (N) and S proteins of SARS-CoV-2 (anti-N/S) in T2D group were lower than in control group (68.8% vs 83.2%, p = .032; 18.81 vs 29.57 AU/mL, p = .012) respectively. After adjustment for age, sex, BMI, vaccine type, days after the second vaccine dose, hypertension, kidney disease, and heart disease, T2D was identified as an independent risk factor for negative anti-RBD and anti-N/S seropositivity, odd ratio 0.42 (95% confidence interval 0.19, 0.89) and 0.42 (95% CI 0.20, 0.91), respectively. T2D is associated with impaired antibody response to inactivated COVID-19 vaccine.

Effect of gastric distension with concurrent small intestinal saline or glucose infusion on incretin hormone secretion in healthy individuals: A randomized, controlled, crossover study.

AIM: To evaluate the effect of gastric distension, induced using a gastric 'barostat', on the secretion of glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) in the presence and absence of small intestinal nutrients in healthy individuals. MATERIALS AND METHODS: Eight healthy participants (two females, six males, mean age 69.3 ± 1.2 years, body mass index 23.5 ± 0.8 kg/m2 ) were each studied on four occasions when they received an intraduodenal infusion of either (i) 0.9% saline or (ii) glucose delivered at a rate of 3 kcal/min both with, and without, an intragastric balloon with the pressure set to 8 mmHg above the intragastric minimum distending pressure. RESULTS: Following intraduodenal saline or glucose infusion, there was no difference in plasma GLP-1 with or without gastric distension (P = 1.00 for both saline and glucose infusions). There was also no difference in plasma GIP with or without gastric distension (P = 1.00 for saline infusion and P = .99 for glucose infusion). CONCLUSIONS: Gastric distension, either alone or during small intestinal glucose exposure, does not stimulate incretin hormone secretion significantly in healthy humans.

Determinants of blood glucose concentrations following a high carbohydrate meal in type 2 diabetes: A multiple linear regression analysis.

This study showed that in relatively well-controlled type 2 diabetes blood glucose levels after a high carbohydrate meal were associated positively with fasting blood glucose, but also positively with gastric emptying in the first hour and negatively with the increments in plasma glucagon-like peptide-1 (GLP-1) in the later postprandial phase.

Disparities in the Glycemic and Incretin Responses to Intraduodenal Glucose Infusion Between Healthy Young Men and Women.

CONTEXT: Premenopausal women are at a lower risk of type 2 diabetes (T2D) compared to men, but the underlying mechanism(s) remain elusive. The secretion of the incretin hormones, glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1), from the small intestine is a major determinant of glucose homeostasis and may be influenced by sex. OBJECTIVES: This study compared blood glucose and plasma insulin and incretin responses to intraduodenal glucose infusions in healthy young males and females. DESIGN: In Study 1, 9 women and 20 men received an intraduodenal glucose infusion at 2 kcal/min for 60 minutes. In Study 2, 10 women and 26 men received an intraduodenal glucose at 3 kcal/min for 60 minutes. Venous blood was sampled every 15 minutes for measurements of blood glucose and plasma insulin, GLP-1 and GIP. RESULTS: In response to intraduodenal glucose at 2 kcal/min, the incremental area under the curve between t = 0-60 minutes (iAUC0-60min) for blood glucose and plasma GIP did not differ between the 2 groups. However, iAUC0-60min for plasma GLP-1 (P = 0.016) and insulin (P = 0.011) were ∼2-fold higher in women than men. In response to intraduodenal glucose at 3 kcal/min, iAUC0-60min for blood glucose, plasma GIP, and insulin did not differ between women and men, but GLP-1 iAUC0-60min was 2.5-fold higher in women (P = 0.012). CONCLUSION: Healthy young women exhibit comparable GIP but a markedly greater GLP-1 response to intraduodenal glucose than men. This disparity warrants further investigations to delineate the underlying mechanisms and may be of relevance to the reduced risk of diabetes in premenopausal women when compared to men.

Cumulative muscle strength and risk of diabetes: A prospective cohort study with mediation analysis.

AIMS: Previous studies assessing the association of muscle strength with risk of diabetes have seldomly accounted for the cumulative exposure over time. This study examined the association of 4-year cumulative muscle strength with risk of diabetes in middle-aged and older adults. METHODS: We included participants without diabetes, who had 3 repeated measurements of muscle strength, which was assessed by grip strength (normalized by body-weight) and chair-rising time, over 4 years. Cumulative muscle strength was calculated based on trapezoid rule. Logistic regression analysis and mediation analysis for cumulative blood pressure were performed. RESULTS: We included 3731 and 3799 participants with data on cumulative grip strength and cumulative chair-rising time, respectively. The odds of diabetes were gradually reduced with increments in cumulative grip strength or decrements in cumulative chair-rising time, with the corresponding odds ratio being 0.79 and 0.89 per 1 standard deviation change after multivariable-adjustment. Cumulative systolic blood pressure mediated 10.8% and 14.2% of the associations of diabetes with cumulative grip strength and cumulative chair-rising time, respectively. Cumulative grip strength also correlated inversely with blood pressure, glycemia, and inflammation. CONCLUSIONS: Higher cumulative muscle strength was associated with lower risk of diabetes and better cardiometabolic health in middle-aged and older Chinese adults.

Cumulative Muscle Strength and Risk of Cardiovascular Disease and All-cause mortality: A Prospective Cohort Study.

BACKGROUND: The existing literature regarding the association between muscle strength and cardiovascular disease (CVD) and all-cause mortality relies mostly on a single measurement of muscle strength but has seldomly focused on the accumulated exposure. OBJECTIVE: This study explored the association between cumulative muscle strength and risks of CVD and all-cause mortality in middle-aged and older adults. METHODS: A total of 6,972 patients from the China Health and Retirement Longitudinal Study, who underwent 3 repeated measurements of muscle strength over 4 years and were followed-up for another 3 years for CVD and all-cause mortality outcomes participated in this study. Muscle strength was evaluated by grip strength and chair-rising time. Cumulative muscle strength was calculated as the area under the curve. Odds ratio (OR) and 95% confidence intervals (CIs) were analyzed. RESULTS: The odds of CVD and all-cause mortality decreased as cumulative grip strength increased or cumulative chair-rising time decreased. For each 1 standard deviation (SD) increment in cumulative grip strength, the multivariable-adjusted OR for CVD and all-cause mortality were 0.81 (95% CI 0.73-0.91) and 0.85 (95% CI 0.73-0.99), respectively. For each 1 SD decrease in cumulative chair-rising time, the corresponding OR were 0.81 (95% CI 0.75-0.88) and 0.87 (95% CI 0.77-0.98), respectively. However, neither the change-slope of grip strength nor that of chair-rising time was related to decreased OR of CVD or of all-cause mortality. CONCLUSIONS: Cumulative muscle strength was associated with a reduced risk of CVD and all-cause mortality in middle-aged and older Chinese adults.

The 'early' postprandial glucagon response is related to the rate of gastric emptying in type 2 diabetes.

Gastric emptying (GE) is a major determinant of the postprandial glycemic and insulinemic responses in health and type 2 diabetes (T2D). However, the effect of GE on the postprandial glucagon response, which is characteristically augmented in T2D, is unknown. This study examined the relationship between plasma glucagon and GE of a standardized mixed meal in individuals with well-controlled T2D. 89 individuals with T2D (HbA1c 6.6 ± 0.1%) consumed a mashed potato meal labeled with 100 µL 13C-octanoic acid between 0 and 5 min. Venous blood was sampled frequently over 4 h for measurements of blood glucose and plasma glucagon. The gastric half-emptying time (T50) was calculated by quantification of 13C in the breath. Blood glucose peaked at t = 90 min after the meal. Plasma glucagon increased to a peak at t = 30 min and then decreased to a nadir at t = 180 min. The T50 was 68.3 ± 1.6 min. The incremental area under the plasma glucagon curve between t = 0-30 min (glucagon iAUC0-30 min) was related inversely to the T50 (r = -0.23, P = 0.029), while the increase in blood glucose at t = 30 min was related directly to the plasma glucagon iAUC0-30 min (r = 0.25, P = 0.018). Accordingly, individuals with relatively faster GE exhibited higher postprandial glucagon and glucose levels (ANOVA: P<0.01 for each). In well-controlled T2D, the early postprandial glucagon response to a mixed meal is related to the rate of GE, and predictive of the initial glycemic response. These observations suggest that a reduction in plasma glucagon may contribute to the effect of dietary and pharmacological strategies which reduce postprandial glycemia in T2D by slowing GE.

Simultaneous determination of sex hormones and bile acids in rat plasma using a liquid chromatography-tandem mass spectrometry method.

Endogenous steroids, including sex hormones and bile acids, are a group of essential compounds with various biological functions. In this study, we developed an LC-MS method that simultaneously measures 14 sex hormones and metabolites (SH) and 32 bile acids (BA) in rat plasma. Multiple innovative approaches were applied to increase the sensitivity and specificity, including optimization of the mobile phases, gradients, and dynamic multiple reaction monitoring (DMRM) transitions. The method was validated and applied on plasma samples from pregnant rats before and 0.5 h after oral glucose tolerance test (OGTT) at gestational days 0.5 and 18.5. Results showed that the method was applicable, and 9 SH and 30 BA were measurable in the samples. In summary, this method is applicable in studies on SH and BA in rat plasma, and may also be used on other matrix and species.

Circulating irisin in nonalcoholic fatty liver disease: an updated meta-analysis.

INTRODUCTION: Exogenous administration of recombinant irisin may reverse hepatic steatosis and steatohepatitis. However, it remains controversial as to whether nonalcoholic fatty liver disease (NAFLD) shows reduced circulating (serum/plasma) irisin levels. A meta-analysis was conducted to address this issue. MATERIAL AND METHODS: A literature search of databases was performed up to June 2021. Observational studies that reported circulating irisin in NAFLD ascertained by any methods (e.g. ultrasonography or magnetic resonance) and compared with any controls were eligible for inclusion. Standardized mean differences (SMDs) and 95% confidence intervals (CIs) were obtained using a random-effects meta-analysis model. RESULTS: Eleven studies enrolling 1277 NAFLD cases and 944 non-NAFLD controls were included. The approaches used for NAFLD ascertainment included ultrasonography (4 studies), magnetic resonance (3 studies), and liver biopsy (5 studies). Meta-analysis showed that circulating irisin in NAFLD was comparable to any non-NAFLD controls (10 studies with 11 datasets; SMD -0.09, 95% CI: -0.48 to 0.29), including the body mass index (BMI)-matched and lean controls (both p ≥ 0.80). Restricting studies to NAFLD ascertained by magnetic resonance or liver biopsy rather than ultrasonography showed that serum irisin was reduced in NAFLD (5 studies, SMD -0.63, 95% CI: -1.14 to -0.13). Meta-analysis also suggested that circulating irisin did not differ between mild and moderate-to-severe NAFLD (7 studies; SMD 0.02, 95% CI: -0.25 to 0.30), and this association was not significantly moderated by study location (Europe versus Asia). CONCLUSIONS: Circulating irisin in NAFLD did not differ from any non-NAFLD controls and was unlikely to be affected by disease severity or racial-ethnic difference.