Non-alcoholic fatty liver disease (NAFLD) is a very common liver disease associated with obesity, unhealthy diet, and lack of physical exercise. Short-term aerobic or resistance exercise has been shown to result in reduced liver fat in patients with NAFLD; however, the impact of the combination of these types of exercise has received less attention. This study investigated the effect of a short-term (7 days) concurrent exercise training program performed daily on liver steatosis indices, as well as the glycemic and lipidemic profile of overweight/obese sedentary volunteers. Twenty adult patients (age: 47.3 ± 12.3 yrs, body mass index: 32.4 ± 3.4 kg/m2) with NAFLD, detected by ultrasound and hematological indices, participated in the study. Pre- and post-exercise intervention assessment included body weight (BW), waist circumference (WC), hip/waist ratio (H/W), Homeostasis Model Assessment Insulin Resistance (HOMA-IR), blood lipids, and steatosis indices. Fatty Liver Index, Lipid Accumulation Index, WC, H/W, triglycerides, and total cholesterol were improved (p < 0.05) post-exercise, while no differences (p > 0.05) were observed in BW, HOMA-IR, HDL, LDL, Hepatic Steatosis Index, and Framingham Steatosis Index compared to pre-exercise values. It is concluded that a 7-day combined exercise program can have beneficial effects on hepatic steatosis and central adiposity indices, independently of weight loss, in patients with NAFLD.

Dipeptidyl peptidase-4 inhibitors (DPP-4I), key regulators of the actions of incretin hormones, exert anti-hyperglycemic effects in type 2 diabetes mellitus (T2DM) patients. A major unanswered question concerns the potential ability of DPP-4I to improve intrahepatic lipid (IHL) content in nonalcoholic fatty liver disease (NAFLD) patients. The aim of this study was to evaluate the effects of sitagliptin on IHL in NAFLD patients.
A prospective, 24-week, single-center, open-label, comparative study enrolled 68 Chinese NAFLD patients with T2DM. Subjects were randomly divided into 4 groups: control group who did not take medicine (14 patients); sitagliptin group who received sitagliptin treatment (100mg per day) (17 patients); metformin group who received metformin (500mg three times per day) (17 patients); and sitagliptin plus metformin group who received sitagliptin (100mg per day) and metformin (500 mg three times per day) (20 patients). IHL, physical examination (waist circumstances, WC; body mass index, BMI), glucose-lipid metabolism (fasting plasma glucose, FPG; hemoglobin A1c, Hb1A1c; triglycerides; cholesterol; alanine aminotransferase, ALT; aspartate aminotransferase, AST) were measured at baseline and at 24 weeks.
1) WC and BMI were decreased significantly in all groups except control group (all P<0.05). 2) There was no statistically significant difference in IHL among the sitagliptin, metformin, and sitagliptin plus metformin groups before and after treatment(all P>0.05). Only the metformin group showed a statistically significant difference in IHL before and after treatment(P<0.05). 3) Sitagliptin treatment led to a significant decrease in FBG and HbA1c when compared with the control group (all P<0.01). Additionally, HhA1c was significant decreased in the sitagliptin group when compared with the metformin group (P< 0.05). 4) HbA1c and FBG were decreased by 0.8% and 0.7 mmol/l respectively and the percentage of patients with HbA1c less than 7% was 65% with sitagliptin treatment.
Sitagliptin improves abnormalities in glucose metabolism, but not reduces the IHL in T2DM with NAFLD, indicating that sitagliptin might be a therapeutic option for treatment of NAFLD indirectly while not directly on IHL. Clinical Trial Registration: https://clinicaltrials.gov/, identifier CTR# NCT05480007.

There is an ongoing debate on whether fructose plays a role in the development of nonalcoholic fatty liver disease.
The aim of this study was to investigate the effects of fructose restriction on intrahepatic lipid (IHL) content in a double-blind randomized controlled trial using an isocaloric comparator.
Between March 2017 and October 2019, 44 adult overweight individuals with a fatty liver index ≥ 60 consumed a 6-wk fructose-restricted diet (<7.5 g/meal and <10 g/d) and were randomly assigned to supplementation with sachets of glucose (= intervention group) or fructose (= control group) 3 times daily. Participants and assessors were blinded to the allocation. IHL content, assessed by proton magnetic resonance spectroscopy, was the primary outcome and glucose tolerance and serum lipids were the secondary outcomes. All measurements were conducted in Maastricht University Medical Center.
Thirty-seven participants completed the study protocol. After 6 wk of fructose restriction, dietary fructose intake and urinary fructose excretion were significantly lower in the intervention group (difference: -57.0 g/d; 95% CI: -77.9, -39.5 g/d; and -38.8 μmol/d; 95% CI: -91.2, -10.7 μmol/d, respectively). Although IHL content decreased in both the intervention and control groups (P < 0.001 and P = 0.003, respectively), the change in IHL content was more pronounced in the intervention group (difference: -0.7% point, 95% CI: -2.0, -0.03% point). The changes in glucose tolerance and serum lipids were not significantly different between groups.
Six weeks of fructose restriction per se led to a small, but statistically significant, decrease in IHL content in comparison with an isocaloric control group.This trial was registered at clinicaltrials.gov as NCT03067428.

We have previously reported negative energy balance and health benefits during an Alaska backcountry expeditionary hunting (ABEH) immersion in two males. The purpose of our present study was to increase the number of participants, include females, and evaluate macronutrient intake and serum lipids. Four men (age: 46 ± 6 year, BMI: 26 ± 1 kg/m2 ) and three women (age: 46 ± 11 year, BMI: 25 ± 3 kg/m2 ) were recruited. Doubly labeled water methodology and dietary recall were utilized to assess energy expenditure and energy intake, respectively. Data were collected during pre- and post-ABEH visits. Body composition was measured using dual-energy x-ray absorptiometry and the cross-sectional area of skeletal muscle in the upper leg (XT), and intrahepatic lipid (IHL) was determined using magnetic resonance imaging and/or spectroscopy (MRI/MRS). Blood parameters were measured by LabCorp. Paired T-tests were used for statistical analysis. Data are reported as mean ± SD and considered significant at p < 0.05. Total energy intake was 7.7 ± 3.4 MJ/day and total energy expenditure was 17.4 ± 2.6 MJ/day, resulting in a negative energy balance of -9.7 ± 3.4 MJ/day. Protein intake(grams)/body weight(kilograms)/day was 1.0 ± 0.4. There were reductions in body weight (Δ-1.5 ± 0.7 kg), BMI (Δ-0.3 ± 0.2 kg/m2 ), fat mass (Δ-1.7 ± 0.9 kg), and IHL (Δ-0.3 ± 0.3% water peak). There were no changes in lean tissue mass (Δ0.6 ± 1.4 kg) or XT (Δ-1.3 ± 3.3 cm2 ). There were significant reductions in total cholesterol (Δ-44 ± 35 mg/dl), LDL-cholesterol (Δ-25 ± 14 mg/dl), VLDL-cholesterol (Δ-7 ± 7 mg/dl), and triglycerides (Δ-35 ± 33 mg/dl). The ABEH immersion resulted in considerable negative energy balance and provided comprehensive benefits in metabolic health without any reduction in skeletal muscle.

To investigate relationships between insulin clearance, insulin secretion, hepatic fat accumulation and insulin sensitivity in black African (BA) and white European (WE) men.
Twenty-three BA and twenty-three WE men with normal glucose tolerance, matched for age and body mass index, underwent a hyperglycaemic clamp to measure insulin secretion and clearance, hyperinsulinaemic-euglycaemic clamp with stable glucose isotope infusion to measure whole-body and hepatic-specific insulin sensitivity, and magnetic resonance imaging to quantify intrahepatic lipid (IHL).
BA men had higher glucose-stimulated peripheral insulin levels (48.1 [35.5, 65.2] × 103 vs. 29.9 [23.3, 38.4] × 103 pmol L-1  × min, P = .017) and lower endogeneous insulin clearance (771.6 [227.8] vs. 1381 [534.3] mL m-2 body surface area min -1 , P < .001) compared with WE men. There were no ethnic differences in beta-cell insulin secretion or beta-cell responsivity to glucose, even after adjustment for prevailing insulin sensitivity. In WE men, endogenous insulin clearance was correlated with whole-body insulin sensitivity (r = 0.691, P = .001) and inversely correlated with IHL (r = -0.674, P = .001). These associations were not found in BA men.
While normally glucose-tolerant BA men have similar insulin secretory responses to their WE counterparts, they have markedly lower insulin clearance, which does not appear to be explained by either insulin resistance or hepatic fat accumulation. Low insulin clearance may be the primary mechanism of hyperinsulinaemia in populations of African origin.

Although metabolic abnormalities commonly occur in non-obese Asians, their pathogenesis is not fully understood. Proton magnetic resonance spectroscopy has been used to analyze intracellular lipids in humans, and results suggest that ectopic fat accumulation in muscle and liver may induce insulin resistance in each tissue independently of obesity. Thus, measurement of ectopic fat currently plays an important role in the study of insulin resistance in non-obese Asians. In addition, studies using 2-step hyperinsulinemic euglycemic clamp with a glucose tracer may clarify how tissue-specific insulin resistance in muscle, liver, and adipose tissue contributes to the development of metabolic disease in non-obese Japanese. Although numerous studies have elucidated the pathophysiology of insulin resistance in obese subjects, research on \"metabolic gradation,\" defined as the gradual transition from an insulin-sensitive to an insulin-resistant state, is less common, especially in terms of early metabolic changes. This review addresses a simple question: when and how is insulin resistance induced in non-obese East Asians? Several studies revealed that impaired insulin clearance and hyperinsulinemia not only compensated for insulin resistance, but also secondarily facilitated insulin resistance and weight gain. In this regard, we recently found that impaired insulin clearance and hyperinsulinemia could occur in apparently healthy subjects without significant insulin resistance, suggesting that this change may be an initial trigger that drives subsequent insulin resistance and weight gain. Further research is required to clarify the pathogenesis of metabolic gradation in non-obese Asians.

The purported healthy aspects of subsistence foods have led to the popularity of the Paleo diet. There has been very little focus, surprisingly, on health benefits derived from the nomadic nature of humans during the Paleolithic era. The purpose of our study was to examine total energy expenditure (TEE), total energy intake (TEI), body composition, blood lipids, and intrahepatic lipid in humans during a 12-day Alaskan backcountry expeditionary hunting (ABEH) immersion. Four healthy men (age: 42 ± 3 year, BMI: 27 ± 1 kg/m2 ) were recruited for the study. TEE was measured using the doubly labeled water method and a food diary was utilized to assess TEI. Body composition was measured using dual energy X-ray absorptiometry (DXA); cross-sectional area of the thigh (XT) and intrahepatic lipid (IHL) were measured using molecular imaging. Blood samples were collected for the measurement of blood lipids. DXA, XT, IHL, and blood data were collected pre- and immediately post-ABEH. Results were analyzed using paired t-tests and considered significant at P < 0.05. TEE and TEI averaged 18.1 ± 1.2 and 9.1 ± 2.5 MJ/day, respectively, indicating substantial negative energy balance (-9.0 ± 1.3 MJ/day). There was a reduction in percent body fat (∆-3.3 ± 0.2%), total fat mass (∆-3.3 ± 0.4 kg), and visceral fat volume (Δ-261 ± 188 cm3 ). Lean tissue mass and XT was unchanged. There was a decrease in IHL (Δ-0.5 ± 0.1% water peak), and a trend (P = 0.055) toward reduction in LDL-cholesterol. We conclude that constancy of physical activity during negative energy balance may provide metabolic benefits above and beyond variations in diet that exist with the hunter-gatherer lifestyle.

Women with a history of gestational diabetes mellitus (GDM) have raised liver triacylglycerol. Restriction of energy intake in type 2 diabetes can normalise glucose control and liver triacylglycerol concentration but it is not known whether similar benefits could be achieved in GDM. The aim of this work was to examine liver triacylglycerol accumulation in women with GDM and the effect of modest energy restriction.
Sixteen women with GDM followed a 4 week diet (5 MJ [1200 kcal]/day). Liver triacylglycerol, before and after diet and postpartum, was measured by magnetic resonance. Insulin secretion and sensitivity were assessed before and after diet. Twenty-six women who underwent standard antenatal care for GDM (matched for age, BMI, parity and ethnicity) were used as a comparator group.
Fourteen women, who completed the study, achieved a weight loss of 1.6 ± 1.7 kg over the 4 week dietary period. Mean weight change was -0.4 kg/week in the study group vs +0.3 kg/week in the comparator group (p = 0.002). Liver triacylglycerol level was normal but decreased following diet (3.7% [interquartile range, IQR 1.2-6.1%] vs 1.8% [IQR 0.7-3.1%], p = 0.004). There was no change in insulin sensitivity or production. Insulin was required in six comparator women vs none in the study group (eight vs two required metformin). Blood glucose control was similar for both groups. The hypo-energetic diet was well accepted.
Liver triacylglycerol in women with GDM was not elevated, unlike observations in non-pregnant women with a history of GDM. A 4 week hypo-energetic diet resulted in weight loss, reduced liver triacylglycerol and minimised pharmacotherapy. The underlying pathophysiology of glucose metabolism appeared unchanged.

It is unclear whether regular exercise alone (no caloric restriction) is a useful strategy to reduce adiposity and obesity-related metabolic risk factors in obese girls. We examined the effects of aerobic (AE) vs. resistance exercise (RE) alone on visceral adipose tissue (VAT), intrahepatic lipid, and insulin sensitivity in obese girls. Forty-four obese adolescent girls (BMI ≥95th percentile, 12-18 yr) with abdominal obesity (waist circumference 106.5 ± 11.1 cm) were randomized to 3 mo of 180 min/wk AE (n = 16) or RE (n = 16) or a nonexercising control group (n = 12). Total fat and VAT were assessed by MRI and intrahepatic lipid by proton magnetic resonance spectroscopy. Intermuscular AT (IMAT) was measured by CT. Insulin sensitivity was evaluated by a 3-h hyperinsulinemic (80 mU·m(2)·min(-1)) euglycemic clamp. Compared with controls (0.13 ± 1.10 kg), body weight did not change (P > 0.1) in the AE (-1.31 ± 1.43 kg) and RE (-0.31 ± 1.38 kg) groups. Despite the absence of weight loss, total body fat (%) and IMAT decreased (P < 0.05) in both exercise groups compared with control. Compared with control, significant (P < 0.05) reductions in VAT (Δ-15.68 ± 7.64 cm(2)) and intrahepatic lipid (Δ-1.70 ± 0.74%) and improvement in insulin sensitivity (Δ0.92 ± 0.27 mg·kg(-1)·min(-1) per μU/ml) were observed in the AE group but not the RE group. Improvements in insulin sensitivity in the AE group were associated with the reductions in total AT mass (r = -0.65, P = 0.02). In obese adolescent girls, AE but not RE is effective in reducing liver fat and visceral adiposity and improving insulin sensitivity independent of weight loss or calorie restriction.

Erythropoietin (Epo) administration improves aerobic exercise capacity and insulin sensitivity in renal patients and also increases resting energy expenditure (REE). Similar effects are observed in response to endurance training. The aim was to compare the effects of endurance training with erythropoiesis-stimulating agent (ESA) treatment in healthy humans. Thirty-six healthy untrained men were randomized to 10 wk of either: 1) placebo (n = 9), 2) ESA (n = 9), 3) endurance training (n = 10), or 4) ESA and endurance training (n = 8). In a single-blinded design, ESA/placebo was injected one time weekly. Training consisted of biking for 1 h at 65% of wattmax three times per week. Measurements performed before and after the intervention were as follows: body composition, maximal oxygen uptake, insulin sensitivity, REE, and palmitate turnover. Uncoupling protein 2 (UCP2) mRNA levels were assessed in skeletal muscle. Fat mass decreased after training (P = 0.003), whereas ESA induced a small but significant increase in intrahepatic fat (P = 0.025). Serum free fatty acid (FFA) levels and palmitate turnover decreased significantly in response to training, whereas the opposite pattern was found after ESA. REE corrected for lean body mass increased in response to ESA and training, and muscle UCP2 mRNA levels increased after ESA (P = 0.035). Insulin sensitivity increased only after training (P = 0.011).
CONCLUSIONS: 1) insulin sensitivity is not improved after ESA treatment despite improved exercise capacity, 2) the calorigenic effects of ESA may be related to increased UCP2 gene expression in skeletal muscle, and 3) training and ESA exert opposite effects on lipolysis under basal conditions, increased FFA levels and liver fat fraction was observed after ESA treatment.