Milk protects against sarcopenic obesity due to increase in the genus Akkermansia in faeces of db/db mice.

BACKGROUND: Sarcopenic obesity, a combination of sarcopenia and obesity, is a pathological feature of type 2 diabetes. Several human studies have shown that milk is useful in the prevention of sarcopenia. This study was aimed at clarifying the effect of milk on the prevention of sarcopenic obesity in db/db mice. METHODS: A randomized and investigator-blinded study was conducted using male db/db mice. Eight-week-old db/db mice were housed for 8 weeks and fed milk (100 µL/day) using a sonde. The faecal microbiota transplantation (FMT) group received antibiotics for 2 weeks, starting at 6 weeks of age, followed by FMT twice a week until 16 weeks of age. RESULTS: Milk administration to db/db mice increased grip strength (Milk-: 164.2 ± 4.7 g, Milk+: 230.2 ± 56.0 g, P = 0.017), muscle mass (soleus muscle, Milk-: 164.2 ± 4.7 mg, Milk+: 230.2 ± 56.0 mg, P < 0.001; plantaris muscle, Milk-: 13.3 ± 1.2 mg, Milk+: 16.0 ± 1.7 mg, P < 0.001) and decreased visceral fat mass (Milk-: 2.39 ± 0.08 g, Milk+: 1.98 ± 0.04 mg, P < 0.001), resulting in a significant increase in physical activity (light: P = 0.013, dark: P = 0.034). FMT from mice fed milk not only improved sarcopenic obesity but also significantly improved glucose intolerance. Microarray analysis of gene expression in the small intestine revealed that the expression of amino acid absorption transporter genes, namely, SIc7a5 (P = 0.010), SIc7a1 (P = 0.015), Ppp1r15a (P = 0.041) and SIc7a11 (P = 0.029), was elevated in mice fed milk. In 16S rRNA sequencing of gut microbiota, the genus Akkermansia was increased in both the mice fed milk and the FMT group from the mice fed milk. CONCLUSIONS: The findings of this study suggest that besides increasing the intake of nutrients, such as amino acids, milk consumption also changes the intestinal environment, which might contribute to the mechanism of milk-induced improvement of sarcopenic obesity.

Brazilian green propolis improves gut microbiota dysbiosis and protects against sarcopenic obesity.

INTRODUCTION: Brazilian green propolis is an important honeybee product that is considered beneficial for health. Here, we examined the therapeutic potential of dietary supplementation with propolis against sarcopenic obesity using Db/Db mice. METHODS: Db/m mice fed a normal diet alone and Db/Db mice fed normal diet alone, or supplemented with different amounts of propolis (0.08, 0.4 and 2%), were examined for effects on sarcopenic obesity. RESULTS: Propolis improved the glucose tolerance (P < 0.001), increased the grip strength (P < 0.001) and the weight of soleus (P = 0.006) and plantaris muscles (P = 0.008). Moreover, propolis improved the non-alcoholic fatty liver disease activity score (P < 0.001) and decreased the expression of genes related to inflammation, liver fibrosis and fatty acid metabolism. Propolis decreased the accumulation of saturated fatty acids in the liver and increased their excretion in faeces. With regard to the innate immunity, propolis decreased the ratio of M1 macrophages (P = 0.008) and Type 1 and 3 innate lymphoid cells to CD45-positive cells (P < 0.001) and increased the ratio of M2 macrophages (P = 0.002) and ILC2s (P = 0.007) in the liver. Additionally, propolis decreased the expression of genes related to muscle atrophy and inflammation and the concentration of saturated fatty acids in the soleus muscle. 16S rRNA phylogenetic sequencing revealed that propolis increased the Bacteroidetes/Firmicutes ratio, and the abundance of Butyricicoccus and Acetivibrio genera. Gut microbiota related to the pentose phosphatase pathway and glycerolipid metabolism was more prevalent after the administration of propolis. CONCLUSIONS: This is the first study to demonstrate that propolis can improve sarcopenic obesity by improving dysbiosis due to overeating and provides new insights into diet-microbiota interactions during sarcopenic obesity.

Relationship between serum creatinine to cystatin C ratio and subclinical atherosclerosis in patients with type 2 diabetes.

INTRODUCTION: Sarcopenia index (SI), calculated by (serum creatinine/cystatin C)×100, is reported to be associated with sarcopenia. Few studies reported the association between SI and subclinical atherosclerosis. We evaluated the association between SI and subclinical atherosclerosis, assessed by brachial-ankle pulse wave velocity (baPWV). RESEARCH DESIGN AND METHODS: One hundred seventy-four patients with type 2 diabetes were included in this cross-sectional study. The relationship between SI and baPWV was assessed by Pearson's correlation coefficient. To calculate area under the receiver operator characteristic (ROC) curve (AUC) of SI for the presence of subclinical atherosclerosis, which was defined as baPWV >1800 cm/s, ROC analysis was performed. Logistic regression analyses were performed to assess the effect of SI on the prevalence of subclinical atherosclerosis adjusting for covariates. RESULTS: Mean age, duration of diabetes, baPWV, and SI were 66.9 (10.1) years, 17.7 (11.6) years, 1802 (372) cm/s, and 77.6 (15.8), respectively. There was an association between SI and baPWV (men; r=-0.25, p=0.001, and women; r=-0.37, p=0.015). The optimal cut-off point of SI for the presence of subclinical atherosclerosis was 77.4 (sensitivity=0.72, specificity=0.58, p<0.001, AUC 0.66 (95% CI: 0.57 to 0.74)). In addition, SI was associated with the prevalence of subclinical atherosclerosis (adjusted OR 0.95, 95% CI: 0.91 to 0.99, p=0.015). CONCLUSIONS: SI is associated with the prevalence of subclinical atherosclerosis in patients with type 2 diabetes.

Extracellular lipidome change by an SGLT2 inhibitor, luseogliflozin, contributes to prevent skeletal muscle atrophy in db/db mice.

BACKGROUND: Diabetes mellitus increases the excretion of urinary glucose from the renal glomeruli due to elevated blood glucose levels. In the renal tubules, SGLT2 is expressed and reabsorbs the excreted urinary glucose. In the pathogenesis of diabetes mellitus, glucose reabsorption by SGLT2 is increased, and SGLT2 inhibitors improve hyperglycaemia by inhibiting this reabsorption. When urinary glucose excretion is enhanced, glucose supply to skeletal muscle may be insufficient and muscle protein catabolism may be accelerated. On the other hand, SGLT2 inhibitors not only ameliorate hyperglycaemia but also improve fatty acid metabolism in muscle, which may prevent muscle atrophy. METHODS: Eight-week-old male db/m mice or db/db mice were fed a standard diet with or without the SGLT2i luseogliflozin (0.01% w/w in chow) for 8 weeks. Mice were sacrificed at 16 weeks of age, and skeletal muscle and serum lipidomes, as well as skeletal muscle transcriptome, were analysed. RESULTS: Administration of SGLT2i led to not only decreased visceral fat accumulation (P = 0.004) but also increased soleus muscle weight (P = 0.010) and grip strength (P = 0.0001). The levels of saturated fatty acids, especially palmitic acid, decreased in both muscles (P = 0.017) and sera (P = 0.041) upon administration of SGLT2i, while the content of monosaturated fatty acids, especially oleic acid, increased in both muscle (P < 0.0001) and sera (P = 0.009). Finally, the accumulation of transcripts associated with fatty acid metabolism, such as Scd1, Fasn, and Elovl6, and of muscle atrophy-associated transcripts, such as Foxo1, Mstn, Trim63, and Fbxo32, decreased following SGLT2i administration. CONCLUSIONS: Intramuscular fatty acid metabolism and gene expression were influenced by the extracellular lipidome, which was modified by SGLT2i. Hence, secondary effects, other than the hypoglycaemic effects of SGLT2i, might lead to the alleviation of sarcopenia.

Sarcopenia Is Associated With a Risk of Mortality in People With Type 2 Diabetes Mellitus.

Background: Sarcopenia has reportedly been associated with increased risk of mortality in general populations. However, few studies have investigated the association between sarcopenia and mortality in older people with type 2 diabetes mellitus (T2D). This study aimed to investigate the effect of sarcopenia on incident all-cause mortality in older people with T2D. Methods: Low muscle strength were set at handgrip strength <28 kg for men and <18 kg for women, and low skeletal muscle mass index (SMI), evaluated using the impedance body composition analyzer, were set at SMI <7.0 kg/m2 for men and <5.7 kg/m2 for women. People who had both low muscle strength and low SMI were diagnosed with sarcopenia. Due to a low incidence of all-cause mortality, the propensity score was used. The propensity score was evaluated using multivariable logistic regression models with the following parameters: age, sex, duration of diabetes, history of heart disease, history of cancer, smoking, exercise, alcohol, sodium-glucose cotransporter-2 inhibitor, glucagon-like peptide-1 receptor agonist, insulin, corticosteroid, hypertension, body mass index, glycosylated hemoglobin A1c, triglycerides, and creatinine, and the C-statistic was 0.89. Results: In this prospective cohort study, 396 people with an average age and duration of diabetes of 71.3 (6.3) years and 16.3 (11.3) years, respectively, were included. Of those included, 14.6% had sarcopenia. During the average 40.5 (16.5) months of follow-up, 13 people (6 out of the 338 without sarcopenia and 7 out of the 58 with sarcopenia) died. Incident rate were 5.1/1000 person years of follow-up in people without sarcopenia and 41.3/1000 person years of follow-up in people with sarcopenia. According to Cox regression analysis, sarcopenia was associated with all-cause mortality (adjusted hazard ratio: 6.12, 95% confidence interval: 1.52-24.7, p = 0.011). Conclusion: Sarcopenia is associated with incident all-cause mortality in older outpatients with T2D.

Vitamin Intake and Loss of Muscle Mass in Older People with Type 2 Diabetes: A Prospective Study of the KAMOGAWA-DM Cohort.

The aim of this prospective cohort study was to examine the relationships between the intakes of various vitamins and the loss of muscle mass in older people with type 2 diabetes (T2DM). The change in skeletal muscle mass index (SMI, kg/m2) (kg/m2/year) was defined as follows: (SMI at baseline (kg/m2) - SMI at follow-up (kg/m2))/follow-up period (year). The rate of SMI reduction (%) was calculated as follows (the change in SMI (kg/m2/year)/SMI at baseline (kg/m2)) × 100. The rate of SMI reduction ≥ 1.2% was considered as the loss of muscle mass. Among 197 people with T2DM, 47.2% of them experienced the loss of muscle mass at the 13.7 ± 5.2 month follow-up. Vitamin B1 (0.8 ± 0.3 vs. 0.8 ± 0.3 mg/day, p = 0.031), vitamin B12 (11.2 ± 8.3 vs. 13.4 ± 7.5 µg/day, p = 0.049), and vitamin D (16.5 ± 12.2 vs. 21.6 ± 13.0 µg/day, p = 0.004) intakes in people with the loss of muscle mass were significantly lower than those without. Vitamin D intake was related to the loss of muscle mass after adjusting for sex, age, exercise, alcohol, smoking, body mass index, SMI, glucagon-like peptide-1 agonist, sodium glucose cotransporter-2 inhibitor, insulin, HbA1c, creatinine, energy intake, and protein intake (adjusted odds ratio 0.93, 95% confidence interval: 0.88-0.97, p = 0.003). This study showed that vitamin D intake was related to the loss of muscle mass in older people with T2DM. Vitamin B12 intake tended to be related to the loss of muscle mass, although vitamin A, vitamin B2, vitamin B6, vitamin C, and vitamin E intake were not related.

ILC2s Improve Glucose Metabolism Through the Control of Saturated Fatty Acid Absorption Within Visceral Fat.

Background and aims: Group 2 innate lymphoid cells (ILC2s) have been implicated in the regulation of metabolic homeostasis in mice. Methods: In this study, the role of ILC2s in white adipose tissue (WAT) was investigated using ST2, an IL-33 receptor that is expressed on ILC2 knockout mice. Results: The deficiency of ST2 decreased ILC2s in WAT, whereas ex-ILC2, which acquired group 1 innate lymphoid cell (ILC1)-like traits, was increased. This led to significant metabolic disorders such as visceral fat obesity, decreased browning in WAT, reduction of energy metabolism, and impaired glucose tolerance, compared to wild type (WT) mice. Those metabolic abnormalities of ST2-knockout (ST2KO) mice were not ameliorated by IL-33 administration, but impaired glucose tolerance and visceral fat obesity were significantly improved by transplantation of ILCs from the bone marrow of WT mice. The relative expression of Cd36 in WAT increased due to the deficiency of ST2, and the storage of saturated fatty acids in WAT of ST2KO mice was significantly higher than that of WT mice. Moreover, saturated fatty acids aggravated the chronic inflammation in adipocytes, promoted the differentiation of M1-like macrophages, and inhibited that of M2-like macrophages. Conclusions: Our results indicated that ILC2 regulates diet-induced obesity and chronic inflammation through the regulation of saturated fatty acid absorption in visceral adipose tissue.

Trans Fatty Acid Intake Induces Intestinal Inflammation and Impaired Glucose Tolerance.

Background and Aims: Many nutritional and epidemiological studies have shown that high consumption of trans fatty acids can cause several adverse effects on human health, including cardiovascular disease, diabetes, and cancer. In the present study, we investigated the effect of trans fatty acids on innate immunity in the gut by observing mice fed with a diet high in trans fatty acids, which have been reported to cause dysbiosis. Methods: We used C57BL6/J mice and fed them with normal diet (ND) or high-fat, high-sucrose diet (HFHSD) or high-trans fatty acid, high-sucrose diet (HTHSD) for 12 weeks. 16S rRNA gene sequencing was performed on the mice stool samples, in addition to flow cytometry, real-time PCR, and lipidomics analysis of the mice serum and liver samples. RAW264.7 cells were used for the in vitro studies. Results: Mice fed with HTHSD displayed significantly higher blood glucose levels and advanced fatty liver and intestinal inflammation, as compared to mice fed with HFHSD. Furthermore, compared to mice fed with HFHSD, mice fed with HTHSD displayed a significant elevation in the expression of CD36 in the small intestine, along with a reduction in the expression of IL-22. Furthermore, there was a significant increase in the populations of ILC1s and T-bet-positive ILC3s in the lamina propria in mice fed with HTHSD. Finally, the relative abundance of the family Desulfovibrionaceae, which belongs to the phylum Proteobacteria, was significantly higher in mice fed with HFHSD or HTHSD, than in mice fed with ND; between the HFHSD and HTHSD groups, the abundance was slightly higher in the HTHSD group. Conclusions: This study revealed that compared to saturated fatty acid intake, trans fatty acid intake significantly exacerbated metabolic diseases such as diabetes and fatty liver.

Group 3 Innate Lymphoid Cells Protect Steatohepatitis From High-Fat Diet Induced Toxicity.

Background and Aims: Emerging evidence has revealed that innate lymphoid cells (ILCs) play a key role in regulating metabolic disorders. Here, we investigated the role of group 3 ILCs (ILC3s) in the modulation of Non-alcoholic fatty liver disease (NAFLD). Methods: RORγ gfp/gfp (RORgt KI/KI) and Rag2-/- mice with the administration of A213, RORgt antagonist, fed with a high-fat-diet (HFD) for 12 weeks, were used. We performed flow cytometry, real time PCR, and lipidomics analysis of serum and liver, and used RAW264.7 cells and murine primary hepatocytes in vitro. Results: HFD increased ILC3s and M1 macrophages in the liver, and RORgt KI/KI mice deficient in ILC3 showed significant fatty liver, liver fibrosis and significantly increased palmitic acid levels in serum and liver. In addition, administration of A213 to Rag2-/- mice caused significant fatty liver, liver fibrosis, and a significant increase in serum and liver palmitate concentrations, as in RORgt KI/KI mice. Addition of palmitc acid stimulated IL-23 production in cell experiments using RAW264.7. IL-22 produced by ILC3s inhibited the palmitate-induced apoptosis of primary hepatocytes. Conclusions: HFD stimulates IL-23 production by M1 macrophages, thus promoting ILC3 proliferation, whereas IL-22 secreted by ILC3s contributes to the upregulation of hepatic lipid metabolism and has anti-apoptosis activity.

Short energy intake is associated with muscle mass loss in older patients with type 2 diabetes: A prospective study of the KAMOGAWA-DM cohort.

BACKGROUND & AIM: Past studies reported that the intake of adequate energy is more important than protein intake; however, the relationship between energy intake and muscle mass loss remains unclear thus far. This study therefore explored the association between energy intake and muscle mass loss in people with type 2 diabetes (T2D). METHODS: In this prospective cohort study, impedance body composition and a brief-type self-administered diet history questionnaire were used for analyzing body composition and habitual diet intake, respectively. Skeletal muscle mass index (SMI, kg/m2) was defined as appendicular muscle mass (kg) ÷ height-squared (m2). Rate of SMI change (%) was calculated as ([SMI at baseline - SMI at follow-up]/[follow-up duration (years) × baseline SMI (kg/m2)]) × 100, and muscle mass loss was defined as rate of SMI change ≥0.5%. Energy intake was defined as total energy intake (kcal/day) divided by ideal body weight (kg), defined as 22 × patient height-squared (m2). RESULTS: Among non-older and older participants, 54.8% (n = 51/93) and 58.9% (n = 116/197) experienced muscle mass loss at 16.3 (6.4) and 18.1 (7.1) months' follow-up, respectively. Logistic regression analyses showed that energy intake was associated with incident muscle mass loss after adjusting for age, sex, insulin, sodium glucose cotransporter-2 inhibitor, glucagon-like peptide-1 agonist, steroids, smoking, exercise, alcohol intake, body mass index, SMI, presence of renal failure, and protein intake (g/actual body weight/day) in the older people (odds ratio [OR] 0.94 [95% confidence interval [CI] 0.88-0.996], p = 0.037), whereas energy intake was not associated with incident muscle mass loss in the non-older people (OR 0.96 [95% CI 0.86-1.06], p = 0.423). CONCLUSIONS: Insufficient energy intake is associated with muscle mass loss in older people with T2D. Therefore, it is recommended to consume enough energy for older people with T2D to keep muscle mass.

Late-night-dinner is associated with poor glycemic control in people with type 2 diabetes: The KAMOGAWA-DM cohort study.

Skipping breakfast or irregular breakfast is associated with poor glycemic control. However, a relationship between the timing of dinner and glycemic control in people with type 2 diabetes remains indefinite. Therefore, we investigated the relationship between late-night-dinner and glycemic control in people with type 2 diabetes. We performed questionnaire survey for lifestyle factors in this cross-sectional study. We defined having dinner later than eight pm as late-night-dinner. We examined the differences in clinical and metabolic parameters between those who have late-night-dinner and those who do not have. We also examined the relationship between late-night-dinner and HbA1c, using multiple regression analysis. Ninety-five people (23.2%) had a late-night-dinner, among 409 people with type 2 diabetes. Metabolic parameters (mean (SD) or median (interquartile range)) of people with late-night-dinner were worse than those of without, including body mass index (BMI) (24.4 (4.0) vs. 23.2 (3.4) kg/m2, p = 0.006), triglycerides (1.5 (1.1-2.1) vs. 1.2 (0.8-1.7) mmol/L, p < 0.001), HDL-cholesterol (1.4 (0.4) vs. 1.6 (0.4) mmol/L, p = 0.004) and hemoglobin A1c (58.1 (13.3) vs. 55.2 (10.2) mmol/mol, (7.5 (1.2) vs. 7.2 (0.9) %), p = 0.023)). Late-night-dinner (standardized regression coefficient = 0.13, p = 0.028) was associated with hemoglobin A1c after adjusting for age, BMI, sex, duration of diabetes, smoking, exercise, alcohol, snacking after dinner, nighttime sleep duration, time from dinner to bedtime, skipping breakfast, and medication for diabetes. Late-night-dinner is independently associated with poor glycemic control in people with type 2 diabetes.

Is home blood pressure reporting in patients with type 2 diabetes reliable?

The aim of this study was to evaluate the reliability of self-reported home blood pressure (HBP) in patients with type 2 diabetes by comparing the self-reported values with HBP measurements stored in the memory of the blood pressure (BP) monitor. We also examined what factors affect the reliability of HBP measurements. A cross-sectional study was conducted in 280 patients with type 2 diabetes. Patients were requested to perform triplicate morning and evening measurements over a span of 2 weeks and to enter their HBP values into logbooks. Patients were not informed about the memory function of their BP monitoring devices. The concordance rate of HBP reporting was 78.6%. A total of 51.4% of patients (n=144) had >90% concordant data, and 15.7% of patients (n=44) had ⩽50% concordant data. In general, HBP values from the logbook were significantly lower and less variable than those from the stored memory (P<0.05). The most common type of incorrect data was selected data that were reported in the logbooks that were randomly selected from multiple readings by the HBP monitors (55.8%). The concordance rate of HBP reporting significantly correlated with hemoglobin A1c levels (ß=-0.156; P=0.0149) and with smoking status (current vs. never, ß=-0.165; P=0.0184). In conclusion, HBP measurements from the patients' logbooks were lower and less variable than those from the stored memory in the BP monitors of patients with type 2 diabetes, and the reliability of HBP reporting was affected by glycemic control and smoking status. Repeated instructions regarding HBP measurement to the patients or the use of stored BP measurements is recommended to ensure accurate HBP measurements in patients with type 2 diabetes.

Low body mass index is associated with impaired quality of life in patients with rheumatoid arthritis.

AIM: To investigate the relationship between quality of life (QOL) and rheumatoid chachesia, malnutrition in patients with rheumatoid arthritis (RA). METHODS: EuroQol Group 5-Dimension Self-Report Questionnaire (EQ5D) and Japanese Health Assessment Questionnaire (JHAQ) scores, body mass index (BMI), arm muscle area (AMA) and clinical indicators were measured in 385 RA patients. One-way analysis of variance for obtained data was conducted among three groups: 131 with low BMI (< 20), 163 with moderate (20-25) and 91 with high BMI (≥25). Then multiple regression analyses for JHAQ and EQ5D scores with nutritional and clinical indicators as independent variables were performed. RESULTS: EQ5D and JHAQ scores were significantly lower and higher, respectively, in the low BMI group than those in the moderate BMI group. Clinical indicators including doses of corticosteroid were similar among the three groups except for disease duration. Disease activity score (DAS) 28, disease duration, C-reactive protein and AMA were significant variables in the regression model for EQ5D. CONCLUSION: Low BMI deteriorates the QOL of RA patients. Muscle protein loss apparently leads to a reduction in BMI and QOL.