Oral Semaglutide Induces Loss of Body Fat Mass Without Affecting Muscle Mass in Patients With Type 2 Diabetes.

Background: Excessive body fat may be a major cause of insulin resistance and diabetes. But body weight reduction by energy restriction may simultaneously reduce both fat and muscle. Skeletal muscle is an important organ for glucose metabolism regulation, and loss of muscle may deteriorate glucose metabolism. Therefore, it is preferable to predominantly reduce fat without significant loss of muscle with weight loss in patients with type 2 diabetes. Previously, the anti-diabetic agent glucagon-like peptide-1 receptor agonists (GLP-1RAs) liraglutide and semaglutide given by injection were reported to decrease fat with less effect on muscle in diabetic patients. Recently oral semaglutide was developed and was reported to decrease body weight, but the effect on muscle has not been fully evaluated. Methods: This was a non-interventional retrospective longitudinal study. We evaluated the effect of 24-week treatment with oral semaglutide on body fat and muscle mass in 25 Japanese patients with type 2 diabetes. Laboratory examination and body composition test by bioelectrical impedance analysis (BIA) were performed at baseline, 12 weeks, and 24 weeks, and the effects on glycemic control and body composition were assessed. Results: Hemoglobin A1c significantly decreased at 12 weeks and further ameliorated at 24 weeks (8.7±0.87% at baseline; 7.6±1.00% at 12 weeks; 7.0±0.80% at 24 weeks; mean ± standard error (SE)). While body fat significantly decreased (28.3 ± 1.52 kg at baseline; 26.8 ± 1.59 kg at 12 weeks; 25.5 ± 1.57 kg at 24 weeks; mean ± SE), whole-body lean mass was not significantly changed (48.1 ± 1.92 kg at baseline; 47.7 ± 1.93 kg at 12 weeks; 47.6 ± 1.89 kg at 24 weeks; mean ± SE). Furthermore, the appendicular skeletal muscle index (SMI) defined as appendicular skeletal muscle mass (ASM)/height squared (units; kg/m2) was also unchanged. Conclusion: The 24-week treatment with oral semaglutide ameliorated glycemic control with reduction of body fat but not muscle mass in Japanese patients with type 2 diabetes.

Associations of phase angle obtained by bioelectrical impedance analysis with muscle mass and strength in Japanese patients with type 2 diabetes.

The age-dependent decrease in muscle mass and function is known as sarcopenia. The risk of sarcopenia is higher in patients with diabetes, and assessment of muscle mass and function is especially important in patients with diabetes. Recent reports suggest that the phase angle (PhA), which is obtained from bioelectrical impedance analysis (BIA), may be a good marker of not only muscle mass but also muscle function in healthy people. However, the clinical significance of PhA in patients with diabetes has not been fully investigated. Therefore, we evaluated the association of PhA with muscle mass, muscle strength, and physical performance in 159 patients with type 2 diabetes (male 102; female 57) aged 40 to 89 years. We measured PhA and appendicular skeletal muscle index (SMI) by BIA and handgrip and leg extension strength and performed the Short Physical Performance Battery (SPPB). In a simple correlation analysis, both right and left PhA correlated with SMI, handgrip and leg extension strength, and SPPB score, and in multiple regression analysis, PhA on each side correlated with SMI and ipsilateral handgrip strength. These data suggest that PhA may be a useful marker of muscle mass, muscle strength, and physical performance in patients with type 2 diabetes. A large-scale prospective study should be performed to confirm the results and clarify the clinical usefulness of PhA in patients with diabetes.

A Case of Exacerbation of Haloperidol-Induced Rhabdomyolysis Following the Onset of COVID-19.

BACKGROUND Rhabdomyolysis is a condition in which intracellular components are released into the blood and urine. Rhabdomyolysis can be caused by drug-related complications and COVID-19; however, the underlying mechanism is not clear. In this study, we report a case of rhabdomyolysis complicated by COVID-19, in which we presumed that the cause of rhabdomyolysis was related to prior administration of haloperidol by assessment of the drug history and progression of myopathy. CASE REPORT A 52-year-old man with schizophrenia experienced worsening insomnia 10 days before admission. Thus, haloperidol was increased from 1.5 mg to 3 mg once daily, and 2 to 3 days later, he developed hand tremors and weakness. One day prior to admission, the patient suddenly developed severe back pain. Based on the examination, the patient was diagnosed with COVID-19 complicated with rhabdomyolysis. Laboratory findings on admission were as follows: creatine phosphokinase: 41 539 IU/L; urinary myoglobin, 190×10³ ng/mL; and hematuria scale, grade 4. On day 1, he was started on saline infusion; therefore, haloperidol was discontinued. On day 2, the hematuria resolved. On day 5, the tremor, weakness, and back pain had resolved. On day 7, his creatine kinase level was 242 IU/L, and saline was administered. CONCLUSIONS It has been suggested that the onset of COVID-19 can exacerbate haloperidol-induced rhabdomyolysis. Therefore, if there is a complication of rhabdomyolysis and COVID-19, it is important to review the drug history, specifically that of haloperidol. We recommend hydration and discontinuation of haloperidol to avoid acute kidney injury, in addition to treating COVID-19.

Liraglutide Reduces Visceral and Intrahepatic Fat Without Significant Loss of Muscle Mass in Obese Patients With Type 2 Diabetes: A Prospective Case Series.

BACKGROUND: Glucagon-like peptide-1 receptor agonists have been reported to reduce body fat as well as improving glycemic control in obese patients with type 2 diabetes. However, the maximum dose of liraglutide is limited to 0.9 mg in Japan, while the international dose is 1.8 mg; and the effect of this low dose on body composition has not been assessed in detail. Accordingly, this study was performed to evaluate the effect of liraglutide on body composition when administered at 0.9 mg once daily for 24 weeks. METHODS: Nine patients were enrolled and started liraglutide at 0.3 mg once daily, which was titrated to 0.9 mg once daily after 1 - 2 weeks and continued for 24 weeks. To comprehensively investigate changes of body composition, the body fat and muscle weight were determined by dual energy absorptiometry, visceral fat volume (VFV) and abdominal subcutaneous fat volume (SFV) were measured by abdominal computed tomography (CT), and the intrahepatic lipid content (IHL) was assessed by proton magnetic resonance spectroscopy. Measurements were obtained before starting liraglutide therapy and after 12 and 24 weeks of treatment. RESULTS: Fasting plasma glucose was significantly reduced from 127 ± 22 to 101 ± 14 mg/dL at 24 weeks and hemoglobin A1c (HbA1c) showed significant reduction from 6.4±0.9% to 5.2±0.5%. Body weight was reduced from 103.4 ± 14.7 to 97.0 ± 12.4 kg (mean reduction: 11.7%) and BMI decreased from 37.4 ± 6.4 to 35.0 ± 5.3 kg/m2 (mean reduction: 5.8%). Furthermore, VFV and IHL decreased from 5,192 ± 1,730 to 4,513 ± 1,299 cm3 (mean reduction: 11.9%) and 32.1±12.6% to 15.2±9.2% (mean reduction: 49.2%), respectively, but SFV did not change. Moreover, the fat index was reduced from 14.8 ± 4.4 to 12.9 ± 3.4 kg/m2 (mean reduction: 10.9%), but the skeletal muscle index did not change. CONCLUSIONS: In obese Japanese drug-naive patients who had type 2 diabetes, treatment with liraglutide (0.9 mg once daily for 24 weeks) reduced body fat, especially visceral fat and intrahepatic fat, while having no significant effect on skeletal muscle.

Effect of 24-week treatment with ipragliflozin on proinsulin/C-peptide ratio in Japanese patients with type 2 diabetes.

BACKGROUND: Chronic hyperglycemia has an adverse influence on beta-cell function, which is known as 'glucotoxicity'. Sodium-glucose cotransporter-2 (SGLT2) inhibitors lower the blood glucose concentration by enhancing urinary glucose excretion. This study was performed to clarify the influence of the SGLT2 inhibitor ipragliflozin on beta-cell function assessed from the plasma intact proinsulin/C-peptide ratio in Japanese patients with type 2 diabetes. RESEARCH DESIGN AND METHODS: This was a 24-week, prospective, single-center, open-label, single-arm study. The subjects were 19 Japanese patients with type 2 diabetes. After a 4- to 8-week period of lifestyle modification, ipragliflozin (50 mg/d) was added to their existing treatment. At baseline and at 12 and 24 weeks after starting ipragliflozin treatment, a meal test was performed to evaluate the fasting and 2-hour proinsulin/C-peptide ratio. RESULTS: After 24 weeks, the body mass index, fasting plasma glucose, and hemoglobin A1c were all decreased significantly. Both the fasting and 2-hour proinsulin/C-peptide ratio decreased significantly from 25.0 ± 18.9 × 10-3 to 14.3 ± 9.0 × 10-3 and from 23.2 ± 14.9 × 10-3 to 13.7 ± 5.4 × 10-3, respectively (both p < 0.01 vs. baseline). CONCLUSIONS: These findings indicate that ipragliflozin might have a beneficial effect on beta-cells.

Proposed cut-off value of the intrahepatic lipid content for metabolically normal persons assessed by proton magnetic resonance spectroscopy in a Japanese population.

AIMS: To determine the threshold intrahepatic lipid (IHL) content separating metabolically normal from abnormal in a Japanese population based on proton magnetic resonance spectroscopy ((1)H-MRS). METHODS: A total of 305 Japanese subjects aged 20-69years were investigated. The subjects underwent general examination, blood tests, and (1)H-MRS of the liver after an overnight fast. They completed a questionnaire about daily drinking habits and their daily alcohol intake was calculated. RESULTS: The median IHL content was 4.7% in men and 1.7% in women, and it increased along with the number of features of metabolic syndrome (MetS). The optimum IHL cut-off value for separating normal subjects from those with at least one feature of MetS was 6.5% in men (AUC of ROC: 0.727, 95%-CI: 0.649-0.804) and 1.8% in women (0.765, 0.685-0.844). Alcohol intake was not correlated with the IHL content according to multiple logistic regression analysis. CONCLUSION: This study demonstrated a close association of IHL with features of MetS and identified IHL content cut-off values for metabolic normality in Japanese subjects.

Proposed cut-off values of the waist circumference for metabolic syndrome based on visceral fat volume in a Japanese population.

AIM/INTRODUCTION: Waist circumference (WC) is the most important parameter for diagnosis of metabolic syndrome. The present study was carried out to obtain optimal WC cut-off values for diagnosis of metabolic syndrome in a Japanese population based on the measurement of total intra-abdominal visceral fat volume (VFV), which could be expected to reflect visceral obesity more precisely than visceral fat area. MATERIALS AND METHODS: A total of 405 Japanese persons undergoing health screening were investigated. visceral fat volume was calculated from the data in 700-800 computed tomography slices from the top of the liver to the floor of the pelvic cavity. Then, receiver operating characteristic analysis was used to determine the cut-off value of the VFV/height ratio. Subsequently, the corresponding WC value was obtained by linear regression analysis. RESULTS: The cut-off value of the VFV/height ratio was 2,317 cm(3) /m in men and 1,425 cm(3) /m in women. The sensitivity and specificity of the ratio were 52.9 and 86.4% in men vs 63.4 and 82.2% in women, respectively. The corresponding cut-off value of WC was 86.0 cm in men and 80.9 cm in women. CONCLUSIONS: The proposed cut-off values of WC for metabolic syndrome are 85 cm in Japanese men and 80 cm in Japanese women.

Effect of sitagliptin on intrahepatic lipid content and body fat in patients with type 2 diabetes.

AIMS: To evaluate the effect of the DPP-4 inhibitor sitagliptin on intrahepatic lipid (IHL) content and body fat in overweight Japanese patients with type 2 diabetes. METHODS: A prospective, 24-week, single-center, open-label comparative study enrolled 20 Japanese patients with type 2 diabetes (male: 11, female: 9) with a BMI≥25 kg/m(2) or fatty liver. Subjects were randomly assigned to receive treatment with sitagliptin (25 mg titrated up to 50 mg: S) or glimepiride (0.5 mg titrated up to 1 mg: G). After starting each treatment, IHL and total fat mass were evaluated by (1)H-magnetic resonance spectroscopy ((1)H-MRS) and dual energy X-ray absorptiometry (DEXA), respectively at baseline and at 12 weeks and 24 weeks. RESULTS: After 24 weeks, HbA1c levels showed a similar significant decrease in both groups from 7.2 (7.0, 7.5) to 6.6 (6.4, 6.8)%, (54 (53, 56) to 48(47, 49) mmol/mol) with S and 7.3(6.8, 7.4) to 6.6 (6.3, 6.7)%, (55 (51, 56) to 48 (46, 49) mmol/mol) with G, median (interquartile range), p<0.05 vs. baseline, with no significant differences between the two groups. The IHL and total body fat mass were decreased in S group from 24.5(18.9, 36.6) to 20.5 (14.6, 28.5)% (p=0.009) and 22.5 (20.6, 33.7) to 21.6 (19.7, 32.4)kg (p=0.028), respectively, but not in G group. CONCLUSIONS: Our findings indicate that sitagliptin and glimepiride achieved similar glycemic control, but only sitagliptin reduced IHL and total body fat (UMIN: 000013356).

Comparison between shorter straight and thinner microtapered insulin injection needles.

BACKGROUND: Many diabetes patients who require insulin perform multiple subcutaneous injections every day that often cause pain, discomfort, and anxiety. We compared efficacy (glycemic control) and patient preference for two types of needle: a shorter straight needle (32 gauge×4 mm, straight wall; Nippon Becton Dickinson Co., Ltd., Tokyo, Japan; hereafter referred to as BD32S4) and a thinner microtapered needle (33-gauge tip and 28-gauge base×5 mm, double-tapered wall; Terumo Corp., Tokyo, Japan; hereafter referred to as TR33T5) in a single-center study. PATIENTS AND METHODS: Eighty-four patients with diabetes were enrolled in a randomized, open-label crossover trial. The patients injected their usual insulin dosage with one type of needle for 4 weeks and then switched to the other type for the next 4 weeks. The serum glycated albumin level was measured before and after each 4-week period. Each patient assessed pain during injection on a 150-mm visual analog scale (VAS). Needle preference, perceptions of handling, and acceptance were assessed by the patients, who completed a questionnaire after using each type of needle for 4 weeks. RESULTS: In total, 79 patients completed the study. There was no difference of glycemic control between the two needles. The mean VAS score was -14.5 mm (95% confidence interval, -20.9, -8.0 mm), indicating that the patients perceived less pain with the BD32S4 needle. In the overall evaluation, a significantly higher percentage of patients selected the BD32S4 as the better needle compared with the TR33T5 (60.3% vs. 19.2%; P<0.0001). CONCLUSIONS: The BD32S4 needle was more highly evaluated and was preferred by the patients with respect to pain during injection, usability, and visual impression, without having a negative impact on glycemic control. The overall preference of patients for the shorter needle in this study suggests that needle length may be one of the major contributing factors for patients' comfort in insulin injection, although the other relevant factors of needles still need to be considered.

Effect of the α-glucosidase inhibitor miglitol on the glucose profile in Japanese type 2 diabetic patients receiving multiple daily insulin injections.

Strict postprandial glycemic control may have a preventive effect on atherogenesis in patients with type 2 diabetes. The α-glucosidase inhibitor (α-GI) miglitol is useful for controlling the early postprandial increase of glucose, but the combined effect of miglitol and multiple daily insulin injections (MDI) on glucose excursion has not been evaluated. First, we retrospectively compared the daily glucose profile, evaluated by self-monitoring of blood glucose (SMBG) at nine times on the day before discharge from hospital, between type 2 diabetic patients receiving MDI (n=81) or MDI plus miglitol at 150 mg daily (n=24). Second, we prospectively examined the effect of adding miglitol to MDI on the daily glucose profile (SMBG) in 19 other type 2 diabetic patients. Although the daily insulin dosage and the glucose level before meals did not differ between the two groups, the 1-h postprandial glucose level after each meal, 2-h glucose level after lunch and dinner, mean and standard deviation of glucose, and amplitude of glucose excursion were significantly lower or smaller in the MDI plus miglitol group than in the MDI group. All of these glucose parameters were significantly improved by adding miglitol to MDI in the prospective cohort of 19 patients. In conclusion, adding miglitol to MDI reduces postprandial glucose levels and attenuates daily glucose fluctuation in type 2 diabetic patients. This trial was registered with UMIN (no. UMIN000005383).

Intrahepatic lipid content is linked to insulin resistance in obese subjects.

BACKGROUND: Abdominal visceral fat (VAT) and intrahepatic lipid (IHL) are associated with insulin resistance in obese subjects, but VAT is usually measured on CT scans at the umbilical level or on MRI images of the partial abdomen. Thus, the association of the total abdominal visceral fat volume (VFV) with insulin resistance is unclear. In this study, we evaluated the correlations of obesity-related factors, including VFV and IHL, with clinical markers of insulin resistance (HOMA-R and the MATSUDA Index), and then assessed the effect of weight loss on these factors and markers. METHODS: The study population consisted of 30 obese Japanese subjects with a BMI > 25 kg/m(2) (13 men and 17 women) who underwent a 75-g oral glucose tolerance test to calculate HOMA-R and the MATSUDA Index, dual energy X-ray absorptiometry (DEXA) for measurement of body fat (%-Fat), proton magnetic resonance spectroscopy ((1)H MRS) to assess IHL, and whole abdominal CT scanning (from the top of the liver to the floor of the pelvic cavity = about 700 slices) to determine the total abdominal subcutaneous fat volume (SFV) and VFV. Seven subjects from the original population were placed on a diet and exercise program, and these indices were examined again after 5% reduction of body weight. RESULTS: Abdominal SFV, VFV, and IHL were mutually independent, but BMI and %-Fat were not independent of the other factors. According to multiple regression analysis, IHL (but not SFV or VFV) was significantly correlated with both HOMA-R and the MATSUDA Index in obese patients. Weight reduction by 5% led to improvement of the MATSUDA Index and decreased the number of subjects with metabolic syndrome, and the reduction of IHL was greater than that of SFV or VFV. These results suggest that IHL may be a superior marker of insulin resistance.

Relationship between clinical markers of glycemia and glucose excursion evaluated by continuous glucose monitoring (CGM).

In order to evaluate the relationship between clinical markers of glycemia and glucose excursion, we performed 48-hour continuous glucose monitoring (CGM) in 43 diabetic patients. For the clinical markers, HbA(1c), glycoalbumin (GA), and 1,5-anhydroglucitol (1,5-AG) were measured, and for the parameters of glucose excursion from CGM, average glucose (AG), standard deviation of glucose (SD), the area under the curve for glucose levels >180 mg/dL (AUC(>180)), and the difference between the maximum and minimum glucose levels during 48 hours (DeltaG(48hr)) were analyzed. All patients were treated without any changes of the dosages of oral anti-diabetic agents or insulin for at least the previous 3 months with coefficient of variation (CV) of HbA(1c) less than 4 %. In results, while HbA(1c) did not show any single correlation with AG, SD, AUC(>180), or DeltaG(48hr), both GA and 1,5-AG were significantly related to all these parameters. Furthermore, GA significantly correlated to all CGM parameters, and SD significantly correlated to GA in multiple regression analyses. These results suggest that GA may be a different marker from HbA(1c) for diabetic complications, because GA, but not HbA(1c), may reflect not only short-term average glucose but also fluctuation of glucose.