Kunio Hieshima

Liraglutide, a Glucagon-Like Peptide-1 Analog, Increased Insulin Sensitivity Assessed by Hyperinsulinemic-Euglycemic Clamp Examination in Patients with Uncontrolled Type 2 Diabetes Mellitus

Aims. Glucagon-like peptide-1 (GLP-1) analog promotes insulin secretion by acting on pancreatic β-cells. This antihyperglycemic treatment for type 2 diabetes mellitus (DM) has attracted increased clinical attention not only for its antihyperglycemic action but also for its potential extrapancreatic effects. We investigated whether liraglutide, a GLP-1 analog, could enhance insulin sensitivity as assessed by the hyperinsulinemic-euglycemic clamp in type 2 DM patients. Materials. We prospectively enrolled 31 uncontrolled type 2 DM patients who were hospitalized and equally managed by guided diet- and exercise-therapies and then introduced to either liraglutide- or intensive insulin-therapy for 4 weeks. Insulin sensitivity was assessed by the glucose infusion rate (GIR) using hyperinsulinemic-euglycemic clamp before and after the therapies. Results. Values of HbA1c, postprandial plasma glucose, and body mass index (BMI) were significantly decreased by hospitalized intensive insulin-therapy or liraglutide-therapy. GIR was significantly increased by liraglutide-therapy but not by insulin-therapy, indicating that liraglutide-therapy significantly enhanced insulin sensitivity. BMI decreased during liraglutide-therapy but was not significantly correlated with changes in GIR. Multivariate logistic regression analysis demonstrated that liraglutide-therapy significantly correlated with increased insulin sensitivity in uncontrolled DM patients. Conclusions. Liraglutide may exhibit favorable effects on diabetes control for type 2 DM patients by increasing insulin sensitivity as an extrapancreatic action. Clinical trial registration Unique Identifier is UMIN000015201.

Correlation of body muscle/fat ratio with insulin sensitivity using hyperinsulinemic-euglycemic clamp in treatment-naïve type 2 diabetes mellitus

AIMS Fat deposition and obesity are crucial pathological components of diabetes mellitus (DM). In clinical practice, assessment of insulin resistance is important. We hypothesized that body muscle and fat composition might be a key factor for insulin resistance in patients with type 2 DM. METHODS Subjects included 61 untreated DM patients. Hyperinsulinemic-euglycemic clamp examination was performed to calculate the M/I value as the insulin resistance reference indicator. Elementary body composition was measured by impedance analysis using InBody770. RESULTS Simple regression analysis showed that total muscle quantity/total fat quantity ratio (muscle/fat) was significantly correlated with M/I value (B=0.806, P<0.001). The regression equation was M/I value=3.6934×(muscle/fat ratio)+0.0347 (R(2)=0.6503, P<0.001). Multivariate logistic regression analysis showed that muscle/fat ratio was independently and significantly associated with insulin resistance, defined by M/I value <9 (odds ratio, 0.89; 95% confidence interval, 0.80-0.99, P=0.04). With receiver operating curve analysis, the cutoff value of muscle/fat ratio for insulin resistance was 2.40 and area under the curve was 0.87 (sensitivity 91% and specificity 76%, P<0.001), indicating that muscle/fat ratio was significantly effective for predicting insulin resistance in treatment-naïve DM. The result could provide a possible estimation of the M/I value using the regression equation M/I value=2.5438×(muscle/fat ratio)+48.6194×QUICKI-13.6522 (R(2)=0.7012). CONCLUSION In treatment-naïve DM, the muscle/fat ratio, assessed by InBody770 is clinically useful for evaluating the presence of insulin resistance in daily clinical practice.

Dapagliflozin Reduces Fat Mass without Affecting Muscle Mass in Type 2 Diabetes

Aim: Sodium-glucose co-transporter 2 inhibitor (SGLT2i) therapy has been demonstrated to improve glycemic control and reduce body weight and fat mass in type 2 diabetes mellitus (T2DM). Here, our aim was to investigate the effects of SGLT2i dapagliflozin-treatment on body muscle mass and muscle fat content in patients with T2DM. Methods: We prospectively recruited uncontrolled (hemoglobin A1c [HbA1c] > 7%) Japanese T2DM patients who had a body mass index (BMI) < 35 kg/m2. Patients were treated with dapagliflozin (5 mg/day) or non-SGLT2i medicines for six months to improve HbA1c. We investigated changes in body composition using bioelectrical impedance analysis and changes in psoas muscle mass using abdominal computed tomography (CT). Results: Subjects were 50 T2DM patients (72% male) with a mean age of 56.1 years, mean BMI of 27.1 kg/m2 and mean HbA1c of 7.9%. HbA1c, body weight, and BMI were significantly decreased in both treatment groups, and the HbA1c decrease was not significantly different between groups. Dapagliflozin treatment significantly decreased body weight and total fat mass without affecting skeletal muscle mass. The absolute change in soft lean mass and skeletal muscle mass was not significantly different between groups. Dapagliflozin treatment did not significantly decrease psoas muscle index, and the absolute change in this index was not significantly different between groups. Dapagliflozin therapy also produced a significant increase in CT radiation attenuation in the third lumbar paraspinal muscles compared with non-SGLT2i therapy. Conclusions: Treatment with dapagliflozin for six months significantly improved glycemic control and reduced body weight without reducing muscle mass in T2DM patients.

Ratio of muscle mass to fat mass assessed by bioelectrical impedance analysis is significantly correlated with liver fat accumulation in patients with type 2 diabetes mellitus

AIMS Obesity and ectopic fat accumulation are important conditions of type 2 diabetes mellitus (T2DM). Our aim was to determine whether bioelectrical impedance body composition analysis combined with blood test results could estimate liver ectopic fat accumulation in patients with treatment-naïve T2DM. METHODS Subjects were 119 untreated T2DM patients. Computed tomography scans were performed to calculate the liver to spleen attenuation ratio (L/S ratio) as a measure of liver fat accumulation, with excess liver fat accumulation defined as an L/S ratio <1.0. Elementary body composition was measured by bioelectrical impedance analysis using InBody770. RESULTS The Nagelkerke R2 test showed that the muscle mass/fat mass ratio (muscle/fat ratio) was the most suitable variable among anthropometric factors and body component indexes for estimating liver fat accumulation. The muscle/fat ratio was significantly correlated with the L/S ratio (ρ = 0.4386, P < 0.0001). Multivariable logistic regression analysis showed that the muscle/fat ratio (odds ratio 0.40, 95% confidence interval 0.22-0.73, P < 0.01) and alanine aminotransferase (odds ratio 1.06, 95% confidence interval 1.02-1.10, P < 0.01) were independently and significantly associated with liver fat accumulation. In receiver operating characteristic curve analysis, the cutoff value of the muscle/fat ratio for excess liver fat accumulation was 2.34. CONCLUSION In patients with treatment-naïve T2DM, the muscle/fat ratio and ALT are useful for estimating the presence of excess liver fat accumulation in daily clinical practice.

Insulin supersensitivity and normoinsulinaemic hypoglycaemia in uncontrolled type 2 diabetes mellitus: clinical usefulness of 3 h assessment in the 75 g oral glucose tolerance test.

A 60-year-old man with uncontrolled type 2 diabetes mellitus (DM) (glycated haemoglobin 11%) had the unusual symptoms of palpitations and sweating after drinking an excessive amount of soft drinks. Three-hour data in the 75-g oral glucose tolerance test (75g-OGTT) repeatedly showed normoinsulinaemic hypoglycaemia. His diabetic disorder was based on a delayed insulin secretory response to hyperglycaemia and daily excessive intake of glucose from a high caloric diet and soft drinks. However, we paradoxically observed increased insulin sensitivity evaluated by a hyperinsulinaemic-euglycaemic clamp (glucose infusion rate: 64.83 μmol/kg/min). We considered that insulin supersensitivity might be involved in the pathogenic mechanisms of his clinical normoinsulinaemic hypoglycaemia. He was successfully treated by diet and exercise therapy without any hypoglycaemic medications or insulin. Assessment after the 75g-OGTT is useful for investigating the pathogenesis of DM. Insulin supersensitivity and normoinsulinaemic hypoglycaemia might play a role in clinical manifestation and pathogenesis of type 2 DM.

The SGLT2 Inhibitor Dapagliflozin Significantly Improves the Peripheral Microvascular Endothelial Function in Patients with Uncontrolled Type 2 Diabetes Mellitus

Objective Sodium-glucose co-transporter 2 (SGLT2) inhibitors reduce cardiovascular events and decrease the body fat mass in patients with type 2 diabetes mellitus (T2DM). We examined whether or not the SGLT2-inhibitor dapagliflozin can improve the endothelial function associated with a reduction in abdominal fat mass. Methods We prospectively recruited patients with uncontrolled [hemoglobin A1c (HbA1c) >7.0%] T2DM who were not being treated by SGLT2 inhibitors. Patients were treated with add-on dapagliflozin (5 mg/day) or non-SGLT2 inhibitor medicines for 6 months to improve their HbA1c. We measured the peripheral microvascular endothelial function as assessed by reactive hyperemia peripheral arterial tonometry (RH-PAT) and calculated the natural logarithmic transformed value of the RH-PAT index (LnRHI). We then investigated changes in the LnRHI and abdominal fat area using computed tomography (CT). Results The subjects were 54 patients with uncontrolled T2DM (72.2% men) with a mean HbA1c of 8.1%. The HbA1c was significantly decreased in both groups, with no significant difference between the groups. Dapagliflozin treatment, but not non-SGLT2 inhibitor treatment, significantly increased the LnRHI. The changes in the LnRHI were significantly greater in the dapagliflozin group than in the non-SGLT2 inhibitor group. Dapagliflozin treatment, but not non-SGLT2 inhibitor treatment, significantly decreased the abdominal visceral fat area, subcutaneous fat area (SFA), and total fat area (TFA) as assessed by CT and significantly increased the plasma adiponectin levels. The percentage changes in the LnRHI were significantly correlated with changes in the SFA, TFA, systolic blood pressure, and adiponectin. Conclusion Add-on treatment with dapagliflozin significantly improves the glycemic control and endothelial function associated with a reduction in the abdominal fat mass in patients with uncontrolled T2DM.

Combined arteriosclerotic assessment of ankle-brachial index and maximum intima-media thickness via CCTA is useful for predicting coronary artery stenosis in patients with type 2 diabetes.

AIMS Patients with diabetes mellitus (DM) are likely to develop asymptomatic myocardial infarction as a complication. However, coronary artery lesions are difficult to assess in internal medicine. This study aimed to develop a prediction formula for coronary artery stenosis, as determined by coronary computed tomographic angiography (CCTA), by analyzing risk factors in patients with type 2 DM. METHODS A prediction formula was developed based on a multivariate analysis of common factors in patients with ⩾50% coronary artery stenosis in a cohort of 327 patients with type 2 DM who underwent CCTA between 2007 and 2009, and cutoff values were calculated (derivation study). The validity of the optimal cutoff value was confirmed in a separate cohort of 317 patients with type 2 DM who underwent CCTA between 2010 and 2011 (validation study). RESULTS In the derivation study, five predictive factors (presence/absence of hypertension, estimated glomerular filtration rate, maximum intima-media thickness [max-IMT], ankle-brachial index [ABI], and use/nonuse of diabetic medication) were used to develop a prediction formula. In the validation study, positive predictive value (PPV) and negative predictive value (NPV) of the cutoff value derived from the prediction formula were 53% and 73%, respectively. CONCLUSIONS We developed a novel formula to predict coronary artery stenosis using five predictive factors. This formula is useful for determining whether computed tomography (CT) examination is necessary, even in clinical settings without CCTA equipment. Early detection of coronary artery stenosis in patients with DM may also lead to better health outcomes.

Clinical usefulness of the body muscle-to-fat ratio for screening obstructive sleep apnea syndrome in patients with inadequately controlled type 2 diabetes mellitus

AIMS To investigate whether body composition measures can be used for screening obstructive sleep apnea syndrome (OSAS) in patients with type 2 diabetes mellitus (T2DM) suspected of having OSAS. METHODS Subjects were 186 hospital inpatients with inadequately controlled T2DM. We measured the respiratory disturbance index (RDI) as an indicator of OSAS using a sheet-type breath detection monitor, defining OSAS as an RDI ≥ 19 events/hour. Elementary body composition was measured by bioelectrical impedance analysis using InBody770. RESULTS Simple logistic regression analysis identified body weight, body mass index (BMI), waist circumference, total body fat mass, body fat percentage, and body muscle-to-fat ratio (BMFR) as significantly associated with OSAS. The Nagelkerke R2 test showed that the BMFR was the most suitable measure for screening OSAS. Multivariate logistic regression analysis demonstrated that BMFR was significantly and independently associated with OSAS. In receiver operating characteristic curve analysis, the area under the BMFR curve was 0.70 (P < 0.001), indicating that BMFR was significantly predictive of OSAS. Furthermore, BMFR was the most suitable measure for screening OSAS in a sub-group analysis of non-obese patients with relatively low BMI (<27.5 kg/m2). CONCLUSIONS In patients with T2DM, the BMFR is useful for screening OSAS in daily clinical practice.