Self‐perception of glycemic control among Japanese type 2 diabetic patients: accuracy of patient perception and characteristics of patients with misperception

Aims

Some diabetic patients, despite reporting a good perception of their glycemic control, actually show poor control and this misperception might well hinder successful diabetes management. This study aimed to assess patients'' self‐perception of glycemic control and to clarify factors associated with misperception of glycemic control status.

Methods

Baseline data from a hospital‐based prospective cohort of 519 type 2 diabetic patients were analyzed. Self‐perception of glycemic control and other items, including sociodemographic factors and blood test data, were determined from a self‐administered questionnaire and medical records. Factors associated with misperception were examined by age group (elderly [aged ≥ 65 years] vs non‐elderly [aged < 65 years]) using multiple logistic regression analysis.

Results

Among poorly controlled patients, misperception was higher in the elderly (glycated hemoglobin [HbA_1c] 7.4–8.3, 55.1%; HbA_1c >8.4, 44.8%) than in the non‐elderly (HbA_1c 7.4–8.3, 20.0%; HbA_1c >8.4, 18.9%). The factors significantly associated with misperception were as follows: high lifestyle regimen adherence in both age groups (non‐elderly group odds ratio [OR] 5.23; elderly group OR 5.15, respectively); high family support (OR = 7.32), failure to achieve blood pressure control (OR = 6.94) and having diabetic complications (OR = 0.06) among the non‐elderly; and long duration of diabetes (OR = 4.06) among the elderly.

Conclusions

For better management of diabetes, physicians should pay attention to the patient characteristics associated with misperception among uncontrolled diabetic patients, particularly among those who are elderly.     

Dipeptidyl peptidase‐4 inhibitors are effective in Japanese type 2 diabetic patients with sustained endogenous insulin‐secreting capacity,a higher body mass index and insulin resistance

Aims/Introduction

Recently, dipeptidyl peptidase‐4 (DPP‐4) inhibitors have become available in Japan. It has not yet been clarified what clinical parameters could discriminate DPP‐4 inhibitor‐effective patients from DPP‐4 inhibitor‐ineffective patients.

Materials and Methods

We reviewed 33 consecutive patients with type 2 diabetes admitted to Osaka University Hospital for glycemic control. All of the patients were treated with medical nutrition therapy plus insulin therapy to improve fasting plasma glucose (FPG) and postprandial glucose below 150 and 200 mg/dL, respectively. After insulin secretion and insulin resistance were evaluated, insulin was replaced by DPP‐4 inhibitors. The efficacy of DPP‐4 inhibitors was determined according to whether glycemic control was maintained at the target levels.

Results

Dipeptidyl peptidase‐4 inhibitors were effective in 16 of 33 patients. DPP‐4 inhibitor‐effective patients were younger than DPP‐4 inhibitor‐ineffective patients. Body mass index (BMI) was significantly higher in DPP‐4 inhibitor‐effective patients. Endogeneous insulin‐secreting capacity, including insulinogenic index (II), fasting plasma C‐peptide (F‐CPR) and C‐peptide index (CPI), was more sustained in DPP‐4 inhibitor‐effective patients than DPP‐4 inhibitor‐ineffective patients. Insulin resistance evaluated by homeostasis model assessment of insulin resistance (HOMA‐IR) was significantly higher in DPP‐4 inhibitor‐effective patients than DPP‐4 inhibitor‐ineffective patients. In receiver operating characteristic analyses, the cut‐off values for predicting the efficacy of DPP‐4 inhibitors were 0.07 for II, 1.5 ng/mL for F‐CPR, 1.0 for CPI, 23.0 kg/m² for BMI, 1.3 for HOMA‐IR and 67.5 years for age.

Conclusions

Dipeptidyl peptidase‐4 inhibitors were effective in Japanese type 2 diabetic patients with sustained endogenous insulin‐secreting capacity, a higher BMI and insulin resistance.     

Effect of serum 25‐hydroxyvitamin D3 on insulin resistance and β‐cell function in newly diagnosed type 2 diabetes patients

Aims/Introduction

To evaluate serum 25‐hydroxyvitamin D₃ (25(OH)D₃) in newly diagnosed type 2 diabetes patients and to explore the associations of 25(OH)D₃ with insulin resistance and β‐cell function.

Materials and Methods

A total of 97 newly diagnosed type 2 diabetes patients and 69 healthy controls were recruited. Serum 25(OH)D₃ was determined using high‐pressure liquid chromatography. Insulin resistance was measured using a homeostasis model assessment of insulin resistance (HOMA‐IR). β‐Cell function was determined using the HOMA β‐cell function index (HOMA‐β), early‐phase insulin secretion index (ΔI30/ΔG30) and area under the insulin curve (AUCins). Correlation analysis was carried out using Pearson''s correlation and multiple stepwise regression analysis.

Results

Serum 25(OH)D₃ was much lower in patients with newly diagnosed type 2 diabetes (t = −13.00, P < 0.01), and the prevalence of hypovitaminosis 25(OH)D₃ was 62.9% (61/97) in diabetic patients. Among the diabetic patients, patients with hypovitaminosis 25(OH)D₃ showed higher glycosylated hemoglobin and AUCglu (P < 0.01) as well as lower HOMA‐β, ΔI30/ΔG30 and AUCins. Serum 25(OH)D₃ was independently positively correlated with ΔI30/ΔG30 and AUCins (P < 0.05), but was not significantly correlated with either HOMA‐IR or HOMA‐β. Only triglycerides, glycosylated hemoglobin and ΔI30/ΔG30 emerged as independent factors associated with serum 25(OH)D₃ in both diabetes patients and the health control group.

Conclusions

The present results further showed a low serum 25(OH)D₃ concentration in patients with newly diagnosed type 2 diabetes. 25(OH)D₃ deficiency is associated with disturbances in glucose metabolism and lipid metabolism. Serum 25(OH)D₃ is not correlated with basal insulin resistance or β‐cell function, but is significantly positively correlated with glucose‐stimulated insulin secretion and β‐cell function.     

Insulin degludec compared with insulin glargine in insulin‐naïve patients with type 2 diabetes: A 26‐week,randomized, controlled,Pan‐Asian,treat‐to‐target trial

Introduction

Insulin degludec (IDeg) is an ultra‐long‐acting basal insulin with a consistent action profile of >42 h. This trial compared the efficacy and safety of IDeg with insulin glargine (IGlar) in insulin‐naïve Asian patients with type 2 diabetes.

Materials and Methods

In this multinational, 26‐week, open‐label, treat‐to‐target trial, 435 participants (202 females, 233 males; mean age 58.6 years; mean body mass index 25 kg/m²; mean glycated hemoglobin [HbA_1c] 8.5%) were randomized (2:1) to IDeg or IGlar, each administered once daily with ≥1 oral antidiabetic drug(s) (OAD).

Results

After 26 weeks, HbA_1c had decreased by 1.24 and 1.35% in the IDeg and IGlar groups, respectively (treatment difference [IDeg – IGlar] 0.11%, 95% confidence interval [CI] −0.03 to 0.24), confirming non‐inferiority. Rates of overall confirmed hypoglycemia were similar for IDeg and IGlar during the full trial period (3.0 vs 3.7 episodes/patient‐year of exposure [PYE]; rate ratio [RR] 0.82, 95% CI 0.60 to 1.11, P = 0.20), but significantly lower (by 37%) for IDeg during the maintenance period (from week 16 onward; RR 0.63, 95% CI 0.42 to 0.94, P = 0.02). No significant difference in the rate of nocturnal confirmed hypoglycemia was found between IDeg and IGlar in the full trial period (0.8 vs 1.2 episodes/PYE; RR 0.62, 95% CI 0.38 to 1.04, P = 0.07) or maintenance period (RR 0.52, 95% CI 0.27 to 1.00, P = 0.05). Adverse event rates were similar between treatments.

Conclusions

Initiating insulin therapy with IDeg in Asian patients with type 2 diabetes, inadequately controlled with OADs, provides similar improvements in long‐term glycemic control to IGlar, but at a significantly lower rate of overall confirmed hypoglycemia once stable glycemic control and insulin dosing are achieved. This trial was registered with www.clinicaltrials.gov (no. NCT01059799).     

Usefulness of the insulin tolerance test in patients with type 2 diabetes receiving insulin therapy

Aims/Introduction

To establish the validity of the plasma glucose disappearance rate (KITT), derived from an insulin‐tolerance test (ITT), for evaluating the insulin sensitivity of patients with type 2 diabetes after insulin therapy.

Materials and Methods

In the first arm of the study, 19 patients with poorly controlled diabetes were treated with insulin and underwent an ITT and a euglycemic clamp test (clamp‐IR). The relationship between the insulin resistance index, as assessed by both the clamp‐IR and KITT tests, was examined. In the second arm of the study, the relationships between KITT values and various clinical parameters were investigated in 135 patients with poorly controlled diabetes, after achieving glycemic control with insulin.

Results

In study 1, a close correlation between KITT and the average glucose infusion rate during the last 30 min of the standard clamp‐IR test (M‐value) was noted (P < 0.001). In study 2, body mass index (P = 0.0011), waist circumference (P = 0.0004), visceral fat area (P = 0.0011) and the log‐transformed homeostasis model assessment of insulin resistance value (P = 0.0003) were negatively correlated with the log‐transformed KITT. High‐density lipoprotein cholesterol (P = 0.0183), low‐density lipoprotein cholesterol (P = 0.0121) and adiponectin (P = 0.0384) levels were positively correlated with the log‐transformed KITT.

Conclusions

The ITT is a valid and useful test for evaluating the insulin sensitivity of patients with diabetes, even after treatment with insulin.     

Effect of combination therapy with repaglinide and metformin hydrochloride on glycemic control in Japanese patients with type 2 diabetes mellitus

Aims/Introduction

We investigated the efficacy and safety of repaglinide as an add‐on therapy for Japanese patients with type 2 diabetes mellitus receiving metformin monotherapy (at a dose of 1,500 mg/day, mainly) in addition to diet and exercise.

Materials and methods

In the 16‐week multicenter, placebo‐controlled, randomized, double‐blind, parallel‐group trial (the phase III study), patients with type 2 diabetes mellitus with metformin monotherapy were randomly assigned to the repaglinide or placebo group. Thereafter, a 36‐week, multicenter, uncontrolled, dose‐titration method study was extended to a total duration of 52 weeks (the long‐term study). The primary end‐point of each study was a change in glycated hemoglobin (HbA_1c) from baseline.

Results

After 16 weeks, mean reductions in HbA_1c were significantly greater for the repaglinide group than for the placebo group (–0.98 ± 0.72% vs 0.13 ± 0.63%, P < 0.001). In the long‐term study, the mean change in HbA_1c was −0.76 ± 0.83%. The rate of adverse events was 60.6 and 50.0% in the repaglinide and placebo groups, respectively, in the phase III study, and 78.3% in the long‐term study. Hypoglycemia was reported in 11.7, 0 and 13.3% of patients in the repaglinide group, placebo group and long‐term study, respectively.

Conclusions

Combination therapy with repaglinide and metformin resulted in an approximately 1% reduction in HbA_1c at week 16 and in a significant long‐term improvement in HbA_1c at the end of the study. No safety problems were noted during the concomitant use of repaglinide and metformin. These studies were registered with JapicCTI (nos. JapicCTI‐101202 and JapicCTI‐101203).     

Effect of periodontal treatment on glycemic control of patients with diabetes: A systematic review and meta‐analysis

Aims/Introduction

The aim of the present study was to investigate whether non‐surgical periodontal treatment reduces glycated hemoglobin (HbA_1c) and fasting plasma glucose (FPG) levels in diabetic patients.

Materials and Methods

An electronic search was carried out on MEDLINE (through PubMed interface), EMBASE and the Cochrane Central Register of Controlled Trials. Randomized controlled trials with a minimum of 3 months follow up were included. The risk of bias was assessed for each study. A meta‐analysis was carried out to evaluate the effect of non‐surgical periodontal treatment on HbA_1c and FPG levels. The effect of the adjunctive use of antimicrobials was also assessed.

Results

A total of 15 studies were included. A reduction of −0.38% (95% confidence interval [CI] −0.23 to −0.53) after 3–4 months (P < 0.001) and of −0.31% (95% CI 0.11 to −0.74) after 6 months (P = 0.15) of follow‐up was found for HbA_1c, favoring the treatment group. Similarly, in treated patients, a significantly greater decrease in FPG was observed in respect to control participants. Such difference amounted to −9.01 mg/dL (95% CI −2.24 to −15.78) after 3–4 months (P = 0.009) and −13.62 mg/dL (95% CI 0.45 to −27.69) after 6 months (P = 0.06) from treatment, respectively. In participants treated with adjunctive antimicrobials, a non‐significant increase of HbA_1c was observed 3 months after treatment, whereas FPG decreased by 0.27 mg/dL (95% CI 39.56 to −40.11; P = 0.99).

Conclusions

The meta‐analysis showed that non‐surgical periodontal treatment improves metabolic control in patients with both periodontitis and diabetes.     

Combination therapy with an angiotensin‐converting‐enzyme inhibitor and an angiotensin II receptor antagonist ameliorates microinflammation and oxidative stress in patients with diabetic nephropathy

Aims/Introduction

Recent studies have pointed to the effectiveness of combination therapy with an angiotensin‐converting‐enzyme inhibitor (ACEI) and an angiotensin receptor blocker (ARB) for diabetic nephropathy. However, some controversy over this combination treatment remains and the mechanisms underlying its renoprotective effects have not been fully clarified. Therefore, we compared the renoprotective effects of imidapril (ACEI) and losartan (ARB) combination therapy with losartan monotherapy in patients with diabetic nephropathy. We also compared the anti‐inflammatory and anti‐oxidative stress effects of these two treatments.

Materials and Methods

A total of 32 Japanese patients with type 2 diabetes and nephropathy were enrolled. Patients were randomized to either 100 mg/day losartan (n = 16) or 50 mg/day losartan plus 5 mg/day imidapril (n = 16). We evaluated clinical parameters, serum concentrations of high‐sensitivity C‐reactive protein (hs‐CRP), soluble intercellular adhesion molecule‐1 (sICAM‐1), interleukin‐18 (IL‐18) and monocyte chemotactic protein‐1 (MCP‐1), and the urinary concentrations of IL‐18, MCP‐1 and 8‐hydroxy‐2′‐deoxyguanosine (8‐OHdG) at 24 and 48 weeks after starting treatment.

Results

Blood pressure was not significantly different between the two groups. The serum levels of hs‐CRP, sICAM‐1 and IL‐18, as well as urinary excretion of albumin, IL‐18 and 8‐OHdG decreased significantly in the combination therapy group at 48 weeks. The percent decreases in serum IL‐18 concentrations and urinary IL‐18 and 8‐OHdG were significantly greater in the combination therapy group than in the monotherapy group.

Conclusions

Combination therapy with an ACEI and an ARB could be beneficial for treating diabetic nephropathy through its anti‐inflammatory and anti‐oxidative stress effects.     

Postprandial serum C‐peptide value is the optimal index to identify patients with non‐obese type 2 diabetes who require multiple daily insulin injection: Analysis of C‐peptide values before and after short‐term intensive insulin therapy

Aims/Introduction

Type 2 diabetes is a progressive disease characterized by a yearly decline in insulin secretion; however, no definitive evidence exists showing the relationship between decreased insulin secretion and the need for insulin treatment. To determine the optimal insulin secretory index for identifying patients with non‐obese type 2 diabetes who require multiple daily insulin injection (MDI), we evaluated various serum C‐peptide immunoreactivity (CPR) values.

Materials and Methods

We near‐normalized blood glucose with intensive insulin therapy (IIT) over a 2‐week period in 291 patients with non‐obese type 2 diabetes, based on our treatment protocol. After improving hyperglycemia, we challenged with oral hypoglycemic agent (OHA), and according to the responsiveness to OHA, patients were classified into three therapy groups: OHA alone (n = 103), basal insulin plus OHA (basal insulin‐supported oral therapy [BOT]; n = 56) and MDI (n = 132). Glucagon‐loading CPR increment (ΔCPR), fasting CPR (FCPR), CPR 2 h after breakfast (CPR2h), the ratio of FCPR to FPG (CPI), CPI 2 h after breakfast (CPI2h) and secretory unit of islets in transplantation (SUIT) were submitted for the analyses. Receiver operating characteristic (ROC) and multiple logistic analyses for these CPR indices were carried out.

Results

Many CPR values were significantly lower in the MDI group compared with the OHA alone or BOT groups. ROC and multiple logistic analyses disclosed that post‐prandial CPR indices (CPR2h and CPI2h) were the most reliable CPR markers to identify patients requiring MDI.

Conclusions

Postprandial CPR level after breakfast is the most useful index for identifying patients with non‐obese type 2 diabetes who require MDI therapy.     

Oral glucose‐stimulated serum C‐peptide predicts successful switching from insulin therapy to liraglutide monotherapy in Japanese patients with type 2 diabetes and renal impairment

Aims/Introduction

In Japan, liraglutide was recently approved for patients with type 2 diabetes. To our knowledge, there are no markers predicting successful switching from insulin therapy to liraglutide monotherapy in Japanese patients with type 2 diabetes and renal impairment. We therefore assessed clinical characteristics predicting successful switching.

Materials and Methods

We analyzed 21 patients with type 2 diabetes and estimated glomerular filtration rates <60 mL/min/1.73 m² receiving long‐term insulin in Shiga University of Medical Science Hospital, Otsu, Shiga, Japan. Their β‐cell function was assessed by measuring urinary C‐peptide and C‐peptide immunoreactivity (CPR) index, along with glucagon loading and oral glucose tolerance tests. Blood glucose concentration and blood pressure were measured daily before and after switching from insulin to liraglutide, and glycated hemoglobin (HbA1c; National Glycohemoglobin Standardization Program) was assessed 12 weeks after switching to liraglutide.

Results

Baseline HbA1c was significantly lower in successfully switched than in unsuccessfully switched patients. CPR index, urinary C‐peptide concentration and 6‐min post‐glucagon increment in CPR (ΔCPR) did not differ significantly in the two groups. ΔCPR 120 min after 75 g oral glucose was significantly higher in successfully than unsuccessfully switched patients. Mean blood glucose concentrations before breakfast, after breakfast, before lunch and after dinner were significantly lower in successfully switched patients. HbA1c did not change significantly in either group.

Conclusions

Measurement of oral glucose‐stimulated ΔCPR120 min is recommended when considering switching Japanese type 2 diabetes patients with renal impairment from insulin to liraglutide monotherapy.     

Retrospective analysis of safety and efficacy of insulin‐to‐liraglutide switch in Japanese type 2 diabetes: A caution against inappropriate use in patients with reduced β‐cell function

Aims/Introduction

The safety and efficacy of insulin‐to‐liraglutide switch in type 2 diabetes has not been studied adequately. Here, we retrospectively characterize clinical parameters that might predict insulin‐to‐liraglutide treatment switch without termination due to hyperglycemia, and examine the effects of switching the therapies on glycated hemoglobin (HbA_1c) and bodyweight in Japanese type 2 diabetes.

Materials and Methods

Japanese type 2 diabetes patients who underwent the switch of therapy were evaluated for their clinical data including β‐cell function‐related indices, such as increment of serum C‐peptide during glucagon stimulation test (GST‐ΔCPR). HbA_1c and bodyweight were analyzed in patients continuing with liraglutide after switching from insulin for 12 weeks.

Results

Of 147 patients, 28 failed in the switch due to hyperglycemia, nine failed because of other reasons and 110 continued with liraglutide for the 12‐week period. Patients failing in the switch due to hyperglycemia showed longer duration and higher daily insulin dose, as well as lower GST‐ΔCPR. Receiver–operating characteristic analysis showed that GST‐ΔCPR of 1.34 ng/mL is a cut‐off point for insulin‐to‐liraglutide switch without termination due to hyperglycemia. In patients continuing liraglutide for 12 weeks, the switch significantly reduced HbA_1c and bodyweight with no severe hypoglycemia, irrespective of sulfonylurea co‐administration, body mass index, duration and total daily insulin dose. The switch also significantly reduced the percentage of body fat and visceral fat areas.

Conclusions

Insulin‐to‐liraglutide switch can improve glycemic control and reduce bodyweight in Japanese type 2 diabetes patients. However, caution must be taken with the switch in patients with reduced insulin secretory capacity as predicted by GST‐ΔCPR.     

Efficacy and safety of exenatide once‐weekly vs exenatide twice‐daily in Asian patients with type 2 diabetes mellitus

Aims/Introduction

To compare safety and efficacy of the extended‐release formulation exenatide once weekly (EQW) vs exenatide twice daily (EBID) for 26 weeks in type 2 diabetes patients from China, India, Japan, South Korea and Taiwan.

Materials and Methods

A randomized, comparator‐controlled, open‐label study included 681 patients with type 2 diabetes inadequately controlled (hemoglobin A1c [HbA_1c] ≥7 and ≤11%) with oral antihyperglycemic medications (OAMs). Patients added 2 mg EQW or 10 μg EBID to current OAMs. Safety was re‐evaluated 10 weeks after last treatment.

Results

EQW was superior to EBID on HbA_1c measures at week 26 (Least‐squares mean treatment difference: −0.31% [95% confidence interval −0.49, −0.14%]). More EQW‐treated patients achieved target HbA_1c ≤7.0% (P = 0.003), ≤6.5% (P < 0.001), or ≤6.0% (P = 0.003). Fasting serum glucose reductions were greater among EQW‐treated patients (P < 0.001). Blood glucose profiles improved in both treatment groups (P < 0.001). Weight loss occurred with both treatments, but was greater with EBID. Adverse events (≥10%, either group) were nausea, injection‐site induration, dyslipidemia and vomiting. Injection‐site induration was more frequent with EQW, whereas nausea, vomiting and hypoglycemia were less frequent. One episode each of major hypoglycemia (EBID) and pancreatitis (EQW) were reported.

Conclusion

In this population, EQW and EBID showed efficacious glucose and weight control; safety and tolerability were consistent with observations in non‐Asian patients. This trial was registered with ClinicalTrials.gov (no. NCT00917267).     

Expression profiling analysis: Uncoupling protein 2 deficiency improves hepatic glucose,lipid profiles and insulin sensitivity in high‐fat diet‐fed mice by modulating expression of genes in peroxisome proliferator‐activated receptor signaling pathway

Aims/Introduction

Uncoupling protein 2 (UCP2), which was an important mitochondrial inner membrane protein associated with glucose and lipid metabolism, widely expresses in all kinds of tissues including hepatocytes. The present study aimed to explore the impact of UCP2 deficiency on glucose and lipid metabolism, insulin sensitivity and its effect on the liver‐associated signaling pathway by expression profiling analysis.

Materials and Methods

Four‐week‐old male UCP2−/− mice and UCP2+/+ mice were randomly assigned to four groups: UCP2−/− on a high‐fat diet, UCP2−/− on a normal chow diet, UCP2+/+ on a high‐fat diet and UCP2+/+ on a normal chow diet. The differentially expressed genes in the four groups on the 16th week were identified by Affymetrix gene array.

Results

The results of intraperitoneal glucose tolerance test and insulin tolerance showed that blood glucose and β‐cell function were improved in the UCP2−/− group on high‐fat diet. Enhanced insulin sensitivity was observed in the UCP2−/− group. The differentially expressed genes were mapped to 23 pathways (P < 0.05). We concentrated on the ‘peroxisome proliferator‐activated receptor (PPAR) signaling pathway’ (P = 3.19 × 10⁻¹¹), because it is closely associated with the regulation of glucose and lipid profiles. In the PPAR signaling pathway, seven genes (PPARγ, Dbi, Acsl3, Lpl, Me1, Scd1, Fads2) in the UCP2−/− mice were significantly upregulated.

Conclusions

The present study used gene arrays to show that activity of the PPAR signaling pathway involved in the improvement of glucose and lipid metabolism in the liver of UCP2‐deficient mice on a long‐term high‐fat diet. The upregulation of genes in the PPAR signaling pathway could explain our finding that UCP2 deficiency ameliorated insulin sensitivity. The manipulation of UCP2 protein expression could represent a new strategy for the prevention and treatment of diabetes.     

Effect of endurance training on retinol‐binding protein 4 gene expression and its protein level in adipose tissue and the liver in diabetic rats induced by a high‐fat diet and streptozotocin

Aims/Introduction

The present study was designed to investigate from which tissues the decrease in retinol‐binding protein 4 (RBP4) expression could contribute to the improvement of serum RBP4 and insulin resistance (IR) after endurance training.

Materials and Methods

Male 7‐week‐old Wistar rats were randomly assigned into four groups including control (C), trained (T), diabetic control (DC) and trained diabetic (TD). At 8 weeks‐of‐age, diabetes was induced by a high‐fat diet and intraperitoneal injection of low‐dose streptozotocin (STZ; 35 mg/kg). Rats in the T and TD groups carried out a 7‐week exercise program on a motorized treadmill (15–20 m/min for 20 min/day for 5 weeks), whereas the C and DC remained sedentary in their cages. Tissues gene expression and protein levels of RBP4 were assessed by using real‐time polymerase chain reaction and western blot, respectively, while serum RBP4 was measured using an enzyme‐linked immunosorbent assay kit.

Results

Exercise significantly improved IR and reduced serum concentration of RBP4 in the TD group. This reduction of serum RBP4 was accompanied by decreased RBP4 protein expression in visceral fat tissue. In contrast, exercise had no significant effect on RBP4 expression in liver and subcutaneous fat tissue in the TD group. Exercise also significantly decreased RBP4 gene expression in visceral fat tissue and muscle, whereas the effect of exercise on liver RBP4 messenger ribonucleic acid expression was not significant.

Conclusions

The present study showed that the mechanism for RBP4 reducing the effect of endurance training could involve decreased RBP4 messenger ribonucleic acid expression and its protein level in adipose tissue in STZ‐induced diabetic rats.     

Pharmacokinetic and pharmacodynamic properties of insulin degludec in Japanese patients with type 1 diabetes mellitus reflect similarities with Caucasian patients

Introduction

The present study aimed to evaluate the pharmacokinetic and pharmacodynamic properties of insulin degludec (IDeg) in Japanese patients with type 1 diabetes.

Materials and Methods

This was a randomized, single‐center, double‐blind, two‐period, crossover, multiple‐dose trial. Patients were randomized into two treatment sequences, and received IDeg or insulin detemir for 6 days and a washout period (7–21 days) before switching treatment. Blood samples for pharmacokinetic measurements were obtained before each dose and up to 120 h after the last dose of each treatment period. Pharmacodynamic measurements were obtained using a 26‐h euglycemic clamp procedure after the last dose of each treatment period.

Results

A total of 22 patients were randomized (14 men, 8 women; mean glycosylated hemoglobin at baseline of 7.5% [based on Japanese Diabetes Society value]). At steady state, total glucose‐lowering effect (area under the glucose infusion rate [GIR] curve during one dosing interval [τ, 0–24 h] at steady state [AUC_{GIR ,τ, SS}]) was 1,446 mg/kg and total exposure (geometric mean) of IDeg (AUC_{ID eg,τ, SS}) was 81,270 pmol h/L. Both the glucose‐lowering effect and the exposure of IDeg were evenly distributed over the dosing interval, with AUC for the first 12‐h intervals being approximately 50% of the total (geometric mean; AUC_{GIR ,0–12h, SS}/AUC_{GIR ,τ, SS} = 48%; AUC_{ID eg,0–12h, SS}/AUC_{ID eg,τ, SS} = 53%).

Conclusions

IDeg has a flat, consistent and ultra‐long glucose‐lowering effect that is evenly distributed across a 24‐h interval and an ultra‐long duration of action in Japanese patients with type 1 diabetes. These data support once‐daily dosing of IDeg in all patients. Overall, the pharmacodynamic and pharmacokinetic end‐points and safety observations are consistent with those previously reported in Caucasian patients.     

Circulating cell‐free mitochondrial deoxyribonucleic acid is increased in coronary heart disease patients with diabetes mellitus

Aims/Introduction

Circulating cell‐free mitochondrial deoxyribonucleic acid (ccf‐mtDNA) is presumably derived from injured tissues or cells in the body and has been suggested to be potential biomarker in several diseases. The present study explored whether mtDNA could be used as a biomarker to evaluate disease in coronary heart disease (CHD) patients with or without diabetes mellitus (DM).

Materials and Methods

A total of 50 CHD patients with type 2 diabetes, 50 CHD patients without type 2 diabetes, and 50 age‐ and sex‐matched patients without CHD and DM (non‐CHD‐DM) were recruited. Ccf‐mtDNA levels were assessed by measuring the nicotinamide adenine dinucleotide dehydrogenase 1 gene using quantitative real‐time polymerase chain reaction. Receiver operating characteristic curve analysis of plasma mtDNA in CHD with or without DM was also determined. Multivariate logistic regression analyses were carried out to determine the correlation between the mtDNA levels and traditional CHD risk factors.

Results

The plasma ccf‐mtDNA levels were significantly elevated in CHD patients with DM compared with those without and non‐CHD‐DM. The area under the receiver operating characteristic curves of mtDNA in CHD patients with DM vs non‐CHD‐DM was 0.907%. Correlation analyses of the mtDNA levels and traditional CHD risk factors showed that the mtDNA levels were significantly correlated with fasting blood glucose in CHD patients with DM.

Conclusions

Ccf‐mtDNA levels can be used as a biomarker in CHD patients with DM.     

Efficacy and safety of 40 mg or 60 mg duloxetine in Japanese adults with diabetic neuropathic pain: Results from a randomized, 52‐week,open‐label study

Introduction

To examine the long‐term efficacy and safety of duloxetine in the treatment of Japanese patients with diabetic neuropathic pain, we carried out a 52‐week, randomized, open‐label extension of a 12‐week, double‐blind, placebo‐controlled study.

Materials and Methods

Japanese adults with diabetic neuropathic pain who completed the double‐blind study were eligible for this long‐term study, carried out at 71 sites in Japan (March 2008 to March 2010). Participants (n = 258) were re‐randomized (1:1) to 40 mg/day or 60 mg/day duloxetine. Pain (Brief Pain Inventory severity and interference), quality of life (Patient''s Global Impression of Improvement), and safety (primary outcome; adverse events, vital signs, metabolic measures) were measured.

Results

Significant (P < 0.0001) and sustained improvements (change ± standard deviation; n = 257) were observed in Brief Pain Inventory severity (average pain score −2.1 ± 1.7). Improvements were also seen in Brief Pain Inventory interference (mean of subscores −0.96 ± 1.52) and Patient''s Global Impression of Improvement (−0.9 ± 1.1) scores; these scores decreased significantly (P < 0.0001) during the long‐term study. Frequently reported adverse events included somnolence (13.6%), constipation (13.2%) and nausea (10.5%). Increases were observed in plasma glucose, glycosylated hemoglobin and total cholesterol levels, and in bodyweight and heart rate; however, none of these were clinically meaningful. Overall, there were no clinically significant safety concerns.

Conclusions

This is the first publication of a long‐term study carried out in Asia with an entirely Japanese patient population to suggest that long‐term duloxetine therapy for diabetic neuropathic pain is effective and has an acceptable safety profile.     

Diabetes mellitus,but not small dense low‐density lipoprotein,is predictive of cardiovascular disease: A Korean community‐based prospective cohort study

Aims/Introduction

Small dense low‐density lipoprotein (sdLDL) has been suggested to be a potential risk factor for cardiovascular diseases (CVD).

Materials and Methods

We carried out a prospective nested case–control study in the Korean Health and Genome Study. Participants were men and women aged 40–69 years who developed CVD (n = 313), and were matched by age and sex to controls who remained free of CVD (n = 313) during the 8‐years follow‐up period (from 2001 to 2009). LDL subfractions were analyzed in frozen samples collected from the 626 participants using polyacrylamide tube gel electrophoresis.

Results

Patients with CVD had a significantly higher glycated hemoglobin level compared with the controls (5.72 vs 5.56). The proportion of patients with diabetes mellitus (DM) was higher in those who developed CVD during follow up (8.0% vs 1.9%). The frequency of CVD according to each tertile of LDL particle size and the number of metabolic syndrome components did not differ significantly. In the multivariate analysis, DM (odds ratio 4.244, 95% confidence interval 1.693–10.640, P = 0.002) was the only independent predictive factor of CVD. LDL particle size was not associated with the risk for future CVD.

Conclusions

Small dense LDL might not be a significant predictor of CVD in this Korean community‐based prospective cohort study.     

Changes in oral antidiabetic prescriptions and improved glycemic control during the years 2002–2011 in Japan (JDDM32)

Aims/Introduction

Six kinds of oral antidiabetic drugs (OADs), including the new dipeptidyl peptidase 4 (DPP‐4) inhibitors, are available. The present study aimed to define trends within the prescribing patterns of OADs, as well as changes in glycemic control in Japan over a 10‐year period from 2002 to 2011.

Materials and Methods

We carried out a cross‐sectional study using data of type 2 diabetes mellitus patients from 24 clinics for 2002, 2005, 2008 and 2011. OAD use was analyzed combined with clinical data.

Results

Sulfonylureas (SUs) were the most commonly used OAD, but their use for monotherapy markedly decreased over the study period. Biguanides (BGs) were the second most commonly used OAD, and their prescribing rate increased both for mono‐ and combination therapy. DPP‐4 inhibitors (DPP‐4I), released in 2009, were the third most commonly prescribed OAD in 2011 both for mono‐ and combination therapy. Among combination therapies, two OADs were mostly prescribed, but the use of three OADs and four OADs in 2011 was two‐ and 14.8‐fold those in 2002. These trends were accompanied by an improvement in average glycated hemoglobin from 7.5 ± 1.2% in 2002 to 7.1 ± 0.9% in 2011.

Conclusions

The OAD prescribing trend has moved away from monotherapy with SUs and toward combination therapies to achieve better glycemic control. Increased use of BGs and DPP‐4I was predominant in 2011. These trends were accompanied by an improvement of the glycated hemoglobin level.     

Impact of cigarette smoking on impaired insulin secretion and insulin resistance in Japanese men: The Saku Study

Aims/Introduction

To assess the impact of smoking on impaired insulin secretion and insulin resistance in Japanese men.

Materials and Methods

This study included 1,199 men aged 30–79 years without diabetes, impaired insulin secretion and insulin resistance at baseline who underwent a comprehensive medical check‐up between April 2006 and March 2007 at Saku Central Hospital. Smoking status was categorized as current, ex‐smoker and never‐smoker. Insulinogenic index and homeostasis model assessment‐insulin resistance were determined using a standard 75‐g oral glucose tolerance test. The Japan Diabetes Society criteria were used to define impaired insulin secretion and insulin resistance. Participants were followed up until March 2011.

Results

A total of 449 and 99 men developed impaired insulin secretion and insulin resistance during 3,403 and 4,092 person‐years follow up, respectively. The multivariable‐adjusted hazard ratios (HRs) for impaired insulin secretion were 1.06 (95% confidence interval [CI] 0.84–1.33) in ex‐smokers and 1.95 (95% CI 1.44–2.63) in current smokers compared with never‐smokers after adjustment for age, familial history of diabetes, alcohol consumption, exercise, systolic blood pressure, triglyceride, γ‐glutamyltransferase, waist circumference, leukocyte count, changes in smoking status and changes in waist circumference. The number of pack‐years was positively associated with the risk for impaired insulin secretion in a dose‐dependent manner (P‐values for trend <0.001). The multivariable‐adjusted HRs for insulin resistance were 0.95 (95% CI 0.56–1.61) in ex‐smokers and 1.11 (95% CI 0.67–1.79) in current smokers compared with never‐smokers.

Conclusions

Cigarette smoking is a modifiable risk factor for impaired insulin secretion. The findings might also be important for other Asian populations, which have low insulin secreting ability.