Sitagliptin improves albuminuria in patients with type 2 diabetes mellitus

Introduction

The aim of the present study was to determine the effect of sitagliptin on microalbuminuria in patients with type 2 diabetes mellitus.

Materials and Methods

A total of 85 patients with type 2 diabetes mellitus (age >20 years, <80 years, hemoglobin A1c [HbA1c] <8.4%) were randomized to patients taking sitagliptin 50 mg or other oral glucose‐lowering agents. The following parameters were evaluated at 0, 3 and 6 months after the treatment: bodyweight, blood pressure, HbA1c, fasting plasma glucose, fasting plasma insulin, low‐density lipoprotein cholesterol, high‐density lipoprotein cholesterol, triglycerides, estimated glomerular filtration rate and urinary albumin excretion. The primary outcome was changes in urinary albumin excretion at 6 months.

Results

Significant and comparable falls in HbA1c and fasting plasma glucose were found in both groups. However, sitagliptin significantly reduced urinary albumin excretion within 6 months, especially in patients with high urinary albumin at baseline. A total of 27 patients with normoalbuminuria showed a reduction in urinary albumin excretion, suggesting that sitagliptin prevents the development of albuminuria. A total of 15 patients with albuminuria showed a reduction in urinary albumin excretion, suggesting the beneficial effect of sitagliptin in the early stage of diabetic nephropathy. There was a significant correlation between improvement of proteinuria and that of diastolic blood pressure.

Conclusions

The results suggested that sitagliptin improved albuminuria, in addition to improving glucose. The mechanism of the reduction of albuminuria by sitagliptin could be a direct effect, as well as an increase in active glucagon‐like peptide‐1, independently affecting blood pressure, bodyweight and glucose metabolism. This trial was registered with the University Hospital Medical Information Network (UMIN no. #000010871).     

Comparison of the efficacy of sitagliptin and glimepiride dose‐up in Japanese patients with type 2 diabetes poorly controlled by sitagliptin and glimepiride in combination

Aims/Introduction

The goal of the study was to examine the effects of sitagliptin dose‐up or glimepiride dose‐up in Japanese patients with type 2 diabetes who were controlled inadequately by sitagliptin and glimepiride in combination.

Materials and Methods

A multicenter, prospective, randomized, open‐label study was carried out in 50 patients with type 2 diabetes treated with sitagliptin and low‐dose glimepiride. The patients were randomly assigned to receive the addition of 50 mg/day sitagliptin or 0.5 mg/day glimepiride. The primary end‐point was the percentage change in glycated hemoglobin (HbA1c).

Results

During a follow‐up period, the difference in the percentage changes in HbA1c between the two groups was not significant (P = 0.13). However, HbA1c was significantly decreased by glimepiride dose‐up (P < 0.01 vs baseline), but not by sitagliptin dose‐up (P = 0.74). Univariate linear regression analyses showed that the percentage change in HbA1c was significantly associated with the serum level of arachidonic acid (AA) in both groups.

Conclusions

There was no significant difference in the HbA1c‐lowering effects between the two groups. However, a significant HbA1c‐lowering effect from baseline of glimepiride dose‐up was found, and the AA level showed a negative correlation with the decrease in HbA1c in the sitagliptin dose‐up group, but a positive correlation in the glimepiride dose‐up group. These findings suggest that the AA level is associated with HbA1c reduction in response to dose‐up with these drugs in patients with type 2 diabetes in a combination therapy with sitagliptin and glimepiride. This trial was registered with UMIN (no. 000009544).     

Oral glucose tolerance test‐based calculation identifies different glucose intolerance phenotypes within the impaired fasting glucose range

Aims/Introduction

The conventional oral glucose tolerance test (OGTT) cannot detect future diabetics among isolated impaired fasting glucose (is‐IFG) nor normal glucose tolerant (NGT) groups. By analyzing the relationship between fasting (FPG) and 2‐h plasma glucose (2hPG), the present study identifies is‐IFG subjects liable to worsening glucose homeostasis.

Materials and Methods

Oral glucose tolerance test was carried out in 619 patients suffering from obesity, hypertension or dyslipidemia, whose FPG was in the 100–125 mg/dL range. We calculated the percentage increment of 2hPG with respect to FPG (PG%) in these patients using the formula: ([2hPG − FPG] / FPG) × 100. Differences in β‐cell function within is‐IFG patients were assessed by estimated insulin sensitivity index (EISI), first‐phase insulin release (1stPH) and 1stPH/1/EISI (1stPH_corrected).

Results

Diabetes was diagnosed in 69 patients (11.2%), combined IFG/impaired glucose tolerance (IGT) in 185 patients (29.9%) and is‐IFG in 365 patients (58.9%). Is‐IFG was subdivided into PG% tertile groups: the percentage of females increased from 25% in the lowest to 45.2% in the highest tertile (χ² = 18.7, P < 0.001). Moving from the lowest to the highest PG% tertile group, insulin and 2hPG concentrations rose, whereas FPG, EISI, and 1stPH_corrected decreased progressively and significantly. Furthemore, PG% correlated inversely with EISI (r = −0.44, P < 0.0001) and 1stPH_corrected (r = −0.38, P < 0.0001).

Conclusions

Oral glucose tolerance test does differentiate the great heterogeneity in metabolic disorders of patients with FPG 100–125 mg/dL. Furthermore, PG% can expand the diagnostic power of OGTT in the is‐IFG range by distinguishing metabolic phenotypes very likely to herald different clinical risks.     

Correlation between mean platelet volume and blood glucose levels after oral glucose loading in normoglycemic and prediabetic Japanese subjects

Aims/Introduction

Mean platelet volume (MPV) reflects platelet activity, and high MPV is associated with thrombogenic activation and increased cardiovascular disease risk. Although a positive correlation between MPV and fasting plasma glucose (FPG) levels has been reported, the correlation between MPV and postprandial glucose levels remains unclear. The purpose of the present study was to evaluate the correlation between MPV and postprandial glucose levels in prediabetic and normoglycemic participants.

Materials and Methods

We evaluated 1,080 Japanese participants who underwent the 75‐g oral glucose tolerance test (OGTT). Based on these results, the participants were divided into three groups: normal glucose tolerance group (NGT; n = 582), impaired fasting glucose group (IFG; n = 205) and impaired glucose tolerance group (IGT; n = 252). The relationship between MPV, FPG, and postchallenge glucose levels after 1 h (1 h‐PG) and 2 h (2 h‐PG) were analyzed.

Results

Bivariate correlation analyses showed a significant positive correlation between MPV and both FPG and 1 h‐PG levels in the NGT group, as well as between MPV and 2 h‐PG, total cholesterol, and low‐density lipoprotein cholesterol in the IGT group. In contrast, no significant correlation was observed between MPV and postchallenge glucose levels in the IFG group. Multiple correlation analyses showed that FPG levels significantly correlated with MPV in the NGT and IGT groups. In addition, 1 h‐PG and 2 h‐PG levels correlated with MPV in the NTG and IGT groups, respectively.

Conclusions

These results suggest a possible mechanism by which subjects with postprandial hyperglycemia might be at increased cardiovascular risk.     

Prevalence of retinopathy and its risk factors in a Japanese population

Aims/Introduction

To determine the prevalence and risk factors of retinopathy and validity of the current diagnostic cut‐offs for diabetes by using data of health check‐up examinees.

Materials and Methods

The study comprises 1,864 Japanese who participated in the general health check‐up program and did not have a previous history of cardiovascular disease. Non‐mydriatic 45° digital fundus photographs were taken twice annually. Multivariate logistic regression model was used to identify risk factors for retinopathy in participants without previously diagnosed diabetes.

Results

The overall prevalence of retinopathy in participants with and without previously diagnosed diabetes were 23.3% (28/120) and 4.2% (74/1,744), respectively. Univariate logistic regression analysis identified age, systolic blood pressure (SBP), fasting plasma glucose (FPG) and hemoglobin A1c (HbA_1c) as risk factors for retinopathy. Multivariate logistic regression analysis showed that FPG or both HbA_1c and SBP were significant, positive and independent risk factors for retinopathy. The prevalence of retinopathy increased with deterioration of glucose categories (P < 0.001 for FPG or HbA_1c). However, a statistically significant increased risk of retinopathy remained only in participants with FPG ≥ 7.0 mmol/L or HbA1c ≥ 6.5% compared with those with the lowest quartile of glucose in the participants without previously diagnosed diabetes after adjusting for age and SBP.

Conclusions

The prevalence of retinopathy was 4.2%, and FPG or both HbA_1c and SBP were positive and independent risk factors for retinopathy in health check‐up examinees without previously diagnosed diabetes. The FPG 7.0 mmol/L or HbA_1c 6.5% seems to be appropriate to diagnose diabetes in view of its association with retinopathy.     

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.     

Addition of sitagliptin to ongoing metformin monotherapy improves glycemic control in Japanese patients with type 2 diabetes over 52 weeks

Aims/Introduction

The efficacy and safety of sitagliptin, a highly selective dipeptidyl peptidase‐4 inhibitor, when added to metformin monotherapy was examined in Japanese patients with type 2 diabetes.

Materials and Methods

In this 52‐week, add‐on to metformin study, 149 patients were randomly assigned to receive sitagliptin 50 mg or placebo once daily in a double‐blind fashion for 12 weeks. Thereafter, all patients who completed the double‐blind period of the study received open‐label sitagliptin 50 mg once daily for 40 weeks, with the investigator option of increasing sitagliptin to 100 mg once daily for patients who met predefined glycemic thresholds.

Results

After 12 weeks of treatment, the mean change from baseline in glycated hemoglobin (HbA1c) significantly decreased with sitagliptin relative to placebo (between‐group difference [95% confidence interval] = −0.7% [−0.9 to −0.5] P < 0.001). At week 12, the mean changes in 2‐h post‐meal glucose (−2.6 mmol/L [−3.5 to −1.7]) and fasting plasma glucose (−1.0 mmol/L [−1.3 to −0.6]) also decreased significantly with sitagliptin relative to placebo (P < 0.001 for both). Significant improvements from baseline in glycemic control were also observed in the open‐label period through to week 52. There were no differences between treatment groups in the incidence of adverse events (AEs), including hypoglycemia and predefined gastrointestinal AEs (nausea, vomiting and diarrhea) during the double‐blind period, with similar findings in the open‐label period.

Conclusions

Over a period of 52 weeks, the addition of sitagliptin once‐daily to ongoing metformin therapy was efficacious and generally well tolerated in Japanese patients with type 2 diabetes. This trial was registered with ClinicalTrials.gov (no. NCT00363948).     

Comparison of three α‐glucosidase inhibitors for glycemic control and bodyweight reduction in Japanese patients with obese type 2 diabetes

Aims/Introduction

α‐Glucosidase inhibitors (αGIs) are widely used for the primary treatment of type 2 diabetes. We compared the clinical effects of three αGIs (miglitol, acarbose and voglibose) in patients with obese type 2 diabetes.

Materials and Methods

Japanese patients (n = 81) with obese type 2 diabetes (body mass index [BMI] ≥25 kg/m²) were enrolled in this multicenter, open‐label study. The participants were randomized into the miglitol (n = 18), acarbose (n = 22), voglibose (n = 19) or control (n = 22) groups. Glycemic control (fasting blood glucose and glycated hemoglobin [HbA1c]), bodyweight, BMI, serum insulin, serum lipids (low‐density lipoprotein and high‐density lipoprotein cholesterol, and triacylglycerols) and adipocytokines (leptin and adiponectin) were evaluated every 4 weeks for 12 weeks.

Results

In the miglitol group, HbA1c was improved significantly from the baseline at all points. The changes in HbA1c at 8 and 12 weeks from baseline were greater in the miglitol group than the control group. The voglibose group showed significant improvements in HbA1c at 12 weeks. Bodyweight and BMI were decreased significantly in the miglitol group. In addition, significant correlations were observed between the decrements in HbA1c and bodyweights over 12 weeks in the miglitol (r = 0.759, P < 0.001) and voglibose groups (r = 0.667, P = 0.002). Serum lipid and adipocytokine levels were not altered in any groups.

Conclusions

αGIs, especially miglitol, can effectively control blood glucose and bodyweight in obese type 2 diabetes. This study was registered with UMIN (no. UMIN000006465).     

Efficacy of α‐glucosidase inhibitors combined with dipeptidyl‐peptidase‐4 inhibitor (alogliptin) for glucose fluctuation in patients with type 2 diabetes mellitus by continuous glucose monitoring

Aims/Introduction

The combination therapy of dipeptidyl‐peptidase (DPP)‐4 inhibitor and α‐glucosidase inhibitors (α‐GIs) is highly effective in suppressing postprandial hyperglycemia. The aim of the present study was to compare the effects of voglibose and miglitol on glucose fluctuation, when used in combination with DPP‐4 inhibitor by using continuous glucose monitoring (CGM).

Materials and Methods

In a randomized cross‐over study, 16 patients with type 2 diabetes who presented with postprandial hyperglycemia despite alogliptin (25 mg) were treated with voglibose (0.9 mg) or miglitol (150 mg). We measured standard deviation (SD); mean amplitude of glycemic excursions (MAGE), and mean, minimum and maximum glucose measured by CGM during three phases (alogliptin monotherapy, dual therapy of alogliptin and voglibose, and dual therapy of alogliptin and miglitol). The primary outcome measure was SD between α‐GIs.

Results

SD was significantly improved by the addition of either voglibose (18.9 ± 10.1) or miglitol (19.6 ± 8.2) to alogliptin monotherapy (36.2 ± 8.7). MAGE improved significantly with the addition of either voglibose (57.5 ± 26.1, P < 0.01) or miglitol (64.6 ± 26.2, P < 0.01) to alogliptin monotherapy (101.5 ± 21.5). There was no significant difference in glucose fluctuation between α‐GIs. There were no differences between two groups in mean (132.6 ± 21.4 and 138.7 ± 25.4) and maximum (184.3 ± 48.7 and 191.9 ± 38.3). The minimum glucose under alogliptin plus voglibose (94.9 ± 20.2) was significantly lower than that under alogliptin and miglitol (105.3 ± 21.0).

Conclusions

Glucose fluctuation was improved by the addition of voglibose or miglitol to alogliptin. Glucose fluctuations and postprandial hyperglycemia were similar between α‐GIs. This trial was registered with the University Hospital Medical Information Network (no. UMIN R000010028).     

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.     

Postprandial C‐peptide to glucose ratio as a predictor of β‐cell function and its usefulness for staged management of type 2 diabetes

Aims/Introduction

Type 2 diabetes is characterized by progressive deterioration of β‐cell function. Recently, it was suggested that the C‐peptide‐to‐glucose ratio after oral glucose ingestion is a better predictor of β‐cell mass than that during fasting. We investigated whether postprandial C‐peptide‐to‐glucose ratio (PCGR) reflects β‐cell function, and its clinical application for management of type 2 diabetes.

Materials and Methods

We carried out a two‐step retrospective study of 919 Korean participants with type 2 diabetes. In the first step, we evaluated the correlation of PCGR level with various markers for β‐cell function in newly diagnosed and drug‐naïve patients after a mixed meal test. In the second step, participants with well‐controlled diabetes (glycated hemoglobin <7%) were divided into four groups according to treatment modality (group I: insulin, group II: sulfonylurea and/or dipeptityl peptidase IV inhibitor, group III: metformin and/or thiazolidinedione and group IV: diet and exercise group).

Results

In the first step, PCGR was significantly correlated with various insulin secretory indices. Furthermore, PCGR showed better correlation with glycemic indices than homeostatic model assessment of β‐cell function (HOMA‐β). In the second step, the PCGR value significantly increased according to the following order: group I, II, III, and IV after adjusting for age, sex, body mass index and duration of diabetes. The cut‐off values of PCGR for separating each group were 1.457, 2.870 and 3.790, respectively (P < 0.001).

Conclusions

We suggest that PCGR might be a useful marker for β‐cell function and an ancillary parameter in the choice of antidiabetic medication in type 2 diabetes.     

Correlations of serum visfatin and metabolisms of glucose and lipid in women with gestational diabetes mellitus

Aims/Introduction

Visfatin is a newly discovered adipocytokine hormone, which exerts an insulin‐like effect by binding to the insulin receptor‐1. However, the role of visfatin in human gestational diabetes mellitus (GDM) remains controversial. The purpose of the present study was to investigate the correlation between serum visfatin and metabolism of glucose and lipid in GDM.

Materials and Methods

This was a prospective study. A total of 38 GDM patients and 35 age‐ and body mass index‐matched controls were studied between January 2012 and October 2013. Fasting serum levels of visfatin, fasting plasma glucose, hemoglobin A1c and lipid profile were measured. Two‐tailed t‐tests and Pearson''s correlation coefficient were used to analyze the data.

Results

Perinatal visfatin levels were negatively correlated with fasting plasma glucose, insulin resistance index and triglycerides in controls (r = −0.47, −0.51, −0.57, respectively; P < 0.05), and positively correlated with high‐density lipoprotein cholesterol (r = 0.32, P < 0.05). A positive correlation with visfatin level only appeared in weight gain and body mass index in women with GDM (r = 0.36, 0.45, respectively; P < 0.05).

Conclusions

Visfatin appears to be involved in glucose and lipid metabolism regulation and insulin resistance, suggesting a role in GDM pathogenesis.     

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.     

Pharmacokinetics,pharmacodynamics, safety and tolerability of 4 weeks' treatment with empagliflozin in Japanese patients with type 2 diabetes mellitus

Introduction

To evaluate the pharmacodynamics, pharmacokinetics, safety and tolerability of empagliflozin in Japanese patients with type 2 diabetes mellitus.

Materials and methods

In this 4‐week, multiple dose, randomized, parallel‐group, double‐blind, placebo‐controlled trial, patients (n = 100) were randomized to receive 1, 5, 10 or 25 mg of empagliflozin, or placebo once daily. Key end‐points were urinary glucose excretion (UGE), fasting plasma glucose (FPG) and eight‐point glucose profile.

Results

Data are presented for 1, 5, 10, 25 mg of empagliflozin and placebo groups, respectively. Adjusted mean changes from baseline to day 27 in UGE were 40.8, 77.1, 80.9, 93.0 and −2.1 g (P < 0.0001 for all empagliflozin groups vs placebo). Adjusted mean changes from baseline to day 28 in FPG were −1.56, −1.96, −2.31, −2.37 and −0.86 mmol/L (P < 0.01 for all empagliflozin groups vs placebo). Adjusted mean changes from baseline to day 27 in eight‐point glucose profile were −1.96, −2.21, −2.42, −2.54 and −0.97 mmol/L (P < 0.01 for all empagliflozin groups vs placebo). Empagliflozin reached peak plasma concentration 1.5–2 h after dosing. Mean steady state terminal elimination half‐lives ranged from 13.2 to 18.0 h. Of 100 patients, 25 experienced an adverse event, occurring more frequently for empagliflozin (29.1%) than placebo (9.5%); frequency was not dose related.

Conclusions

In Japanese patients with type 2 diabetes mellitus, empagliflozin at doses up to 25 mg once daily for 4 weeks was well tolerated and resulted in significant improvements in glycemic control compared with placebo. This trial was registered with ClinicalTrials.gov (no. NCT00885118).     

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.     

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.     

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.     

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.     

Albuminuria: Prevalence,associated risk factors and relationship with cardiovascular disease

Aims/Introduction

To investigate the prevalence and associated risk factors of microalbuminuria, and to explore the relationship between albuminuria and cardiovascular disease (CVD).

Materials and Methods

A nationally representative sample of 38,203 Chinese participants was categorized by different levels of urinary albumin‐to‐creatinine ratio (ACR; 0 –10 mg/g, 10 –20 mg/g, 20 –30 mg/g, 30 –300 mg/g). The prevalence of albuminuria was compared by using a single urinary ACR cut‐off point and by sex‐specific ACR cut‐off points. Factors associated with the presence of albuminuria, and the relationship between albuminuria and CVD were analyzed by logistic regression.

Results

Prevalence of albuminuria as measured by a single ACR cut‐point was significantly lower for men compared with women (13.9% vs 19.1% in the normal glucose tolerance group; 20.8% vs 26.8% in the impaired glucose tolerance group, P < 0.01). The prevalence of albuminuria, as measured by sex‐specific ACR cut‐points, was higher for men than women (31.4% vs 29.6% in the normal glucose tolerance group; 42.2% vs 39.3% in the impaired glucose tolerance group, P < 0.01). The independent risk factors for the presence of albuminuria were aging, female sex, hypertension, hyperglycemia, obesity, dyslipidemia, insulin resistance and metabolic syndrome. The subdivided normal ACR group did not show a linear or statistically significant relationship with CVD after adjusting for conventional CVD risk factors (P > 0.05).

Conclusions

The prevalence of albuminuria was high in the general Chinese population. Aging, female sex, hypertension, hyperglycemia, dyslipidemia, insulin resistance, obesity and metabolic syndrome were all independent risk factors for albuminuria. The causal relationship between ACR and CVD might require further follow‐up investigation.     

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.