Lipid droplet accumulation in ß cells in patients with type 2 diabetes is associated with insulin resistance, hyperglycemia and ß cell dysfunction involving decreased insulin granules.

Background and objective: Pancreatic fat is a form of ectopic fat. Lipid droplets (LDs) are also observed in ß cells; however, the pathophysiological significance, especially for ß cell function, has not been elucidated. Our aim was to assess LD accumulation in ß cells in various stages of glucose intolerance and to clarify its relationship with clinical and histological parameters. Methods: We examined 42 Japanese patients who underwent pancreatectomy. The BODIPY493/503-positive (BODIPY-positive) area in ß cells was measured in pancreatic sections from 32 patients. The insulin granule numbers were counted in an additional 10 patients using electron microscopy. Results: The BODIPY-positive area in ß cells in preexisting type 2 diabetes patients was higher than that in normal glucose tolerance patients (p = 0.031). The BODIPY-positive area in ß cells was positively correlated with age (r = 0.45, p = 0.0097), HbA1c (r = 0.38, p = 0.0302), fasting plasma glucose (r = 0.37, p = 0.045), and homeostasis model assessment insulin resistance (r = 0.41, p = 0.049) and negatively correlated with an increase in the C-peptide immunoreactivity level by the glucagon test (r = -0.59, p = 0.018). The ratio of mature insulin granule number to total insulin granule number was reduced in the patients with rich LD accumulation in ß cells (p = 0.039). Conclusions: Type 2 diabetes patients had high LD accumulation in ß cells, which was associated with insulin resistance, hyperglycemia, aging and ß cell dysfunction involving decreased mature insulin granules.

Benefit of Early Add-on of Linagliptin to Insulin in Japanese Patients With Type 2 Diabetes Mellitus: Randomized-Controlled Open-Label Trial (TRUST2).

INTRODUCTION: This trial was conducted to assess the long-term safety, efficacy, and benefit of early add-on of linagliptin to insulin in patients with type 2 diabetes mellitus (T2DM). METHODS: This trial enrolled 246 subjects. The subjects were randomized to the linagliptin group or the control group and were observed for 156 weeks. After week 16, subjects in the control group were also allowed to add linagliptin to evaluate the benefit of early add-on of linagliptin to insulin. The primary end point was a change in HbA1c from baseline to week 16. Secondary end points included fasting plasma glucose, daily insulin dose, and frequency of adverse events. RESULTS: HbA1c and fasting plasma glucose levels significantly decreased from baseline to week 16 in the linagliptin group compared with the control group. The significant improvement in HbA1c continued until week 52. The daily insulin dose significantly decreased in the linagliptin group compared with the control group. The frequency of hypoglycemia and adverse events was comparable in both groups. CONCLUSIONS: Add-on of linagliptin to insulin was tolerated, improved glycemic control, and reduced the daily insulin dose. This study demonstrates the long-term safety, efficacy and benefit of early add-on of linagliptin to insulin in Japanese T2DM patients.

Postabsorptive hyperglucagonemia in patients with type 2 diabetes mellitus analyzed with a novel enzyme-linked immunosorbent assay.

AIMS/INTRODUCTION: The aims of the present study were to investigate the performance of a novel sandwich enzyme-linked immunosorbent assay (ELISA) for measuring glucagon (1-29) with monoclonal antibodies against both the C- and N-terminal regions of glucagon (1-29), and to analyze the differences in plasma levels and responses of glucagon (1-29) to oral glucose loading in normal glucose tolerance (NGT) subjects and patients with type 2 diabetes mellitus. MATERIALS AND METHODS: The cross-reactivity against proglucagon fragments using the ELISA kit and two types of conventional radioimmunoassay (RIA) kits was evaluated. A 75-g oral glucose tolerance test was carried out with NGT subjects and patients with type 2 diabetes mellitus, and the glucagon (1-29) concentration was measured using three types of kit. RESULTS: The ELISA kit clearly had the lowest cross-reactivity against miniglucagon (19-29) and glicentin (1-61). The oral glucose tolerance test was carried out with 30 NGT and 17 patients with type 2 diabetes mellitus. The glucagon (1-29) levels measured by the ELISA kit after glucose loading were significantly higher at all time-points in the type 2 diabetes mellitus group than in the NGT group. However, the glucagon (1-29) levels measured by one RIA kit were significantly higher in the NGT group, and those measured with the other RIA kit were approximately the same among the groups. CONCLUSIONS: The novel sandwich ELISA accurately determines plasma glucagon (1-29) concentrations with much less cross-reactivity against other proglucagon fragments than conventional RIA kits.

[Significance of the regulation of hyperglucagonemia in type 2 diabetes mellitus].

Abstract Generally, pancreatic ß-cell dysfunction and hypoinsulinemia have been known as the cause of development of hyperglycemia in diabetes mellitus. Pancreatic α-cell dysfunction, particularly hyperglucagonemia is also serious problem to increase hepatic glucose production in type 2 diabetes mellitus (T2DM). ß-cell mass decrement and α-cell mass increment in T2DM have been reported in many reports inclusive of our study. Those might be the background to the pancreatic cells dysfunction in T2DM. Glucagon secretion from α-cells could not be suppressed by insufficient insulin, and hyperglucagonemia has been worsening in T2DM. Incretin, particularly glucagon like peptide-1 (GLP-1) could control both α- and ß-cell dysfunction, via the decrease of glucagon and the increase of insulin respectively. We believe that incretin therapy(GLP-1 receptor agonists and DPP-4 inhibitors) is the best strategy to control hyperglucagonemia caused by α-cell dysfunction in T2DM.

Insulin resistance and ß-cell function influence postprandial blood glucose levels in Japanese patients with gestational diabetes mellitus.

AIMS/INTRODUCTION: The aim of this study in patients with gestational diabetes mellitus (GDM) was to evaluate the relationship of insulin resistance and secretion to area-under-the-sensor glucose concentration-time curve from before to 120 min postmeal (CGM-AUC(0-120 min)) as determined with continuous glucose monitoring (CGM). MATERIALS AND METHODS: Immunoreactive insulin and HbA1c were determined in 22 Japanese patients with GDM undergoing a 75 g oral glucose tolerance test. Patients underwent CGM within 3 weeks of receiving a diagnosis of GDM. RESULTS: HbA1c (NGSP) was 5.5 ± 0.4%, BMI was 24.8 ± 5.3 kg/m(2), mean sensor glucose by CGM was 94.2 ± 10.3 mg/dL, standard deviation was 17.5 ± 4.4 mg/dL, and CGM-AUC(0-120 min) was 204.2 ± 23.8 h mg/dL. The insulin resistance indices the homeostasis model assessment ratio (HOMA-R), quantitative insulin sensitivity check index (QUICKI), and the Matsuda Index were correlated with CGM-AUC(0-120 min). The disposition index (DI), which was used to evaluate insulin secretion, was negatively correlated with CGM-AUC(0-120 min). CONCLUSIONS: Not only insulin resistance but also beta cell dysfunction contributes to postprandial hyperglycemia in Japanese patients with GDM.

Asymmetric dimethylarginine, a biomarker of cardiovascular complications in diabetes mellitus.

Cardiovascular (CV) complications are an essential causal element of prospect in diabetes mellitus (DM), with carotid atherosclerosis being a common risk factor for prospective crisis of coronary artery diseases and/or cerebral infarction in DM subjects. From another point of view, asymmetric dimethylarginine (ADMA) has been established as an inhibitor of endogenous nitric oxide synthesis and the relationship between ADMA and arteriosclerosis has been reported. In our study with 87 type 2 DM (T2DM) patients, we have examined whether ADMA and other CV risk factors are the useful predictors of DMCV complications. After the measurement of the respective CV risk factors, we have followed the enrolled T2DM patients for 5 years. We have finally analyzed 77 patients. DMCV complications developed in 15 cases newly within 5 years, and 4 cases recurred. The concentrations of ADMA in plasma were markedly more elevated in 19 DM patients with CV complications than in 58 DM patients without CV complications. Urinary albumin (U-Alb), mean intimal-medial thickness (IMT) and ankle brachial index (ABI) were also higher in patients with CV complications. Multiple regression analyses showed that U-Alb had an influence on the high level of ADMA (standardized ß = 6.59, P = 0.00014) independently of age, systolic BP, fibrinogen, mean IMT, plaque score, and ABI. The review indicates what is presently known regarding plasma ADMA that might be a new and meaningful biomarker of CV complications in DM subjects.

Evaluation of blood glucose fluctuation in Japanese patients with type 1 diabetes mellitus by self-monitoring of blood glucose and continuous glucose monitoring.

AIMS: Accurate assessment of blood glucose fluctuation is essential for managing blood glucose control while avoiding hypoglycemia in patients with diabetes mellitus. In this study, blood glucose was measured by continuous glucose monitoring (CGM) in patients with type 1 diabetes mellitus (T1DM) whom self-monitoring of blood glucose (SMBG) was carried out three or more times per day, and evaluation was performed using blood glucose fluctuation parameters obtained by CGM and SMBG. METHODS: Twenty-nine insulin-depleted patients with T1DM were enrolled. Their blood glucose fluctuations were measured at the same time by SMBG and CGM, and the correlations were evaluated. RESULTS: Correlations were found between the following values obtained by SMBG and CGM: mean and standard deviation of blood glucose levels, average daily risk range, Morbus value and high-blood-glucose index. The hypoglycemia duration and the nocturnal hypoglycemia duration showed no correlation with any of the blood glucose fluctuation parameters obtained by SMBG. CONCLUSIONS: The findings suggest that routine SMBG and glycated hemoglobin (HbA1c) measurement are sufficient for evaluation of hyperglycemia in T1DM. On the other hand, blood glucose fluctuation parameters obtained by SMBG and HbA1c have been shown to have no correlations with either hypoglycemia duration or nocturnal hypoglycemia duration.

Very short-term effects of the dipeptidyl peptidase-4 inhibitor sitagliptin on the secretion of insulin, glucagon, and incretin hormones in Japanese patients with type 2 diabetes mellitus: analysis of meal tolerance test data.

BACKGROUND: Sitagliptin inhibits dipeptidyl peptidase-4, which inactivates the incretin hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide. To assess its antidiabetic potency, we used meal tolerance tests (MTTs) to determine the very short-term effects of sitagliptin on plasma concentrations of insulin and glucagon. METHODS: On day 1, patients with newly diagnosed or uncontrolled type 2 diabetes mellitus started a calorie-restricted diet. On day 2, the first MTT was performed, before treatment with sitagliptin 50 mg/day started later the same day. On day 5, a second MTT was performed. Area under the concentration-time curves (AUCs) of relevant laboratory values were calculated [AUC from time zero to 2 h (AUC0-2h) and from time zero to 4 h (AUC0-4h)]. RESULTS: Fifteen patients were enrolled. AUCs for postprandial plasma glucose were decreased after 3 days of sitagliptin treatment [AUC0-2h 457 ± 115 mg/dL·h (25.4 ± 6.4 mmol/L·h) to 369 ± 108 mg/dL·h (20.5 ± 6.0 mmol/L·h); AUC0-4h 896 ± 248 mg/dL·h (49.7 ± 13.8 mmol/L·h) to 701 ± 246 mg/dL·h (38.9 ± 13.7 mmol/L·h); both p < 0.001]. AUC0-2h and AUC0-4h for postprandial plasma glucagon also decreased: 195 ± 57 to 180 ± 57 pg/mL·h (p < 0.05) and 376 ± 105 to 349 ± 105 pg/mL·h (p < 0.01), respectively. The AUC0-2h [median with quartile values (25%, 75%)] for active GLP-1 increased: 10.5 (8.5, 15.2) to 26.4 (16.7, 32.4) pmol/L·h (p = 0.03). CONCLUSIONS: Very short-term (3-day) treatment with sitagliptin decreases postprandial plasma glucose significantly. This early reduction in glucose may result partly from suppression of excessive glucagon secretion, through a direct effect on active GLP-1. Improvement in postprandial plasma glucose, through suppression of glucagon secretion, is believed to be an advantage of sitagliptin for the treatment of patients with type 2 diabetes.

Hepatocyte growth factor, a biomarker of macroangiopathy in diabetes mellitus.

Atherosclerotic involvements are an essential causal element of prospect in diabetes mellitus (DM), with carotid atherosclerosis (CA) being a common risk-factor for prospective crisis of coronary artery diseases (CAD) and/or cerebral infarction (CI) in DM subjects. From another point of view, several reports have supplied augmenting proof that hepatocyte growth factor (HGF) has a physiopathological part in DM involvements. HGF has been a mesenchymal-derived polyphenic factor which modulates development, motion, and morphosis of diverse cells, and has been regarded as a humor intermediator of epithelial-mesenchymal interplays. The serum concentrations of HGF have been elevated in subjects with CAD and CI, especially during the acute phase of both disturbances. In our study with 89 type 2 DM patients, the association between serum concentrations of HGF and risk-factors for macrovascular complications inclusive of CA were examined. The average of serum HGF levels in the subjects was more elevated than the reference interval. The serum HGF concentrations associated positively with both intimal-media thickness (IMT) (r = 0.24, P = 0.0248) and plaque score (r = 0.27, P = 0.0126), indicating a relationship between the elevated HGF concentrations and advancement of CA involvements. Multivariate statistical analysis accentuated that serum concentrations of HGF would be associated independently with IMT (standardized = 0.28, P = 0.0499). The review indicates what is presently known regarding serum HGF might be a new and meaningful biomarker of macroangiopathy in DM subjects.

Response of incretins (GIP and GLP-1) to an oral glucose load in female and male subjects with normal glucose tolerance.

The aim of this study was to analyze the blood glucose profile and the response of incretins in healthy young subjects by the 75 g oral glucose tolerance test (OGTT). We first reported that plasma glucose and GIP levels were higher in males during the early phase of the OGTT.

Profile of saxagliptin in the treatment of type 2 diabetes: focus on Japanese patients.

Saxagliptin is a selective and potent dipeptidyl peptidase (DPP)-4 inhibitor, approved as an adjunct to diet and exercise to improve glycemic control in type 2 diabetes mellitus (T2DM) in the USA on July 2009, and had been launched globally in over 86 countries by September 2013. In patients with T2DM, once-daily administration of saxagliptin before breakfast achieves sustained inhibition of plasma DPP-4 activity and reduction of postprandial hyperglycemia, including after dinner, associated with an increase in plasma glucagon-like peptide-1 levels. This paper reviews the safety and efficacy of saxagliptin in Japanese patients with T2DM. The clinical development study in Japan supported its usefulness for the disease. Saxagliptin 1, 2.5, and 5 mg led to significant improvements in glycated hemoglobin (HbA1c), and was generally well tolerated. Treatment with saxagliptin 5 mg induced a sustained reduction in HbA1c over 52 weeks. Long-term combination therapy with saxagliptin and other oral hypoglycemic agents also provided sustained glycemic control and was well tolerated for up to 52 weeks. Saxagliptin as add-on to sulfonylureas or glinides has a tendency to increase hypoglycemia, but not with other oral antidiabetic agents, such as α-glucosidase inhibitors, metformin, or thiazolidinediones. The results of clinical trials have confirmed the long-term efficacy and safety of saxagliptin monotherapy as well as its use as add-on combination therapy, and support its usefulness as a therapeutic agent for T2DM. Saxagliptin has less concern for hypoglycemia and weight gain, which often becomes problematic in routine care of T2DM. Meta-analysis of clinical trials in the USA showed no evidence of increased risk of cardiovascular events associated with saxagliptin, suggesting the superior of saxagliptin in terms of safety. Recently, investigators in the SAVOR-TIMI (Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus-Thrombolysis in Myocardial Infarction) 53 study suggested that DPP-4 inhibition with saxagliptin did not increase or decrease the rate of ischemic events, although the rate of hospitalization for heart failure was increased. Although saxagliptin improves glycemic control, other approaches are necessary to reduce cardiovascular risk in patients with diabetes. Saxagliptin is applicable for various pathological conditions, and is considered to be clinically significant as a new therapeutic option for Japanese patients with T2DM.

Medium-term effects of insulin degludec on patients with type 1 diabetes mellitus.

OBJECTIVE: The aim of this study was to analyze the changes in daily blood glucose fluctuation and insulin dose in patients with type 1 diabetes mellitus (T1DM) undergoing basal-bolus therapy following a switching of basal insulin used from insulin glargine or detemir to insulin degludec. METHODS: Seven patients with T1DM were enrolled. All patients treated with insulin glargine or detemir twice daily were switched to insulin degludec with 80-90 % of the prior insulin dose. During the study period, the basal insulin doses were adjusted by the attending physician. The patients underwent continuous glucose monitoring before, 3 days after, and 24 weeks after switching to insulin degludec. The daily insulin dose was analyzed before, 3 days after, and 24 weeks after switching. Glycated hemoglobin levels were measured before and 24 weeks after switching. RESULTS: The blood glucose profile did not change significantly before and after switching. On the other hand, the total daily insulin dose and total daily basal insulin dose decreased significantly 24 weeks after switching. DISCUSSION: In patients with T1DM undergoing insulin glargine or detemir treatment, it is possible to achieve similar glycemic control in the medium term with a once daily, lower dose of insulin degludec.

Effects of exenatide on metabolic parameters/control in obese Japanese patients with type 2 diabetes.

The effects of exenatide on glycemic control, lipid metabolism, blood pressure, and gastrointestinal symptoms were investigated in obese Japanese patients with type 2 diabetes mellitus. Twenty-six outpatients were enrolled and administered 5 µg of exenatide twice daily. If there was insufficient weight loss and/or insufficient improvement in glycemic control, the dose was increased to 10 µg twice daily. Follow-up was continued until the 12th week of administration. Hemoglobin A1c, glycoalbumin, fasting plasma glucose, body weight, fasting serum C-peptide, serum lipids, blood pressure, and pulse rate were measured before and after the observation period. In the initial phase of exenatide therapy, each patient received a diary to record gastrointestinal symptoms. During treatment with exenatide, hemoglobin A1c decreased significantly and serum C-peptide increased significantly. Body weight, low-density lipoprotein cholesterol, and systolic blood pressure decreased significantly. Nausea was the most frequent gastrointestinal symptom and occurred in 16 patients. Its onset was noted at a mean of 1.7 h after injection, the mean duration was 1.1 h, and it continued for a mean of 9.3 days after the initiation of administration. Patients with nausea showed a significant decrease in hemoglobin Alc, glycoalbumin, or body weight compared with those without nausea. These findings suggest that a more marked improvement in metabolic parameters by exenatide can be partly dependent on the manifestation of gastrointestinal symptoms.

A novel resting strategy for improving islet engraftment in the liver.

BACKGROUND: Several studies have revealed that posttransplant insulin treatment is beneficial to rest the islet grafts. However, insulin infusion per se is not enough to completely suppress the heavy workload arising caused by postprandial hyperglycemia. Therefore, the present study examined whether short-term fasting combined with insulin treatment could effectively prevent graft exhaustion after intraportal islet transplantation. METHODS: A marginal dose of syngeneic rat islet grafts were transplanted intraportally into the control, insulin-treated, and insulin+rest groups of streptozotocin-induced diabetic rats. The control group fed freely without insulin treatment, and the other groups were continuously treated with an optimal amount of insulin to maintain normoglycemia. In addition, the insulin+rest group fasted and received total parenteral nutrition during the 2 weeks after transplantation. RESULTS: The curative rate was significantly higher in both the insulin and insulin+rest groups than the control group (P<0.0001). The glucose tolerance, residual graft mass, and graft function were significantly ameliorated in the insulin+rest group, but not in the insulin group, compared to the control group (P<0.01, P=0.03, P=0.001). CONCLUSIONS: These data suggest that short-term fasting combined with insulin treatment, especially during the avascular period of the grafts, could therefore be a promising regimen for improving pancreatic islet engraftment in the liver.

Effects of switching from insulin glargine or detemir to insulin degludec in patients with type 1 diabetes mellitus.

INTRODUCTION: Insulin degludec is a new, ultra-long-acting basal insulin. The aim of this study was to analyze the changes of basal insulin dose and blood glucose profile in basal-bolus therapy of type 1 diabetes mellitus (T1DM) at the switching of basal insulin from insulin glargine or detemir to insulin degludec. METHODS: Sixteen patients with T1DM were enrolled. The patients underwent continuous glucose monitoring before and after the switching of insulin glargine or detemir to degludec. Ten patients treated with insulin glargine or detemir twice daily, were switched to insulin degludec with 80-90% of the prior insulin dose. The remaining six patients treated with insulin glargine once daily, were switched to insulin degludec without down titration. The changes of daily insulin dose and glycated hemoglobin (HbA1c) were also examined for 12 weeks after switching to insulin degludec. RESULTS: In the patients switched from twice-daily basal insulin, no significant difference was found between before and after switching in the blood glucose profile. In the once-daily group, blood glucose levels showed a tendency to decrease after switching to the degludec treatment. During the study period, total daily insulin dose (TDD) and total daily basal insulin dose (TBD) decreased significantly in the twice-daily group, and TDD and TBD showed a tendency to decrease after switching to degludec in the once-daily group. In both groups, the changes of HbA1c were not significantly different. CONCLUSION: It is possible to achieve similar glycemic control with once-daily injection and lower doses of insulin degludec in patients with T1DM who have been treated with insulin glargine or detemir.

Effects of combination therapy with mitiglinide and voglibose on postprandial plasma glucose in patients with type 2 diabetes mellitus.

Patients with diabetes mellitus are at increased risk from cardiovascular-related morbidity and mortality as compared with healthy individuals. An association between the postprandial metabolic state and atherogenesis has been observed in patients with diabetes mellitus. In the Study to Prevent Non-Insulin-Dependent Diabetes Mellitus (STOP-NIDDM), treatment with an α-glucosidase inhibitor (α-GI) in patients with impaired glucose tolerance not only reduced the rate of conversion from impaired glucose tolerance to type 2 diabetes mellitus (T2DM), but was also associated with a reduction in the risk of cardiovascular events. These results suggested the importance of treating postprandial hyperglycemia in the early stages of T2DM. Glinides are rapid and short-acting insulin secretagogues that bind to the sulfonylurea receptors on pancreatic ß-cells to facilitate rapid insulin secretion, restore postprandial early insulin secretion, and reduce the postprandial glucose spike. Moreover, α-GIs reduce postprandial hyperglycemia and insulin secretion by delaying the digestion of carbohydrates and polysaccharides in the small intestine. Then, both glinides and α-GI have beneficial effects for treating patients with T2DM and impaired glucose tolerance. Considering the ameliorating effects of these drugs on postprandial metabolic disorders, combinations of glinides and α-GI might constitute a promising therapeutic strategy for managing patients with T2DM, and also appear to be suitable for Japanese people, who consume more carbohydrates, such as polished rice, than Caucasians. It has recently been reported that combined use of mitiglinide and voglibose reduces postprandial insulin secretion and blunts diurnal glycemic changes in T2DM patients. This therapy can thus be regarded as being suitable for achieving strict postprandial glycemic control. In this report, we outline the effects of this combination therapy on postprandial plasma glucose and assess its safety.

Evaluation of a minimally invasive system for measuring glucose area under the curve during oral glucose tolerance tests: usefulness of sweat monitoring for precise measurement.

AIMS: We developed a system for measuring glucose area under the curve (AUC) using minimally invasive interstitial fluid extraction technology (MIET). Sweat contamination during interstitial fluid glucose (IG) extraction affects the accuracy of glucose AUC measurement, because this technology uses extracted sodium ion levels as an internal standard. Therefore, we developed a sweat monitoring patch to reduce this effect and investigated its efficacy in volunteers undergoing oral glucose tolerance tests (OGTTs). MATERIALS AND METHODS: Fifty diabetes mellitus inpatients and 10 healthy subjects undergoing the 75 g OGTT were included. Two sites on the forearm were pretreated with microneedle arrays, then hydrogels for interstitial fluid extraction were placed on the treated sites. Simultaneously, hydrogels for sweat monitoring were placed on untreated sites near the treated sites. Plasma glucose (PG) levels were measured every 30 min for 2 h to calculate reference AUC values. Using MIET, IG AUC was calculated from extracted glucose and sodium ion levels after attachment of the hydrogel for 2 h. RESULTS: Good correlation between IG AUC measurements using MIET and reference AUCs measured using PG levels was confirmed over a wide AUC range (202-610 mg/h/dl) after correction for the sweat-induced error detected by the hydrogel patches on the nonpretreated skin. Strong correlation between IG AUC and peak glucose levels indicates that glucose spikes can be easily detected by this system. CONCLUSION: We confirmed the effectiveness of a sweat monitoring patch for precise AUC measurement using MIET. This novel, easy-to-use system has potential for glucose excursion evaluation in daily clinical practice.

Add-on therapy with the DPP-4 inhibitor sitagliptin improves glycemic control in insulin-treated Japanese patients with type 2 diabetes mellitus.

The effect of add-on therapy with sitagliptin on glycemic control was prospectively investigated in patients with type 2 diabetes mellitus (T2DM) receiving insulin alone or insulin combined with oral antidiabetic drugs. Seventy-one patients were evaluated (38 men and 33 women aged 63.9 ± 10.2 years). They were divided into three groups, which were 45 patients receiving premixed insulin twice daily, 15 patients receiving multiple daily insulin injections, and 11 patients receiving basal insulin with oral antidiabetic drugs (basal insulin therapy). Concomitant oral drugs included sulfonylureas, α-glucosidase inhibitors and metformin. The hemoglobin A1c (HbA1c) of all patients improved significantly from 8.1 ± 1.2% to 7.6 ± 1.1% after 12 weeks of add-on therapy with sitagliptin (p<0.01), and the insulin dosage was reduced from 27.3 ± 15.8 U/day to 24.5 ± 16.5 U/day (p<0.001). Body weight did not change after the start of concomitant therapy and severe hypoglycemia was not observed. The baseline HbA1c and glycated albumin levels were identified as factors that predicted the response to add-on therapy with sitagliptin. These findings suggest that add-on therapy with sitagliptin can be expected to achieve improvement of poor glycemic control irrespective of a patient's demographic profile. Stratified analysis based on the insulin regimen revealed a stronger antidiabetic effect and a high efficacy of sitagliptin when it was added to basal insulin therapy. The results of this investigation confirmed that add-on therapy with sitagliptin to various insulin regimens could improve glycemic control without severe hypoglycemia and/or weight gain.

New strategy for the treatment of type 2 diabetes mellitus with incretin-based therapy.

Incretin-based therapy was first made available for the treatment of type 2 diabetes mellitus (T2DM) in the US in 2006 and in Japan in 2009. Four DPP-4 inhibitors and two GLP-1 analog/receptor agonists are currently available. The effects of incretin-based therapy are assumed to be exerted mainly through the hormonal and neuronal actions of one of the incretins, GLP-1, which is secreted from L cells localized in the small intestine. The benefits of this therapy over conventional sulfonylureas or insulin injections, such as fewer hypoglycemic events and reduced body weight gain, derive from the glucose-dependent insulinotropic effect. The protective effects of this therapy on vulnerable pancreatic ß-cells and against micro/macroangiopathy in T2DM are also most welcome. Indications and/or contraindications for incretin-based therapy should be clarified by prospectively studying the experiences of Japanese T2DM patients undergoing this therapy in the clinical setting.