Yoshiki Kusunoki

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 β-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.

Effects of the naturally-occurring disaccharides, palatinose and sucrose, on incretin secretion in healthy non-obese subjects.

Incretins might play some pathophysiological role in glucose metabolism in diabetes and obesity; it is not clear whether or not the amount and the pattern of incretin secretion vary with different types of sugars. To evaluate the effect of two types of disaccharides on glucose metabolism and the kinetics of incretin secretion, plasma levels were measured after palatinose or sucrose ingestion in non‐obese healthy participants.

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 β = 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.

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.

Xanthine oxidoreductase activity is correlated with insulin resistance and subclinical inflammation in young humans

BACKGROUND AND AIMS The enzyme xanthine oxidoreductase (XOR) catalyzes the formation of uric acid (UA) from hypoxanthine and xanthine, which in turn are products of purine metabolism starting from ribose-5-phosphate. Besides the synthesis of UA, basic research has suggested that XOR is involved in the regulation of reactive oxygen species, adipogenesis, and peroxisome proliferator-activated receptor-γ (PPAR-γ). XOR activity has shown to be much lower in humans than in rodents, which makes its accurate measurement difficult. Recently, a novel human plasma XOR activity assay has been established using a combination of liquid chromatography (LC) and triple quadrupole mass spectrometry (TQMS) to detect [13C2,15N2]UA using [13C2,15N2]xanthine as a substrate. Using this novel assay, we for the first time determine plasma XOR activity in humans, and evaluate its association with insulin resistance, high-sensitivity C-reactive protein (hsCRP) levels, and other parameters. METHODS Of the 29 volunteers who wished to participate in the study, 3 were excluded; of the remaining, 11 were female and 15 were male with a mean age of 25.9±3.3years. Blood samples were collected under fasting conditions in the early morning to measure XOR activity and other parameters. RESULTS The natural logarithmic value of XOR activity (ln-XOR) in plasma was 3.4±0.8pmol/h/mL. Ln-XOR had a positive correlation with UA and body mass index (BMI) and a negative correlation with quantitative insulin sensitivity check index (QUICKI) and adiponectin. In addition, ln-XOR had a positive correlation with hsCRP levels, which serves as a marker of chronic inflammation. CONCLUSIONS The present study has shown that XOR activity is correlated with serum UA levels in humans. Furthermore, even in young subjects, XOR activity is correlated with insulin resistance, BMI, and subclinical inflammation. Thus, XOR activity may be potentially involved in adiposity and subclinical inflammation in humans.

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

Abstract 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-AUC0–120 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/m2, mean sensor glucose by CGM was 94.2 ± 10.3 mg/dL, standard deviation was 17.5 ± 4.4 mg/dL, and CGM-AUC0–120 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-AUC0–120 min. The disposition index (DI), which was used to evaluate insulin secretion, was negatively correlated with CGM-AUC0–120 min. Conclusions: Not only insulin resistance but also beta cell dysfunction contributes to postprandial hyperglycemia in Japanese patients with GDM.

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.

Incretin responses to oral glucose load in Japanese non-obese healthy subjects

IntroductionRecently, incretin-related therapy has been developed for the new treatment of diabetes mellitus; however, incretin response to glucose ingestion in normal glucose tolerant (NGT) subjects has not been clarified in detail with special reference to the role of incretin hormones, glucagon, and a family history of diabetes.MethodsWe conducted a 75 g oral glucose tolerance test in 30 NGT subjects.ResultsThe total glucose-dependent insulinotropic peptide (GIP)-AUC0–120 (area under the curve over a period of 0–120 minutes) was correlated with immunoreactive insulin (IRI)-AUC0–120 (P<0.05), insulinogenic index (II; P<0.05), ΔIRI between 0 and 120 minutes (P<0.05). Active glucagon-like peptide-1 (GLP-1) AUC0–120 was correlated inversely both with Δ glucose between 0 and 30 minutes (P<0.01) and with Δ immunoreactive glucagon between 0 and 30 minutes (P<0.05). Δ Total GIP between 0 and 15 minutes (P<0.01), Δ total GIP between 0 and 30 minutes (P<0.05), and the total GIP-AUC0–120 (P<0.05) in the subjects with a family history of type 2 diabetes were significantly higher than those in the subjects without a family history.ConclusionThese results suggest that GIP possibly facilitates insulin secretion in response to oral glucose load directly and active GLP-1 may exert the glucoregulatory action via the suppression of glucagon secretion in NGT subjects. Notably, the subjects with a family history of diabetes exert significantly higher GIP response in the early phase of glucose load compared with those without a family history.

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.

A case of type 1 diabetes mellitus with which localized insulin allergy was markedly alleviated by switching to insulin glulisine

There have been numerous reports of allergies with causes such as differences in the amino acid sequences between human insulin and insulin extracted from porcine and bovine pancreas. Insulin allergy leads to deterioration of blood glucose control and decrease in quality of life. However, the availability of genetically recombinant human insulin formulations has led to insulin allergy becoming uncommon [1], and such allergies also occur much more rarely when insulin analog formulations are administered. The present report is about a patient who showed allergic reactions to various insulin formulations, but showed only a weak allergic reaction to insulin glulisine, so the symptoms of insulin allergy ceased when treatment was switched to insulin glulisine.