Ryota Usui

Predicting efficacy of dipeptidyl peptidase-4 inhibitors in patients with type 2 diabetes: Association of glycated hemoglobin reduction with serum eicosapentaenoic acid and docosahexaenoic acid levels

This study was initiated to identify clinical and dietary parameters that predict efficacy of dipeptidyl peptidase‐4 inhibitors. A total of 72 untreated Japanese patients with type 2 diabetes who received DPP‐4 inhibitors (sitagliptin, alogliptin or vildagliptin) for 4 months were examined for changes of glycated hemoglobin (HbA1c) and body mass index (BMI), and self‐administered 3‐day food records, as well as serum levels of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). DPP‐4 inhibitors significantly reduced HbA1c (before initiation of DPP‐4 inhibitors 7.2 ± 0.7%, 4 months after initiation of DPP‐4 inhibitors 6.7 ± 0.6% [paired t‐test, P < 0.01 vs before]). Multiple regression analysis showed that changes of HbA1c were significantly correlated with baseline HbA1c, as well as estimated intake of fish. Furthermore, changes of HbA1c were significantly correlated with serum levels of EPA (r = −0.624, P < 0.01) and DHA (r = −0.577, P < 0.01). HbA1c reduction by DPP‐4 inhibitors is significantly correlated with estimated intake of fish and serum levels of EPA and DHA. (J Diabetes Invest, doi: 10.1111/j.2040‐1124.2012.00214.x, 2012)

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

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 (HbA1c) and bodyweight in Japanese type 2 diabetes.

Glucagon-like peptide-1 receptor agonist therapeutics for total diabetes management: assessment of composite end-points

Abstract Assessment of the benefits of anti-diabetic drugs for type 2 diabetes requires analysis of composite end-points, taking HbA1c, bodyweight, hypoglycemia and other metabolic parameters into consideration; continuous, optimal glycemic control as well as bodyweight, blood pressure and lipid levels are critical to prevent micro- and macro-vascular complications. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are now established as an important total treatment strategy for type 2 diabetes, exerting glucose-lowering effects with little hypoglycemia risk and also ameliorating bodyweight, blood pressure and lipid levels, which are therapeutic targets for prevention of complications of the disease. The available data strongly suggest only beneficial effects of GLP-1RAs; however, long-term evaluation of the relevant composite end-points including health-related quality of life and cost-effectiveness remain to be investigated in adequately powered, prospective, controlled clinical trials. In the meantime, healthcare professionals need to be scrupulously attentive for potential, rare adverse events in patients using GLP-1RAs.

Retrospective analysis of safety and efficacy of liraglutide monotherapy and sulfonylurea-combination therapy in Japanese type 2 diabetes: Association of remaining β-cell function and achievement of HbA1c target one year after initiation

AIMS The GLP-1 receptor agonist liraglutide improves impaired pancreatic β-cell function, thereby exerting glucose-lowering effects. However, the association of remaining β-cell function with long-term therapeutic efficacy of liraglutide remains largely unknown. METHODS Patients with type 2 diabetes who started liraglutide as monotherapy or sulfonylurea-combination therapy were retrospectively analyzed to identify possible associations of indices related to β-cell function including increments of C-peptide immunoreactivity in glucagon stimulation test (GST-ΔCPR) with achievement of HbA1c <7.0% at 54weeks after liraglutide initiation. RESULTS Among 165 subjects continuing liraglutide for 54weeks, 66 received additional oral anti-diabetic drugs (OADs) during the period. Of those continuing liraglutide without receiving additional OADs, 41 subjects achieved HbA1c <7.0% at 54weeks, while 49 subjects did not. Subjects achieving HbA1c <7.0% showed higher values of GST-ΔCPR. Receiver-operating analysis revealed 2.34ng/mL as the cut-off value for HbA1c <7.0% achievement in these subjects. Subjects with GST-ΔCPR >2.34ng/mL showed continuous and substantial HbA1c reduction throughout the 54weeks. In Kaplan-Meier analysis, subjects with GST-ΔCPR >2.34ng/mL showed longer therapeutic durability of initial liraglutide therapy with no additional OADs or insulin. CONCLUSIONS Despite numerous limitations, these results indicate that long-term efficacy of liraglutide is associated with remaining β-cell function at initiation.

Enhanced glucagon-like peptide-1 secretion in a patient with glucagonoma: Implications for glucagon-like peptide-1 secretion from pancreatic α cells in vivo

We examined GLP-1 secretion from the pancreas of a patient with glucagonoma and pancreatic resection by measuring GLP-1 after meal ingestion or selective arterial calcium injection, and immunohistochemical analysis. Our findings support the notion that GLP-1 is secreted from pancreatic α cells in humans.

Src regulates insulin secretion and glucose metabolism by influencing subcellular localization of glucokinase in pancreatic β‐cells

Src, a non‐receptor tyrosine kinase, regulates a wide range of cellular functions, and hyperactivity of Src is involved in impaired glucose metabolism in pancreatic β‐cells. However, the physiological role of Src in glucose metabolism in normal, unstressed β‐cells remains unclear. In the present study, we investigated the role of Src in insulin secretion and glucose metabolism.

Reply to the comment of Wilbrink et al. on Retrospective analysis of liraglutide and basal insulin combination therapy in Japanese type 2 diabetes: The association between remaining β-cell function and the achievement of the HbA1c target 1 year after init

We have reported that the HbA1c‐lowering effects of liraglutide/basal insulin combination rely on remaining β‐cell function and that the cut‐off value of the C‐peptide immunoreactivity index (CPI), a β‐cell function‐related index frequently used in Japanese clinical settings, is 1.103 for the achievement of HbA1c <7.0% at 54 weeks after initiating the liraglutide/basal insulin combination. Wilbrink et al claimed that glucose‐lowering effects of glucagon‐like peptide‐1 receptor agonist liraglutide depend of duration of type 2 diabetes; while our resent study published in the Journal of Diabetes Investigation failed to detect such dependency. This discrepancy might be due to several reasons including co‐administration of basal insulin with liraglutide in our study; ethnic difference in T2D pathophysiology between the two study; and difference in sample size (The Usui study on liraglutide/basal insulin, n = 38; the Usui study on liraglutide monotherapy or SU combination, n=88; and the Wilbrink study, n = 69).

Relationship between deterioration of glycated hemoglobin‐lowering effects in dipeptidyl peptidase‐4 inhibitor monotherapy and dietary habits: Retrospective analysis of Japanese individuals with type 2 diabetes

The present study was designed to assess possible relationships between deterioration of the glycated hemoglobin (HbA1c)‐lowering effects in dipeptidyl peptidase‐4 inhibitor (DPP4i) monotherapy and macronutrient intake among individuals with type 2 diabetes. Type 2 diabetes patients who began and continued DPP4i monotherapy without any prescription change for 1 year were retrospectively stratified into two groups: (i) patients who maintained their HbA1c levels during the 0.5‐ to 1‐year period after DPP4i initiation (group A, ΔHbA1c [1–0.5 year] <0.4%, n = 53); and (ii) those whose HbA1c levels increased [group B, ΔHbA1c (1–0.5 year] ≥0.4%, n = 10). Group B had significantly higher ΔHbA1c (1–0.5 year), Δbodyweight (1–0.5 year) and fat intake, especially of saturated and monounsaturated fats; the carbohydrate and protein intake were similar between groups. Multiple regression analyses showed that fat intake, especially saturated fat intake, was significantly correlated with ΔHbA1c (1–0.5 year). Thus, dietary habits, especially saturated fat intake, might well contribute to deterioration of the HbA1c‐lowering effects in DPP4i monotherapy.

Retrospective analysis of liraglutide and basal insulin combination therapy in Japanese type 2 diabetes patients: The association between remaining β-cell function and the achievement of the glycated hemoglobin target 1 year after initiation

The glucose‐lowering effects of the glucagon‐like peptide‐1 receptor agonist, liraglutide, have been shown to rely on remaining β‐cell function. However, the possible associations of remaining β‐cell function with the glucose‐lowering effects of liraglutide in combination with basal insulin remain unknown and warrant investigation.

Sphingosine kinase 1-interacting protein is a novel regulator of glucose-stimulated insulin secretion

Glucose-stimulated insulin secretion (GSIS) is essential in keeping blood glucose levels within normal range. GSIS is impaired in type 2 diabetes, and its recovery is crucial in treatment of the disease. We find here that sphingosine kinase 1-interacting protein (SKIP, also called Sphkap) is highly expressed in pancreatic β-cells but not in α-cells. Intraperitoneal glucose tolerance test showed that plasma glucose levels were decreased and insulin levels were increased in SKIP−/− mice compared to SKIP+/+ mice, but exendin-4-enhanced insulin secretion was masked. GSIS was amplified more in SKIP−/− but exendin-4-enhanced insulin secretion was masked compared to that in SKIP+/+ islets. The ATP and cAMP content were similarly increased in SKIP+/+ and SKIP−/− islets; depolarization-evoked, PKA and cAMP-mediated insulin secretion were not affected. Inhibition of PDE activity equally augmented GSIS in SKIP+/+ and SKIP−/− islets. These results indicate that SKIP modulates GSIS by a pathway distinct from that of cAMP-, PDE- and sphingosine kinase-dependent pathways.