Ko Ishikawa

Neuropathic pain is associated with increased nodal persistent Na+ currents in human diabetic neuropathy

Abstract Peripheral nerve injury alters function and expression of voltage gated Na+ channels on the axolemma, leading to ectopic firing and neuropathic pain/paresthesia. Hyperglycemia also affects nodal Na+ currents, presumably due to activation of polyol pathway and impaired Na+–K+ pump. We investigated changes in nodal Na+ currents in peripheral sensory axons and their relation with pain in human diabetic neuropathy. Latent addition using computerized threshold tracking was used to estimate nodal persistent Na+ currents in radial sensory axons of 81 diabetic patients. Of these, 36 (44%) had chronic neuropathic pain and severe paresthesia. Compared to patients without pain, those with pain had greater nodal Na+ currents (p = 0.001), smaller amplitudes of sensory nerve action potentials (SNAP) (p = 0.0003), and lower hemoglobin A1c levels (p = 0.006). Higher axonal Na+ conductance was associated with smaller SNAP amplitudes (p = 0.03) and lower hemoglobin A1c levels (p = 0.008). These results suggest that development of neuropathic pain depends on axonal hyperexcitability due to increased nodal Na+ currents associated with structural changes, but the currents could also be affected by the state of glycemic control. Our findings support the view that altered Na+ channels could be responsible for neuropathic pain/paresthesia in diabetic neuropathy.

Efficacy and safety of the dipeptidyl peptidase-4 inhibitor sitagliptin compared with α-glucosidase inhibitor in Japanese patients with type 2 diabetes inadequately controlled on sulfonylurea alone (SUCCESS-2): a multicenter, randomized, open-label, non-inferiority trial.

We assessed the efficacy and safety of sitagliptin compared with α‐glucosidase inhibitor (αGI) in 120 of Japanese patients with type 2 diabetes mellitus (T2DM) inadequately controlled on stable ≤2 mg/day glimepiride alone [mean hemoglobin A1c (HbA1c) 7.7%] by the randomized, active‐controlled, non‐inferiority trial. Patients were randomly assigned to receive additional sitagliptin or αGI for 24 weeks. The primary endpoint was change in HbA1c from baseline to week 12. After 12 weeks, sitagliptin reduced HbA1c by −0.44% (p < 0.001) relative to αGI. At 24 weeks, the reduction was almost identical between the groups (−0.091%, p = 0.47). Gastrointestinal disorders were more common with αGI than with sitagliptin, but only minor hypoglycaemia occurred in both groups at similar frequency. These data suggested that sitagliptin was not inferior to αGI for reduction of HbA1c in Japanese T2DM patients receiving glimepiride alone, and well tolerated with minimum risk of gastrointestinal symptoms and hypoglycaemia.

Brown adipose tissue in the treatment of obesity and diabetes: Are we hot enough?

The identification of functional brown adipose tissue in human adults has intensified interest in exploiting thermogenic energy expenditure for the purpose of weight management. However, food intake and energy expenditure are tightly regulated and it is generally accepted that variation in one component results in compensatory changes in the other. In the context of weight loss, additional biological adaptations occur in an attempt to further limit weight loss. In the present review, we discuss the relationship between increasing energy expenditure and body weight in humans, including the effects of cold exposure. The data raise the possibility that some processes, particularly those involved in thermogenesis, induce less compensatory food intake for a given magnitude of additional energy expenditure, a state we term the ‘thermogenic disconnect’. Although cold exposure increases thermogenesis and can putatively be exploited to induce weight loss, there are multiple adaptive responses to cold, of which many actually reduce energy expenditure. In order to optimally exploit either cold itself or agents that mimic cold for thermogenic energy expenditure, these non‐thermogenic cold responses must be considered. Finally, the relative contribution of brown adipose tissue vs other thermogenic processes in humans remains to be defined. However, overall the data suggest that activation of cold‐induced thermogenic processes are promising targets for interventions to treat obesity and its secondary metabolic complications. (J Diabetes Invest, doi:10.1111/j.2040‐1124.2011.00158.x, 2011)

Accelerated oligosaccharide absorption and altered serum metabolites during oral glucose tolerance test in young Japanese with impaired glucose tolerance

Impaired glucose tolerance (IGT) is a subtype of prediabetes, a condition having high risk for development to diabetes mellitus, but its pathophysiology is not fully understood. In the present study, we examined metabolic changes in IGT by using two types (D‐glucose [Glc] and partial hydrolysate of starch [PHS]) of oral glucose tolerance tests (OGTTs), with emphasis on serum incretins and metabolites.

The anti-ulcer agent, irsogladine, increases insulin secretion by MIN6 cells.

Insulin secretion by pancreatic islets is a multicellular process. In addition to other essential systems, gap junctions are an important component of cell-to-cell communication in pancreatic islets. It is well known that dysfunction of gap junctions causes inappropriate insulin secretion. The anti-ulcer agent, irsogladine, increases gap junctions in some cell types. To examine the effect of irsogladine on insulin secretion, we investigated insulin secretion by MIN6 cells treated with or without irsogladine. The expression of connexin 36 proteins and intracellular cAMP levels were also determined using immunoblotting and ELISA assays, respectively. Irsogladine had no effect on insulin secretion under 5.6mM glucose conditions. However, under 16.7 mM glucose conditions, irsogladine (1.0 × 10(-5)M) induced a 1.7 ± 0.20 fold increase in insulin secretion compared to the control (P<0.05). This effect of irsogladine on insulin secretion was inhibited by the addition of the gap junction inhibitor 18-beta-glycyrrhetinic acid. Irsogladine treatment increased the protein level of connexin 36 in the plasma membrane fraction. The intracellular cAMP level in MIN6 cells was significantly, but mildly, increased by irsogladine treatment. Furthermore, Rp-cAMP and H89 inhibited the effects of irsogladine on insulin secretion under high glucose conditions. Irsogladine increases insulin secretion under high glucose conditions. The up-regulation of gap junction channels and the increased level of intracellular cAMP induced by irsogladine treatment suggest that these phenomena are involved in irsogladine-induced increased insulin secretion.

Exploration of predictive metabolic factors for gestational diabetes mellitus in Japanese women using metabolomic analysis

We aimed to explore novel predictive markers for gestational diabetes mellitus using metabolomic analysis in pregnant Japanese women.

Postpartum risk of diabetes and predictive factors for glucose intolerance in East Asian women with gestational diabetes

AIMS Women with a history of gestational diabetes mellitus (GDM) are likely to develop postpartum diabetes mellitus (DM). We examined women in the early stages of pregnancy who were at high risk of postpartum DM progression to establish a follow-up method for early detection. METHODS We performed the oral glucose tolerance test (OGTT) and identified predictive factors for postpartum impaired glucose tolerance (IGT) or DM in 77 women after GDM, for 2 years after delivery, retrospectively. Cutoff values for each factor were determined. We classified these women with GDM into four groups using these predictive factors and evaluated postpartum glucose intolerance (GI) in each group. RESULTS In total, 44.1% of the women with a GDM history had developed postpartum GI within 2 years. We determined three risk factors for postpartum GI: elevated glucose level 120 min after a 75-g OGTT (Glu120), elevated glycated hemoglobin (HbA1c) level at diagnosis, and perinatal complications. The cutoff Glu120 and the HbA1c level were 155 mg/dl and 5.3% (34 mmol/mol), respectively. Type 2 DM developed in 53.8% of women, and IGT developed in 38.5% of women within 2 years in groups with high Glu120 and high HbA1c. CONCLUSIONS High-risk groups require careful follow-up observation.

Efficacy and safety of ipragliflozin and metformin for visceral fat reduction in patients with type 2 diabetes receiving treatment with dipeptidyl peptidase-4 inhibitors in Japan: a study protocol for a prospective, multicentre, blinded-endpoint phase IV randomised controlled trial (PRIME-V study)

Introduction In Japan, dipeptidyl peptidase-4 (DPP-4) inhibitors are frequently used as the treatment of choice for patients with type 2 diabetes. In some cases, however, poor glycaemic and body weight control issues persist despite treatment with DPP-4 inhibitors. Previous researchers have revealed that sodium-dependent glucose transporter-2 (SGLT-2) inhibitors reduce both plasma glucose levels and body weight in patients with type 2 diabetes. However, further investigation regarding the effects of SGLT-2 inhibitors on body composition, especially in the Asian population who tends to have relatively low-to-moderate body mass indices, is required. Therefore, we aim to determine the effects of treatment with SGLT-2 inhibitors or metformin for reducing visceral fat in 106 Asian patients with type 2 diabetes who were undergoing treatment with the DPP-4 inhibitor sitagliptin (50 mg daily) for poor glycaemic control. Methods and analysis A prospective, multicentre, blinded-endpoint phase IV randomised controlled study will be conducted to evaluate the safety and efficacy of a 24-week treatment with either an SGLT-2 inhibitor (ipragliflozin) or metformin for reducing visceral fat and plasma glucose levels in patients with type 2 diabetes. Patients who satisfy the eligibility criteria will be randomised (1:1) to receive ipragliflozin (50 mg daily) or metformin (1000 mg daily). The primary outcome is the rate of change in the total area of visceral fat for patients in both treatment groups, measured using CT, after 24 weeks of therapy. Two radiologists, blinded to the clinical information, will perform centralised analysis of the images in a unified measurement condition. Ethics and dissemination The protocol was approved by the institutional review board of each hospital. This study is ongoing and due to finish in April 2017. The findings of this study will be disseminated via peer-reviewed publications and conference presentations, and will also be disseminated to participants. Trial registration number UMIN000015170, R000016861 (https://upload.umin.ac.jp/cgi-open-bin/ctr/ctr_view.cgi?recptno=R000016861); Pre-results

A Case of Type 1 Diabetes With Nocturnal Hypoglycemia After Desensitization Therapy for Insulin Allergy

Antibodies against exogenously injected insulin are common with insulin treatment but seldom have serious effects on blood glucose (1). In insulin autoimmune syndrome (IAS), however, the insulin antibody causes hypoglycemia (2) in the absence of exogenous insulin treatment. Here, we report a case of type 1 diabetes with insulin antibody, whereby the patient developed nocturnal hypoglycemia after desensitization therapy for an insulin allergy. After receiving insulin therapy for 1 year, a 61-year-old man was admitted to our hospital because of an insulin allergy and poor control of diabetes. He had an itchy eruption at the insulin injection site. At the time of admission, the patient presented with an HbA1c level of 16.2% (154 mmol/mol); anti-GAD antibody 80.0 U/L (<1.5 U/mL); serum C-peptide level 0.01 ng/mL after glucagon injection (fasting 0.67–2.48 ng/mL); and insulin-specific IgE 41.5 UA/mL (<0.34 …