The Eradication of Helicobacter pylori does not Affect Glycemic Control in Japanese Subjects with Type 2 Diabetes.

Since infection with Helicobacter pylori has been suggested to play a pathogenic role in diabetes mellitus, we investigated whether eradication therapy for H. pylori might affect glycemic control in Japanese subjects with type 2 diabetes. A total of 72 subjects (55 males, 17 females; aged 63.7 years) with type 2 diabetes who received eradication therapy for H. pylori were included. The change of their blood glycosylated hemoglobin (A1C) levels 3 months before (-3 m) the H. pylori eradication, as well as 3 months (3 m) and 6 months (6 m) after were evaluated. Their A1C levels did not show any significant change after therapy {6.9 [0.1]% (-3 m) to 7.0 [0.1]% (3 m); P = 0.3, 7.0 [0.1] (6 m); P = 0.3}. Our findings suggest that the eradication therapy for H. pylori does not, at least profoundly, affect glycemic control in Japanese subjects with type 2 diabetes.

Safety, humoral and cell-mediated immune responses to herpes zoster vaccine in subjects with diabetes mellitus.

OBJECTIVE: To evaluate varicella zoster virus-specific cell-mediated immunity and humoral immunogenicity against the herpes zoster vaccine, which is licensed as the Live Varicella Vaccine (Oka Strain) in Japan, in elderly people with or without diabetes mellitus. METHODS: A pilot study was conducted between May 2010 and November 2010 at Kitano Hospital, a general hospital in the city of Osaka in Japan. A varicella skin test, interferon-gamma enzyme-linked immunospot assay and immunoadherence hemagglutination tests were performed 0, 3, and 6 months after vaccination. Vaccine safety was also assessed using questionnaires for 42 days and development of zoster during the one-year observational period. We enrolled 10 healthy volunteers and 10 patients with diabetes mellitus aged 60-70 years. RESULTS: The live herpes zoster vaccine boosted virus-specific, cell-mediated and humoral immunity between elderly people, with or without diabetes. Moreover, no systemic adverse reaction was found. None of the study participants developed herpes zoster. CONCLUSION: The live herpes zoster vaccine was used safely. It effectively enhanced specific immunity to varicella zoster virus in older people with or without diabetes mellitus.

Less variation of R-R interval of electrocardiogram in nonobese type 2 diabetes with nocturnal intermittent hypoxia.

Obesity is a major risk factor for sleep-disordered breathing (SDB). However, many Japanese subjects with diabetes are less obese despite compared with Caucasian. We evaluated the relationship between SDB and clinical characteristics other than obesity, especially in relation to cardiac autonomic neuropathy (CAN) in Japanese subjects with diabetes. The study included a total of 261 consecutive Japanese subjects with type 2 diabetes, including nonobese subjects defined as BMI <25 kg/m² for Japanese. SDB was screened by 4% oxygen desaturation index (ODI) level of 5 or more events per hour, which was measured by nocturnal pulse oximetry. CAN was examined with the variation of R-R intervals (CVRR). The SDB were found in 24.5% of total subjects and 16.3% of nonobese subjects with type 2 diabetes, respectively. The nonobese type 2 diabetes subjects with SDB had significantly lower coefficient of CVRR than those without SDB. Multiple regression analysis revealed that BMI and heart rate were significant independent factors for SDB in total subjects with type 2 diabetes, but CVRR was the only significant independent factor for SDB in nonobese subjects with type 2 diabetes. These findings suggest that the presence of SDB should be kept in mind in type 2 diabetic patients with abnormality in CVRR variation in electrocardiogram even though they are not obese.

Possible link of pioglitazone with bladder cancer in Japanese patients with type 2 diabetes.

We retrospectively examined the frequency of bladder cancer in Japanese patients with type 2 diabetes in relation to use of pioglitazone. Among a total of 663 patients identified to be taking pioglitazone, 9 had bladder cancer (1.36%). Overall the hazard ratio of 1.75 [95% CI: 0.89-3.45] for pioglitazone for bladder cancer was not significant. However the prevalence of bladder cancer was 2.10% in patients taking pioglitazone for less than 24 months which was significant increased (HR 2.73 [95% CI: 1.11-6.72]).

Relationship between telmisartan dose and glycaemic control in Japanese patients with type 2 diabetes mellitus and hypertension: a retrospective study.

BACKGROUND AND OBJECTIVES: Telmisartan has been reported to have beneficial effects on insulin resistance and lipid profiles by acting as a peroxisome proliferator-activated receptor-γ (PPARγ) agonist. In this study we investigated the relationship between telmisartan dose and glycaemic control in Japanese subjects with type 2 diabetes mellitus and hypertension. METHODS: Patients (n = 263) who were prescribed telmisartan 20, 40 or 80 mg/day at our clinic were retrospectively identified from our clinical database. Only patients without changes in their treatments for diabetes and hypertension for 6 months after starting telmisartan were included in this study. Glycosylated haemoglobin A(1c) (HbA(1c)) levels were measured at 0, 3 and 6 months after starting telmisartan. RESULTS: At 3 and 6 months after starting telmisartan, HbA(1c) levels were significantly decreased in patients treated with telmisartan 40 or 80 mg/day but not in patients treated with telmisartan 20 mg/day (mean ± standard error change at 6 months: -0.29 ± 0.10%, p < 0.001; -0.48 ± 0.15%, p < 0.001; and -0.03 ± 0.10%, p = 0.33; respectively). When patients were classified into two groups by telmisartan dose (20 vs ≥40 mg/day), there was no significant correlation between baseline HbA(1c) and change in HbA(1c) levels over time in the 20 mg/day group. However, in patients treated with ≥40 mg/day of telmisartan, baseline HbA(1c) was negatively correlated with the change in HbA(1c) at 6 months. Multiple regression analysis confirmed that baseline HbA(1c) and telmisartan dose were the predictive factors. CONCLUSION: Our results suggest that telmisartan influences glycaemic control in a dose-dependent manner; doses ≥40 mg/day may be needed to improve glycaemic control. Our data also suggest that patients with higher baseline HbA(1c) may experience greater improvements in glycaemic control with telmisartan.

A case of diabetic ketoacidosis associated with Guillain-Barré syndrome.

A 64-year-old woman was referred to our center presenting with thirst, malaise, and pain in both legs which occurred one week before admission. She was revealed to have hyperglycemia and diabetic ketoacidosis (DKA). After therapy for diabetic ketoacidosis was started, her blood glucose levels were improved, but urinary ketone body excretion persisted. Laboratory examination indicated a significant impairment of insulin secretion, although anti-GAD and anti-IA-2 antibody were not detected. After admission, she complained about weakness of lower extremities, which spread to her upper extremities. The diagnosis of Guillain-Barré syndrome (GBS) was made based on the nerve conduction study and cerebrospinal fluid analysis. The intravenous immunoglobulin therapy was started, and her muscle weakness showed gradual improvement. Although the possibility that GBS was casually accompanied with DKA could not be completely excluded, we considered that DKA triggered the development of GBS in this case. Although GBS is a rare condition, the present case suggests that GBS should be included in the differential diagnosis of DKA with its atypical course.

Lymphocytic panhypophysitis: its clinical features in Japanese cases.

Lymphocytic hypophysitis is divided into three forms according to the involved tissues, lymphocytic adenohypophysitis, lymphocytic infundibulo-neurohypophysitis, and lymphocytic panhypophysitis (LPH). The term LPH was first proposed by us in 1995, although its entity and pathogenesis still remain controversial. Here we report five cases of LPH, who visited our clinics during 1994 to 2009. All cases were female of 20 to 77 years of age, and one case was associated with pregnancy. They presented with polyuria (n = 4), headache (n = 3), general malaise, polydipsia (n = 2), blunted vision, diplopia, amenorrhea or appetite loss (n = 1). Magnetic resonance imaging showed the pituitary swelling, the thickened stalk, the loss of the T1 hyperintense neurohypophysis (n = 4), or the atrophic pituitary (n = 1). Endocrinological examinations revealed deficiencies of TSH, ADH in all cases, GH, ACTH in three cases, LH, PRL in two cases, and FSH in one case, respectively. The severity of ADH deficiency varied among the cases. Anti-pituitary antibody was not detected in the cases examined. The biopsy of the pituitary lesions was performed except for one case, all of which revealed the diffuse lymphocytic infiltration. These results suggest that LPH is characterized by the female predominance, the atypical patterns of anterior pituitary hormone deficiencies and the variable degrees of diabetes insipidus in Japanese.

Japanese cases of acute onset diabetic ketosis without acidosis in the absence of glutamic acid decarboxylase autoantibody.

We report consecutive Japanese patients presented with acute onset diabetic ketosis who had negative glutamic acid decarboxylase autoantibody (GADAb) to clarify the clinical characteristics of them. A total of consecutive 1,296 in-patients with newly diagnosed diabetes mellitus, who were admitted to our center from April 2003 to October 2008, were analyzed. Among them, 17 patients who presented with acute onset diabetic ketosis without acidosis, and found to be negative for GADAb, were included. They showed male preponderance (n = 15). Ten patients had history of excessive ingestion of sugar-containing soft drink. Patients who successfully withdrew insulin therapy by 6 months (n = 7) showed significantly higher insulin secretion capacity and higher body mass index at the time of diagnosis than those who continued insulin therapy at least for 6 months (n = 10). These findings suggest that some of Japanese patients who presented with acute onset diabetic ketosis and negative for GADAb share several clinical characteristics with atypical type 2 diabetes such as ketosis-prone diabetes and "soft-drink ketosis," but others do not.

Species-specific actions of incretin: from the evolutionary perspective.

Two modes of incretin-based therapy, incretin mimetics (ie, glucagon-like peptide-1 (GLP-1) agonists) and incretin enhancers (ie, inhibitors of dipeptidyl peptidase IV (DPP-IV)), have recently been introduced into the clinical use. From the viewpoint of evolutionary endocrinology of GLP-1 and their receptors, the incretin action of GLP-1 seems to be relatively recent. Exendin-3 and exendin-4 are paralogs of GLP-1 from the lizards, and the synthetic exendin-4, exenatide, is a paralog of GLP-1. It has recently been indicated that GLP-1 and its receptor are expressed in the taste buds of the tongue, suggesting their possible function in the taste sensing signal pathway. In order to elucidate unknown functions of GLP-1 and its agonists and enhancers, ie, other than incretin actions in humans, it is possibly useful to consider GLP-1 from the viewpoint of integrated systems biology and evolutionary endocrinology.

Ethanol-induced expression of glutamate-cysteine ligase catalytic subunit gene is mediated by NF-kappaB.

Glutamate-cysteine ligase is a rate-limiting enzyme in the de novo synthesis of glutathione, a known scavenger of electrophiles and reactive oxygen species. Glutamate-cysteine ligase catalytic subunit (GCLC) is regulated transcriptionally by nuclear factor erythroid 2-related factor 2 (Nrf2). It has been reported that ethanol induces human GCLC production via Nrf2-mediated transactivation of the antioxidant-responsive element (ARE). Here, the luciferase reporter assay revealed the presence of an ethanol-responsive element in the human GCLC promoter; it spanned bases -1432 to -832 in hepatocytes and HepG2 cells transfected with cytochrome P450 2E1 (CYP2E1). The region lacked an ARE but had a putative nuclear factor-kappaB (NF-kappaB) element. NF-kappaB DNA-binding activity was activated in response to ethanol treatment. CYP2E1 expression was required for GCLC promoter-driven gene expression and the activation of NF-kappaB. Thus ethanol-induced GCLC transcription is mediated by not only Nrf2 but also NF-kappaB.

Pioglitazone improves obesity type diabetic nephropathy: relation to the mitigation of renal oxidative reaction.

Medications to treat hyperglycemia and hyperinsulinemia are expected to inhibit the accumulation of advanced glycation end-products in the diabetic kidney and improve renal function by inhibiting oxidative reactions. In this study, we examined the effect of pioglitazone, an insulin sensitizer, on diabetic nephropathy. Feed containing pioglitazone at 0.01 or 0.02% was given to Zucker-fatty rats for 27 weeks. Pioglitazone reduced plasma glucose, plasma insulin, and blood HbAlc levels. It also decreased plasma total cholesterol, triglyceride, phospholipid and cystatin C levels and inhibited the increase in urine of 8-hydroxydeoxyguanosine and in plasma of malondialdehyde. In the histopathological examinations, pioglitazone inhibited diffusive or nodular thickening of the mesangial matrix, atrophy of the proximal convoluted tubule, thickening of the basement membrane of the tubule, and mild cellular infiltration (mostly small lymphocytes) in the stroma. Furthermore, pioglitazone inhibited the mRNA expression of the receptor for advanced glycation end-products (RAGE) and that of transforming growth factor-beta. Long-term administration of pioglitazone improved hyperglycemia lipid profiles, hypercholesterolemia, and hyperinsulinemia and had a protective effect on diabetic nephropathy in Zucker-fatty rats.

Sulfonylurea and glinide reduce insulin content, functional expression of K(ATP) channels, and accelerate apoptotic beta-cell death in the chronic phase.

We previously found that chronic exposure to glibenclamide inhibits acute glibenclamide-induced insulin secretion by reducing the number of functional ATP-sensitive K(+) (K(ATP)) channels on the plasma membrane of pancreatic beta-cells. In the present study, we compared sulfonylurea-induced and glinide-induced insulin secretion in pancreatic beta-cells chronically exposed to these widely used oral hypoglycemic agents. Chronic exposure of pancreatic beta-cells to sulfonylureas (glibenclamide or tolbutamide) and glinide (nateglinide) similarly impaired their acute effectiveness by reducing the insulin content and the number of functional K(ATP) channels on the plasma membrane. Functional expression of the voltage-dependent Ca(2+) channels (VDCCs), ion channels that play a critical role in the K(ATP) channel dependent insulin secretory pathway, was similar to that in drug-untreated cells. Chronic exposure to each of the three agents similarly accelerated apoptotic beta-cell death. Thus, reduction of the insulin content, reduction of the number of functional K(ATP) channels on the plasma membrane, and acceleration of apoptotic beta-cell death all are involved in impaired insulinotropic agent-induced acute insulin secretion in the chronic phase of sulfonylurea and glinide treatment. These findings help to clarify the mechanism of secondary failure after long-term therapy by these hypoglycemic agents, and should have important clinical implications regarding pharmacotherapy for type 2 diabetes.

Gatifloxacin acutely stimulates insulin secretion and chronically suppresses insulin biosynthesis.

Gatifloxacin can cause both hypoglycemia and hyperglycemia in both diabetic and non-diabetic patients. Gatifloxacin recently has been reported to stimulate insulin secretion by inhibition of ATP-sensitive K(+) (K(ATP)) channels in pancreatic beta-cells. Gatifloxacin-induced hypoglycemia is associated with concomitant use of sulfonylureas, and usually occurs immediately after administration of the drug. We find that gatifloxacin acutely stimulates insulin secretion from mouse pancreatic islets and that glibenclamide has additive effects on gatifloxacin-induced insulin secretion. On the other hand, gatifloxacin-induced hyperglycemia often takes several days to develop. We also demonstrate that chronic gatifloxacin treatment decreases islet insulin content by inhibiting insulin biosynthesis, which process may be associated with gatifloxacin-induced hyperglycemia. Moreover, discontinuation of gatifloxacin results in improved insulin secretory response. These data clarify the differing mechanisms of gatifloxacin-induced hyper- and hypoglycemia, and suggest that blood glucose levels should be carefully monitored during gatifloxacin administration, especially in elderly patients with renal insufficiency, unrecognized diabetes, or other metabolic disorders. Because the risk of potentially life-threatening dysglycemia is increased during gatifloxacin therapy, these findings have important implications for clinical practice.

Gastric inhibitory polypeptide as an endogenous factor promoting new bone formation after food ingestion.

Calcium plays a fundamental role as second messenger in intracellular signaling and bone serves as the body's calcium reserve to tightly maintain blood calcium levels. Calcium in ingested meal is the main supply and inadequate calcium intake causes osteoporosis and bone fracture. Here, we describe a novel mechanism of how ingested calcium is deposited on bone. Meal ingestion elicits secretion of the gut hormone gastric inhibitory polypeptide (GIP) from endocrine K cells in the duodenum. Bone histomorphometrical analyses revealed that bone formation parameters in the mice lacking GIP receptor (GIPR(-/-)) were significantly lower than those of wild-type (GIPR(+/+)) mice, and that the number of osteoclasts, especially multinuclear osteoclasts, was significantly increased in GIPR(-/-) mice, indicating that GIPR(-/-) mice have high-turnover osteoporosis. In vitro examination showed the percentage of osteoblastic cells undergoing apoptosis to be significantly decreased in the presence of GIP. Because GIPR(-/-) mice exhibited an increased plasma calcium concentration after meal ingestion, GIP directly links calcium contained in meal to calcium deposition on bone.

Three measures of tumor necrosis factor alpha activity and insulin resistance in nonobese Japanese type 2 diabetic patients.

The aim of the present study was to investigate the relationship between insulin resistance and tumor necrosis factor alpha (TNF-alpha) as well as soluble TNF receptors (sTNF-R), body mass index (BMI), leptin, adiponectin, and serum lipid profile including triglycerides in nonobese Japanese patients with type 2 diabetes. A total of 88 nonobese Japanese type 2 diabetic patients were studied. The duration of diabetes was 11.0 +/- 0.8 years. In conjunction with BMI, glycosylated hemoglobin (HbA1c), fasting concentrations of plasma glucose, serum lipids (triglycerides, high-density lipoprotein cholesterol, and total cholesterol), serum leptin, serum adiponectin, serum TNF-alpha, and soluble TNF receptors (sTNF-R1 and sTNF-R2) were also measured. Insulin resistance was estimated by the insulin resistance index of homeostasis model assessment. Insulin resistance was positively correlated with BMI, triglycerides, leptin, and total cholesterol and negatively correlated with adiponectin and high-density lipoprotein cholesterol. In contrast, insulin resistance was not associated with TNF-alpha, nor sTNF-R (sTNF-R1 and sTNF-R2) in our diabetic patients. There was no significant relationship between the 3 measures of TNF-alpha system (TNF-alpha, sTNF-R1, and sTNF-R2) and BMI, serum triglycerides, leptin, or adiponectin in these patients. From these results, it can be concluded that peripheral levels of TNF-alpha system activity are not a major factor responsible for insulin resistance in nonobese Japanese type 2 diabetic patients.

Insulin independence after living-donor distal pancreatectomy and islet allotransplantation.

Rising demand for islet transplantation will lead to severe donor shortage in the near future, especially in countries where cadaveric organ donation is scarce. We undertook a successful transplantation of living-donor islets for unstable diabetes. The recipient was a 27-year-old woman who had had brittle, insulin-dependent diabetes mellitus for 12 years. The donor, who was a healthy 56-year-old woman and mother of the recipient, underwent a distal pancreatectomy. After isolation, 408 114 islet equivalents were transplanted immediately. The transplants functioned immediately and the recipient became insulin-independent 22 days after the operation. The donor had no complications and both women showed healthy glucose tolerance. Transplantation of living-donor islets from the distal pancreas can be sufficient to reverse brittle diabetes.