Basal and Bolus Insulin Dose Changes after Switching Basal Insulin to Insulin Degludec in Patients with Type 1 Diabetes Mellitus: A Pilot Study.

BACKGROUND AND OBJECTIVES: Ultra-long-acting insulin degludec (DEG) has a longer duration of action and less daily variability relative to other basal insulin (BI), and thus may benefit patients with type 1 diabetes mellitus (T1DM). We examined the impact of switching BI to DEG on glycemic control and insulin dose in T1DM. METHODS: T1DM patients (n = 22; six male; mean age: 64.5 ± 12.6 years) receiving basal-bolus insulin therapy were included. Initially, the BI dose was replaced with DEG in a 1:1 ratio; 80-100% of the total dose was replaced with DEG for multiple basal insulin injections. DEG was titrated according to study protocol. Changes in HbA1c, daily insulin dose, glycemic self-monitored blood glucose variations, and hypoglycemia frequency were evaluated for 24 weeks. RESULTS: Once-daily DEG significantly decreased HbA1c levels when switched from once-daily BI (7.9 ± 0.8 vs. 7.5 ± 0.9%, p = 0.020) and maintained HbA1c when switched from twice-daily BI (8.5 ± 1.6 vs. 8.4 ± 1.2%, p = 0.457). The BI dose decreased by -7.8 ± 13.9% (p = 0.017) and -16.6 ± 16.9% (p = 0.050) when switched from once-daily BI and twice-daily BI, respectively. The total bolus insulin dose significantly decreased when switched from once-daily BI (21.7 ± 8.3 to 19.3 ± 8.8 U/day, p = 0.016) especially in the injection before breakfast and evening meal. Body weight and hypoglycemia frequency was not significantly different. CONCLUSION: DEG improved glycemic control when switched from once-daily BI and maintained glycemic control when switched from twice-daily BI without increasing hypoglycemia.

Effects of ozone on growth, net photosynthesis and yield of two African varieties of Vigna unguiculata.

To assess the effects of O(3)on growth, net photosynthesis and yield of two African varieties of cowpea(Vigna unguiculata L.), Blackeye and Asontem were exposed as potted plants to air that was either filtered to remove O(3) (FA), non-filtered air (NF), non-filtered with added O3 of approximately 50 nL L(-1) (ppb) from 11:00 to 16:00 (NF + O(3)) for 88 days in open-top chambers. The mean O(3) concentration (11:00-16:00) during the exposure period had a range from 16 ppb in the FA treatment to 118 ppb in the NF + O(3) treatment. Net photosynthetic rate and leaf area per plant were significantly reduced by exposure to O(3), reducing the growth of both varieties. Exposure to O(3) significantly reduced the 100-seed weight and number of seeds per pod. As a result, cowpea yield was significantly reduced by long-term exposure to O(3), with no difference in sensitivity between the varieties.

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.

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]).

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.

The limited usefulness of the treadmill test or a risk-guided approach in screening for asymptomatic coronary heart disease in Japanese patients with type 2 diabetes.

OBJECTIVE: We prospectively investigated the efficacy of the screening methods for asymptomatic coronary heart disease (CHD) in Japanese patients with type 2 diabetes using the treadmill tolerance test (TTT) as a first-line test or the American Diabetes Association (ADA) guidelines. METHODS: The subjects included consecutive inpatients with type 2 diabetes (n=331) assessed with both electrocardiogram (ECG) at rest and TTT. Subjects with abnormal TTT findings were evaluated using stress myocardial perfusion scintigraphy (MPS). RESULTS: A total of 60 out of 69 subjects with positive TTT findings underwent MPS, among whom a total of 22 subjects (6.6% of the total number of subjects) had positive MPS results. Among those with positive MPS results, a total of 14 subjects underwent coronary angiography, eight of whom were determined to have significant coronary artery stenosis. The prevalence rates of hypertension and micro/macroalbuminuria were significantly higher in the MPS-positive group (77.3% and 54.5%, respectively) than in the TTT-negative group (44.7% and 27.1%, respectively). Among the subjects with positive MPS results, 68.2% met the 1998 ADA criteria. CONCLUSION: Neither the TTT as a first-line test nor the ADA guidelines are sufficiently adequate screening methods to detect asymptomatic CHD in Japanese subjects with type 2 diabetes. Conducting routine screening for asymptomatic CHD in Japanese patients with type 2 diabetes may therefore not be very useful.

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.

Clinical heterogeneity of adult Japanese diabetes depending on titers of glutamic acid decarboxylase autoantibodies.

UNLABELLED: Aims/Introduction: We examined whether levels of glutamic acid decarboxylase autoantibodies (GADAb) might show the clinical heterogeneity of adult Japanese diabetes. MATERIALS AND METHODS: In this cross-sectional study, the serum levels of GADAb were measured in a total of 1857 consecutive adult diabetic patients aged 20 years or older. The patients with positive GADAb, arbitrarily defined as ≥1.5 U/mL, were divided into quartiles according to the number of patients. The age- and sex-matched diabetic patients without GADAb were selected as a control group. RESULTS: A total of 103 (5.5%) of the diabetic patients had GADAb, and showed higher HbA1c and serum high-density lipoprotein (HDL) cholesterol levels, lower body mass index (BMI), urinary C-peptide immunoreactivity (CPR), serum triglycerides (TG) and uric acid (UA) levels, and lower prevalence of metabolic syndrome than the control group (P < 0.05). Quartiles 3 and 4 (i.e. GADAb ≥4.6 U/mL) showed a higher HbA1c level, lower BMI, urinary CPR, serum TG and UA levels, quartile 2 (2.5 ≤ GADAb < 4.6 U/mL) showed a lower BMI level than the control group (P < 0.05). Among the clinical parameters, we observed significant upward trends for both HbA1c and serum HDL cholesterol levels, and significant downward trends for BMI, serum TG and UA, urinary CPR levels, and prevalence of metabolic syndrome across GADAb quartiles (P < 0.05 for trend). CONCLUSIONS: These results show that the clinical phenotype of adult Japanese diabetes correlates with GADAb levels, and that patients with GADAb (≥2.5 U/mL) show different characteristics from those without GADAb, although further longitudinal studies are required. (J Diabetes Invest, doi: 10.1111/j.2040-1124.2011.00190.x, 2011).

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.

Relationship between carotid intima-media thickness and silent cerebral infarction in Japanese subjects with type 2 diabetes.

OBJECTIVE: We examined the relationship between intima-media thickness of common carotid artery (CCA-IMT) and silent cerebral infarction (SCI) with the magnetic resonance imaging (MRI) study in Japanese subjects with type 2 diabetes. RESEARCH DESIGN AND METHODS: The brain MRI study and the carotid ultrasonography were performed in a total of 217 consecutive Japanese subjects with type 2 diabetes. Various risk factors for SCI were examined using multiple logistic analyses. RESULTS: The SCI was found in 60.4% of the diabetic subjects. In the diabetic subjects, age, systolic blood pressure (SBP), pulse wave velocity, and CCA-IMT were significantly higher in the subjects with SCI than in those without it. Multiple logistic analyses indicated that age, SBP, and CCA-IMT were significant and independent risk factors of SCI in the diabetic subjects. CONCLUSIONS: CCA-IMT, but not pulse wave velocity, was independently associated with SCI in Japanese subjects with type 2 diabetes.

Usefulness of serum cystatin C in Japanese patients with type 2 diabetes mellitus and nephropathy.

We examined usefulness of serum cystatin C to detect chronic kidney disease (CKD) stage >or=3, which was defined by Modification of Diet in Renal Disease formula. Serum cystatin C could detect CKD stage >or=3 with high efficacy in 289 Japanese patients with type 2 diabetes and nephropathy.

Olmesartan reduced microalbuminuria in Japanese subjects with type 2 diabetes.

We investigated the effect of olmesartan on early diabetic nephropathy in hypertensive patients with type 2 diabetes by its replacement of other angiotensin II type 1 receptor blockers (ARBs) by olmesartan. The urinary albumin/creatinine ratio significantly decreased. The present result suggests a possibility that olmesartan may have more effect on early nephropathy than other ARBs.

Comparison of effects of amlodipine and angiotensin receptor blockers on the intima-media thickness of carotid arterial wall (AAA study: amlodipine vs. ARB in atherosclerosis study).

Although there have been increasing reports, which suggest that angiotensin receptor blockers (ARBs) may have anti-atherogenic actions, most of them are performed in vitro and there are a few reports about anti-atherogenic action in vivo. Especially, in humans, there have been no reports about effect of ARBs on atheroslocerosis. On the other hand, there have been several reports, including ours, which indicate that amlodipine, a calcium channel blocker, has a unique property to cause a reduction in the intima-media thickness (IMT) of common carotid artery, which is established to be an indicator of early atherosclerotic lesion, in humans. The present study investigated which of amlodipine and/or ARBs might have more profound effect on IMT progression. The study included 104 hypertensive patients with type 2 diabetes. They were divided into the two groups: the amlodipine group (n=58), who received amlodipine (2.5-5mg/day) and the ARB group (n=46), who received losartan (25-50mg/day), candesartan (4-8 mg/day), valsaratan (40-80 mg/day) or telmisartan (20-40 mg/day). IMT changes were examined during an average of 56.9 weeks. The amlodipine group showed a significant decrease in IMT compared to the ARB group (-0.046 [S.E. 0.161] mm vs. 0.080 [S.E. 0.255] mm, P<0.05). These results suggest that amlodipine has an inhibitory effect on early atherosclerotic process, and that ARBs do not have any effect on it in hypertensive patients with type 2 diabetes.

A case of lymphocytic panhypophysitis (LPH) during pregnancy.

A 37-year-old pregnant woman developed continuous headache in the 10th week of pregnancy, followed by bilateral visual field defect and general malaise in the 24th week. The brain magnetic resonance imaging showed a pituitary mass. In laboratory examination, plasma concentration of free thyroxine, thyroid stimulating hormone (TSH), cortisol, and adrenocorticotropic hormone (ACTH) was low. General malaise vanished shortly after the replacement therapy of glucocorticoid and thyroid hormone, but partial central diabetes insipidus (CDI) appeared, which could be treated with desmopressin acetate (DDAVP). The visual field defect having enlarged, transsphenoidal surgery was performed in the 31st week of pregnancy. Adenohypophysis could be resected, and it showed infiltration of mature lymphocytes. After the surgery, the visual defect had improved, but hormone replacement was still necessary. She delivered a baby in the 38th week without any trouble. Provocative tests after delivery revealed a low response in TSH, prolactin (PRL), and follicle stimulating hormone (FSH). Hormone replacement and DDAVP administration was necessary in the same doses after delivery. The diagnosis was lymphocytic panhypophysitis (LPH). In the case of pregnant woman, LPH should be included in the differential diagnosis of pituitary mass for the fetomaternal safety.

Hypothalamic pathogenesis of type 2 diabetes.

There have recently been increasing experimental and clinical evidences suggesting that hypothalamic dysregulation may be one of the underlying mechanisms of abnormal glucose metabolism. First, increased hypothalamic-pituitary-adrenal axis activity induced by uncontrollable excess stress may cause diabetes mellitus as well as dyslipidemia, visceral obesity, and osteoporosis with some resemblance to Cushing's disease. Second, several molecules are known to be expressed both in pancreas and hypothalamus; adenosine triphosphate-sensitive potassium channels, malonyl-CoA, glucokinase, and AMP-activated protein kinase. Those molecules appear to form an integrated hypothalamic system, which may sense hypothalamic fuel status, especially glucose level, and inhibit action of insulin on hepatic gluconeogenesis, thereby forming a brain-liver circuit. Third, hypothalamic resistance to insulin as an adiposity signal may be involved in pathogenesis of peripheral insulin resistance. The results with mice with a neuron-specific disruption of the insulin receptor gene or those lacking insulin receptor substrate 2 in hypothalamus supported this possibility. Finally, it has very recently been suggested that dysregulation of clock genes in hypothalamus may cause abnormal glucose metabolism. Taken together, it is plausible that some hypothalamic abnormality may underlie at least some portion of type 2 diabetes or insulin resistance in humans, and this viewpoint of hypothalamic pathogenesis of type 2 diabetes may lead to the development of new drugs for type 2 diabetes.

Structural and biochemical dissection of photorespiration in hybrids differing in genome constitution between Diplotaxis tenuifolia (C3-C4) and radish (C3).

We compared the structural, biochemical, and physiological characteristics involved in photorespiration of intergeneric hybrids differing in genome constitution (DtDtR, DtDtRR, and DtRR) between the C(3)-C(4) intermediate species Diplotaxis tenuifolia (DtDt) and the C(3) species radish (Raphanus sativus; RR). The bundle sheath (BS) cells in D. tenuifolia included many centripetally located chloroplasts and mitochondria, but those of radish had only a few chloroplasts and mitochondria. In the hybrids, the numbers of chloroplasts and mitochondria, the ratio of centripetally located organelles to total organelles, and the mitochondrial size in the BS cells increased with an increase in the constitution ratio of the Dt:R genome. The P-protein of glycine decarboxylase (GDC) was confined to the BS mitochondria in D. tenuifolia, whereas in radish, it accumulated more densely in the mesophyll than in the BS mitochondria. In the hybrids, more intense accumulation of GDC in the BS relative to the mesophyll mitochondria occurred with an increase in the Dt:R ratio. These structural and biochemical features in the hybrids were reflected in the gas exchange characteristics of leaves, such as the CO(2) compensation point. Our data indicate that the leaf structure, the intercellular pattern of GDC expression, and the gas exchange characteristics of C(3)-C(4) intermediate photosynthesis are inherited in the hybrids depending on the constitution ratio of the parent genomes. Our findings also demonstrate that the apparent reduced photorespiration in C(3)-C(4) intermediate plants is mainly due to the structural differentiation of mitochondria and chloroplasts in the BS cells combined with the BS-dominant expression of GDC.