High frequency of non-nocturnal hypoglycemia was associated with poor sleep quality measure by Pittsburg Sleep Quality Index in patients with diabetes receiving insulin therapy: Diabetes Distress and Care Registry at Tenri (DDCRT 4).

To investigate the temporal association between frequency of non-nocturnal hypoglycemia and sleep quality among patients with diabetes receiving insulin therapy.We used data from 1 513 patients with diabetes receiving insulin therapy. We estimated the relative risks (RR) of the frequency of non-nocturnal hypoglycemia for poor sleep quality measured by the Pittsburgh Sleep Quality Index.The average age and HbA1c value of the patients were 63.7 years and 7.8%, respectively. Compared with poor sleep quality in patients without any type of non-nocturnal disabling hypoglycemia (NNDH), the multivariable-adjusted RR values for poor sleep quality were 1.30 (95% confidence interval [CI], 1.06-1.61) and 1.37 (95% CI, 0.96-1.95) in patients who experienced 1-4 and ≥5 episodes of NNDH, respectively (p=0.004). Experiencing non-nocturnal severe hypoglycemia (NNSH) once in the past 90 days significantly increased the risk of poor sleep quality by 1.54 episodes (95% CI, 1.16-2.05; p=0.003). By adding the presence of depression as a variable to the multivariable-adjusted model, these associations were attenuated because we did not observe any significant association between NNDH and poor sleep quality (p=0.178). However, a significant association between NNSH and poor sleep quality was observed (RR=1.43; 95% CI, 1.09-1.90; p=0.011).A high frequency of non-nocturnal hypoglycemia was associated with poor sleep quality in patients with diabetes receiving insulin therapy. Our data also suggested that the association of NNDH, and not NNSH, was mediated by comorbid depression.

Comparative validity of the WHO-5 Well-Being Index and two-question instrument for screening depressive symptoms in patients with type 2 diabetes.

A simple tool consisting of two questions for screening depressive symptoms has been shown to be useful in primary care settings, but its validity in patients with diabetes has yet to be evaluated. We compared the test performance of this two-question instrument with that of WHO (The World Health Organization)-5. We consecutively enrolled 153 patients with type 2 diabetes who visited a diabetes clinic in Japan. Using the Center for Epidemiologic Studies Depression Scale as a reference standard of depressive symptoms, we calculated the sensitivity and specificity of the two-question instrument and WHO-5, and compared the area under the ROC curves of these tests. The two-question instrument had a sensitivity of 53.6% (95% CI, 39.7-67.0%) and specificity of 67.7% (95% CI, 58.1-74.9%). With the conventional cutoff point equal to or less than 13 points, the WHO-5 had a sensitivity of 57.1% (95% CI, 43.2-70.3%) and specificity of 82.5% (95% CI, 81.9-94.9%). The area under the ROC curve for the WHO-5 and two-item questionnaire, an indicator of discriminatory power, was 0.81 and 0.73, respectively, showing a statistically significant difference (P = 0.0453). The two-question instrument had statistically lower discriminatory power than the WHO-5 in screening depressive symptoms in patients with diabetes. We do not recommend the use of the two-question instrument for screening depressive symptoms in patients with diabetes.

Diabetes distress, but not depressive symptoms, is associated with glycaemic control among Japanese patients with type 2 diabetes: Diabetes Distress and Care Registry at Tenri (DDCRT 1).

AIMS: To investigate the association between glycaemic control, diabetes distress and depressive symptoms among Japanese patients with Type 2 diabetes. METHODS: Cross-sectional data from 3305 patients with Type 2 diabetes were obtained from a baseline assessment of a diabetes registry at a general hospital in Japan. The Centre for Epidemiologic Studies Depression scale and Problem Areas in Diabetes scale were used to measure depressive symptoms and diabetes-related distress, respectively. Modified Poisson regression analysis was used to estimate the relative risks for poor glycaemic control across the quartiles of Centre for Epidemiologic Studies Depression scale and Problem Areas in Diabetes scale scores. RESULTS: The average age of the participants was 64.9 years and the average HbA(1c) level was 58.1 mmol/mol (7.5%). Clinically significant levels of depressive symptoms (Centre for Epidemiologic Studies Depression scale scores ≥ 16) were reported by 27.8% of participants. These scores significantly correlated with Problem Areas in Diabetes scale scores (r = 0.4354, P < 0.0001). Diabetes distress, but not depressive symptoms, was significantly associated with higher HbA(1c) levels. The relative risks for poor glycaemic control (HbA(1c) ≥ 64 mmol/mol; 8.0%), when adjusted for age, sex, BMI, type of diabetes therapy and duration of diabetes, was 67% higher among patients with Problem Areas in Diabetes scale scores in the highest quartile (≥ 26.25) compared with those in the lowest quartile (0-3.75). CONCLUSION: A significant association between glycaemic control and diabetes-related distress, but not depressive symptoms, was observed in Japanese patients with Type 2 diabetes.

Design and synthesis of novel benzofurans as a new class of antifungal agents targeting fungal N-myristoyltransferase. Part 1.

Potent and selective Candida albicans N-myristoyltransferase (CaNmt) inhibitors have been identified through optimization of a lead compound 1 discovered by random screening. The inhibitor design is based on the crystal structure of the CaNmt complex with compound (S)-3 and structure-activity relationships (SARs) have been clarified. Modification of the C-4 side chain of 1 has led to the discovery of a potent and selective CaNmt inhibitor 11 (RO-09-4609), which exhibits antifungal activity against C. albicans in vitro.

Clinical manifestations due to a point mutation of the mitochondrial tRNAleu(UUR) gene in five families with diabetes mellitus.

It has been shown that an adenine (A) to guanine (G) transition at position 3243 of the mitochondrial transfer RNA(tRNA)leu(UUR) gene is associated with a subgroup of diabetes mellitus. Therefore, we screened for this transition in 86 patients with non-insulin-dependent diabetes mellitus (NIDDM) in which two or three generations were affected with diabetes, in 14 patients with insulin-dependent diabetes mellitus, and in 9 families with diabetes mellitus and/or associated disorders suggesting mitochondrial gene abnormalities. We failed to identify the mutation in 100 diabetic patients, 86 NIDDM and 14 insulin-dependent diabetes mellitus (IDDM). Out of the latter 9 families, we identified an A to G transition in 14 individuals in 5 families. Diabetes mellitus was shown to be maternally inherited in one family. In 9 of 14 patients with the mutation, insulin was required to treat diabetes mellitus, indicating impaired insulin secretion. A hyperglycemic clamp test performed in one subject revealed significant impairment of insulin secretion, whereas euglycemic clamp test showed normal insulin sensitivity in this patient. The heteroplasmy of the mutant mitochondrial DNA (mtDNA) in leukocytes does not appear to correlate with the severity of diabetes in terms of the insulin therapy required. Body mass index of the affected individuals was less than 23.3. In one family, in addition to diabetes mellitus and hearing loss, hypoparathyroidism was associated with the mutation, suggesting that hypoparathyroidism is caused by the impaired processing and/or secretion of proparathyroid hormone due to the mutation. In addition, the affected subjects presented with proteinuria at the time of diagnosis of diabetes mellitus which appeared not to be related with diabetic nephropathy.

A beta-3 adrenergic agonist (BRL-37,344) decreases food intake.

This study evaluated the effect of peripheral injections of a beta3 adrenergic agonist, BRL-37,344 on food intake and whether this inhibition could be blocked by a nonspecific beta-adrenergic antagonist, propranolol, given peripherally or into the central nervous system. When BRL-37,344 was injected intraperitoneally (i.p.) into lean and obese Zucker rats, food intake was decreased. The reduction of food intake by BRL-37,344 was attenuated when propranolol was administered i.p. prior to giving the beta adrenergic agonist. When propranolol was administered into the third cerebral ventricle, it increased food intake in lean rats, but not the fatty rats. Propranolol administered into the third cerebral ventricle attenuated the effect on food intake of i.p. injection of BRL-37,344. These studies support the hypothesis that there are peripheral beta-3 adrenergic receptors that can reduce food intake and that there are central beta2 or beta3 adrenergic receptors that mediate the peripheral effect of the beta3 agonist.

A candidate case for lymphocytic infundibulo-neurohypophysitis mimicking a neurohypophysial tumor.

A 56-year-old Japanese man presented with a 2-month duration of polyuria and polydipsia. The diagnosis of diabetes insipidus was confirmed by water deprivation and vasopressin injection. The secretory function of the adenohypophysis was estimated as normal by a variety of provocative tests. Magnetic resonance imaging (MRI) displayed the loss of the hyperintense signal of the neurohypophysis and a tumor-like lesion confined to the neurohypophysis. The tissue specimen resected at transsphenoidal surgery showed diffuse lymphocytic infiltration. These findings suggest that this is a candidate case for lymphocytic infundibuloneurohypophysitis (LIN) that is not identical to classical lymphocytic hypophysitis. This patient will be followed up to determine whether this case simply represents an early stage of classical hypophysitis or a different clinical entity.

Food intake of lean and obese Zucker rats following ventricular infusions of adrenergic agonists.

The effect on food intake of adrenergic agonists administered into the third cerebral ventricle was studied in Zucker fatty and lean rats. The alpha 2 agonist, clonidine, produced a larger dose-related increase in food intake in lean rats than in the fatty rats. Dose-response curves show similar sensitivity, but decreased responsiveness in the lean animal. The beta 2 adrenergic agonist, salbutamol, produced similar food effect in obese and lean rats reducing food intake in the lean rats at the highest dose (300 nmol), and in the fatty rats at the two highest doses. The effects were small in both groups. The beta 3 agonist, BRL 37344, ([4-(2-((2-hydroxy-2-(3-chlorophenyl)ethyl)amino)-propyl)-phenoxy acetate]) produced a larger dose-related decrease in food intake in the fatty rat than in the lean rats. Dose-response curves showed that sensitivity of beta-receptors was similar, but the lean animals were less responsive. The beta-adrenergic blocking drug propranolol blocked the anorectic effect of BRL 37344 in the fatty rat. These studies suggest that in the fatty rat, the alpha 2 receptor system is tonically more active and the beta 3 receptor system tonically less active, a relationship that would explain the hyperphagia and development of obesity in these animals.

Enterostatin suppresses food intake following injection into the third ventricle of rats.

The effect on food intake of an activation peptide from pancreatic pro-colipase, called enterostatin, has been studied after parenteral or third ventricular administration. The activation peptide (enterostatin = Val-Pro-Asp-Pro-Arg = VPDPR) reduced food intake when given intraperitoneally. Low doses of this peptide also reduced food intake when given into the third ventricle, but high doses were ineffective. Enterostatin did not modify the stimulatory effects on food intake of clonidine, an alpha 2-adrenergic agonist, suggesting that its anorectic effects are not mediated via the alpha 2-adrenergic system. These data suggest that enterostatin, an activation peptide from pro-colipase, may play a role in producing satiety.

GABA-related feeding control in genetically obese rats.

Feeding in response to glucoprivation induced by 2-deoxy-D-glucose (2-DG) is impaired in genetically obese (Zucker) rats. Muscimol, a GABAA-agonist (0.5 nmol/0.5 microliter in each area) increased food intake in lean rats over 3 h but in fatty rats only at 30 min after infusion into the VMH. Injection of muscimol into the DMH and PVN increased feeding of both phenotypes. Picrotoxin, a non-competitive GABAA-antagonist (0.1 nmol/0.5 microliter) increased food intake after infusion into the LH of both phenotypes and decreased food intake over a 3 h period when infused into the VMH. DMH and PVN of fatty rats. In the lean littermates, picrotoxin was only effective in reducing food intake at 30 min after infusion into the VMH and PVN but not the DMH. The present results suggest that the fatty Zucker rat has a disturbance in the GABA-related regulatory mechanism of feeding behavior in the ventromedial hypothalamus, which may be responsible for the impaired response to glucoprivation found in these rats.

Effects of glucose, 2-deoxyglucose, phlorizin, and insulin on food intake of lean and fatty rats.

Glucose, 2-deoxyglucose, phlorizin, and insulin were injected into the third ventricle of lean and fatty rats, and food intake recorded hourly for the next 6 h. In the lean rats, there was a significant but unimpressive decrease in food intake after the intraventricular injection of glucose, but there was no effect of glucose in the fatty rat. Phlorizin in the lowest dose (10 micrograms) increased the food intake in lean animals at 1 and 2 h, and all three doses increased it significantly at 6 h after intraventricular injection. The fatty rat, in contrast, showed no response to phlorizin. 2-Deoxyglucose showed a dose-related stimulation of food intake in the lean rats at 1, 2, 3, and 6 h after injection. In the fatty rat, there was no significant effect on food intake at any dose. The intraventricular injection of insulin had no effect on food intake in either the lean or fatty rats. These studies indicate that glucose-responding systems in the region of the third ventricle are defective in the fatty rat to signals that normally increase or decrease food intake in lean animals.

Acetylation alters the feeding response to MSH and beta-endorphin.

The effects on food intake of the N-acetylation of MSH and beta-endorphin have been examined following their injection into the third ventricle. Desacetyl-MSH and alpha-MSH were injected into fasted rats, and beta-endorphin and N-acetyl-beta-endorphin into fed rats. Desacetyl-MSH had no effect on food intake following ICV injection into food-deprived rats at any dose between 100 and 2500 pmoles. Alpha-MSH, the N-acetylated form of MSH, on the other hand, showed a highly significant inhibition of food intake in food-deprived rats with doses of 100 and 250 pmoles but no effect with the higher doses. With beta-endorphin, there was a dose-related biphasic effect. One hour after injection of beta-endorphin (2500 pmole) food intake was inhibited whereas the lowest dose, 100 pmole, significantly stimulated it. By 3 hours, the 2 lowest doses of beta-endorphin both significantly stimulated food intake, but the highest dose remained inhibitory. By 6 hours all doses of beta-endorphin stimulated food intake compared to the vehicle-treated animals. In contrast, N-acetylation of beta-endorphin eliminated all effects on food intake following injection into the third ventricle. These data suggest that N-acetylation of products formed by the processing of POMC can markedly alter their biological properties.

The effect of DQ-2511, a newly synthesized anti-ulcer drug, on the gastric mucosal hemodynamics and ulceration in rats.

DQ-2511, which is a dopamine derivative, is a newly synthesized anti-ulcer drug. Pretreatment with DW-2511 in the hemorrhagic shock-reperfusion model in rats significantly prevented the decreases of gastric mucosal blood volume, mucosal blood oxygenation index and the ulcer formation. The decrease in gastric mucosal blood oxygenation index in hemorrhagic shock state has a linear correlation with the size of the mucosal ulcers both in DQ-2511 and control groups. The results suggested that DQ-2511 exerts its anti-ulcer activity by improving mucosal hemodynamics in hemorrhagic shock-reperfusion rat model.

Effect of food deprivation on regional brain glucose utilization in lean and fatty Zucker rats.

Regional brain glucose utilization was investigated in lean and fatty Zucker rats when feeding status was changed. Ad-lib-fed fat rats exhibited lower glucose utilization in the central amygdala than ad-lib-fed lean rats. Food deprivation for 72 h enhanced glucose utilization in the ventromedial hypothalamus, lateral hypothalamic area of both phenotypes, hippocampus of fat rats, mammillary body and ventral tegmental area of leans. These results suggest association of the central amygdala with the development of genetic obesity and of the latter 5 areas with hunger-motivated behaviors.