Laughter yoga as an enjoyable therapeutic approach for glycemic control in individuals with type 2 diabetes: A randomized controlled trial.

Background: Laughter has been reported to have various health benefits. However, data on the long-term effects of laughter interventions on diabetes are limited. This study aimed to investigate whether laughter yoga can improve glycemic control among individuals with type 2 diabetes. Methods: In a single-center, randomized controlled trial, 42 participants with type 2 diabetes were randomly assigned to either the intervention or the control group. The intervention consisted of a 12-week laughter yoga program. Hemoglobin A1c (HbA1c), body weight, waist circumference, psychological factors, and sleep duration were evaluated at baseline and week 12. Results: Intention-to-treat analysis showed that participants in the laughter yoga group experienced significant improvements in HbA1c levels (between-group difference: -0.31%; 95% CI -0.54, -0.09) and positive affect scores (between-group difference: 0.62 points; 95% CI 0.003, 1.23). Sleep duration tended to increase in the laughter yoga group with a between-group difference of 0.4 hours (95% CI -0.05, 0.86; P = 0.080). The mean attendance rate for laughter yoga program was high (92.9%). Conclusions: A 12-week laughter yoga program is feasible for individuals with type 2 diabetes and improves glycemic control. These findings suggest that having fun could be a self-care intervention. Further studies with larger numbers of participants are warranted to better evaluate the effects of laughter yoga. Clinical trial registration: http://www.chinadrugtrials.org.cn, identifier UMIN000047164.

Improvement of beta-cell function in conjunction with glycemic control after medical nutrition therapy in newly-diagnosed type 2 diabetes mellitus.

BACKGROUND: The current study aimed to reveal the correlation of beta-cell function and insulin sensitivity with glycemic control and weight control before and after medical nutrition therapy (MNT) in patients with newly-diagnosed type 2 diabetes mellitus. METHODS: We retrospectively analyzed consecutive 68 patients with newly-diagnosed type 2 diabetes mellitus who started MNT without antihyperglycemic medications and underwent a 75-g oral glucose tolerance test (OGTT) before and after the therapy. Beta-cell function was evaluated by the OGTT-derived disposition index, whereas insulin sensitivity was evaluated by Matsuda's insulin sensitivity index. RESULTS: After 4.0 ± 1.5 months of MNT, mean HbA1c and body mass index significantly decreased from 9.6 ± 1.8% to 7.2 ± 1.0% and from 26.9 ± 4.1 to 25.4 ± 3.7 kg/m2 (both P < 0.001), while the median disposition index and Matsuda's index significantly increased from 0.34 (0.20-0.68) to 0.88 (0.53-1.52) (P < 0.001) and from 4.70 (2.95-5.93) to 5.17 (3.48-6.89) (P = 0.003), respectively. The disposition index was significantly correlated with HbA1c levels both before and after MNT (r = -0.61 and -0.68; both P < 0.001). The magnitude of the correlation after MNT was not different from that before MNT (P = 0.42). Matsuda's index was correlated not with HbA1c levels but with body mass index, both before (r = 0.07 [P = 0.57] and r = -0.58 [P < 0.001]) and after MNT (r = -0.01 [P = 0.95] and r = -0.52 [P < 0.001]). CONCLUSIONS: Beta-cell function was improved in conjunction with glycemic control after MNT in patients with newly-diagnosed type 2 diabetes mellitus. Insulin sensitivity was linked with weight control rather than glycemic control.

Quality of life in people with type 2 diabetes in the 3 years following initiation of second-line therapy: The DISCOVER study.

AIMS: To assess changes in health-related quality of life (HRQoL) in DISCOVER, a 3-year, longitudinal, observational study of patients with type 2 diabetes initiating a second-line glucose-lowering therapy. METHODS: HRQoL was assessed using the physical and mental component summary (PCS and MCS) scores of the 36-item Short-Form Health Survey version 2 (score ranges: 0-100; higher denotes better HRQoL) and the Hypoglycaemia Fear Survey II (HFS-II; score range: 0-132 scale; higher indicates greater fear of hypoglycaemia). Latent class growth modelling (LCGM) was used to identify patients with similar score trajectories. RESULTS: Mean baseline PCS (n = 7428), MCS (n = 7453), and HFS-II (n = 5005) scores were 48.0, 45.4, and 15.4, respectively, and remained stable during follow-up. LCGM revealed subgroups with low or decreasing HRQoL. Patients in these subgroups tended to be older, had more comorbidities, and a lower socioeconomic status than in other subgroups. Use of insulin and sulfonylureas was highest in the subgroup with the highest fear of hypoglycaemia. CONCLUSIONS: Overall, HRQoL remained stable in DISCOVER patients during follow-up. However, LCGM suggests that some patient characteristics and use of sulfonylureas or insulin are associated with low or decreasing HRQoL, potentially warranting the use of alternative therapies.

Glutamine deficiency induces lipolysis in adipocytes.

Glutamine is the most abundant amino acid in the body, and adipose tissue is one of the glutamine-producing organs. Glutamine has important and unique metabolic functions; however, its effects in adipocytes are still unclear. 3T3-L1 adipocytes produced and secreted glutamine dependent on glutamine synthetase, but preadipocytes did not. The inhibition of glutamine synthetase by l-methionine sulfoximine (MSO) impaired the differentiation of preadipocytes to mature adipocytes, and this inhibitory effect of MSO was rescued by exogenous glutamine supplementation. Glutamine concentrations were low, and Atgl gene expression was high in epididymal white adipose tissues of fasting mice in vivo. In 3T3-L1 adipocytes, glutamine deprivation induced Atgl expression and increased glycerol concentration in culture medium. Atgl expression is regulated by FoxO1, and glutamine deprivation reduced FoxO1 phosphorylation (Ser256), indicating the activation of FoxO1. These results demonstrate that glutamine is necessary for the differentiation of preadipocytes and regulates lipolysis through FoxO1 in mature adipocytes.

Metabolomic Analysis of Diet-Induced Obese Mice Supplemented with Eicosapentaenoic Acid.

Eicosapentaenoic acid (EPA) is an omega-3 fatty acid with anti-inflammatory effects. To determine the effects of EPA on metabolic pathways in obese adipose tissues and liver, mice were fed normal chow diet (NCD), high-fat diet (HFD), or 3% EPA-containing high fat diet (HFD+EPA) for 8 weeks. Metabolomic analysis was performed using epididymal adipose tissues (epi WAT) and liver. Metabolites that were specifically elevated in HFD+EPA, were assessed for their anti-inflammatory properties using RAW264.7 macrophage cells. Body and adipose tissue weights were significantly higher in HFD than NCD, and lower in HFD+EPA than HFD. Plasma insulin levels were significantly higher in HFD than NCD, and lower in HFD+EPA compared with HFD. Plasma monocyte chemotactic protein-1 (MCP-1) levels were higher in HFD than NCD, and tended to be lower in HFD+EPA than HFD. The levels of intermediate metabolites in the glycolytic pathways were lower in HFD compared with NCD and HFD+EPA in both epi WAT and liver, while intermediate metabolites of the TCA cycles were elevated in HFD and HFD+EPA compared with NCD in epi WAT. Among the metabolites in epi WAT, the levels of thiaproline, phenaceturic acid, and pipecolic acid were specifically elevated in HFD+EPA, but not in HFD or NCD. Treatment of RAW264.7 cells with thiaproline significantly ameliorated LPS-induced iNOS expression, while pipecolic acid inhibited LPS-induced IL-1ß expression. These results suggest that EPA normalizes glycolytic pathway intermediates in both epi WAT and liver, and induces metabolites with anti-inflammatory properties.

Population Approaches Targeting Metabolic Syndrome Focusing on Japanese Trials.

The clinical importance of assessment of metabolic syndrome lies in the selection of individuals with multiple risk factors based on visceral fat accumulation, and helping them to reduce visceral fat. Behavioral modification by population approach is important, which adds support to the personal approach. The complexity of visceral fat accumulation requires multicomponent and multilevel intervention. Preparation of food and physical environments could be useful strategies for city planners. Furthermore, actions on various frameworks, including organizational, community, and policy levels, have been recently reported. There are universal public health screening programs and post-screening health educational systems in Japan, and diseases management programs in Germany. Understanding one's own health status is important for motivation for lifestyle modification. The U.S. Preventive Services Task Force recommends that primary care practitioners screen all adults for obesity and offer behavioral interventions and intensive counseling. Established evidence-based guidelines for behavioral counseling are needed within the primary care setting.

Marked recovery from glucotoxicity of ß-cell function after medical nutrition therapy without pharmacotherapy in type 2 diabetic outpatients with extreme hyperglycemia: a pilot retrospective study.

We investigated whether glucotoxicity of ß-cell function could be eliminated after medical nutrition therapy (MNT) without forced correction of hyperglycemia by anti-diabetic medications including exogenous insulin administration. We analyzed newly diagnosed type 2 diabetic outpatients with hemoglobin A1c (HbA1c) of 10.1 ± 1.5%, who were treated by MNT at least for three months, without any aid of anti-diabetic medications. The ß-cell function was calculated as the product of the ΔIns0-120/ΔGlu0-120 and the Matsuda index, where ΔIns0-120/ΔGlu0-120 represents the ratio of the incremental concentrations of insulin to those of glucose during the 0- to 120-min time periods under a 75-g oral glucose tolerance test. After MNT, HbA1c levels were reduced to 7.0 ± 1.0% (p < 0.001). The ß-cell function was significantly improved (n = 13; p = 0.001; effect size d = 1.9). Fasting plasma glucose became below 7.0 mmol/l in 57% (8/13), and 120-minute plasma glucose became below 11.1 mmol/l in 43% (6/13). The ß-cell function after MNT was significantly correlated with HbA1c levels achieved after MNT (Pearson's correlation coefficient r = -0.62, p = 0.025). In conclusion, the ß-cell dysfunction was ameliorated after MNT without glucose-lowering pharmacotherapy in newly diagnosed type 2 diabetic outpatients who presented extreme hyperglycemia.

[Vitamin D, obesity, and diabetes:new technology toward drug development against metabolic diseases].

Obesity and diabetes are rapidly reaching epidemic proportions in many parts of world and are becoming one of the major public health problems. Many studies have been performed to develop treatments for obesity and diabetes. In clinical aspect, for example, vitamin D was assumed to be a causal factor of obesity and diabetes, and the effect of vitamin D supplementation on the patients was assessed. In addition to clinical study, basic researchers have tried to elucidate the mechanisms of obesity and diabetes. Recent studies show novel techniques for finding etiologic factors in obesity and diabetes. These effort will accelerate progress toward total eradication of obesity and diabetes.

Successful treatment of reactive hypoglycemia secondary to late dumping syndrome using miglitol.

We herein describe a 59-year-old woman who had undergone a total gastrectomy for gastric carcinoma and suffered from postprandial hypoglycemia characterized by a loss of consciousness and spasms. She was diagnosed with reactive hypoglycemia and treated with nutrition therapy, but the frequency and severity of the hypoglycemic episodes did not decrease. She was subsequently treated successfully with miglitol, an alpha-glucosidase inhibitor (α-GI) taken twice a day; other α-GIs (acarbose and voglibose) were not effective. In conclusion, the administration of miglitol was effective for preventing reactive hypoglycemia secondary to late dumping syndrome.

Effects of coffee on inflammatory cytokine gene expression in mice fed high-fat diets.

In order to investigate the risk-reducing effects of coffee in metabolic syndrome, we performed a study in mice fed a high-fat diet with added coffee and analyzed gene expression in liver and adipose tissues using cDNA microarray. Male C57BL/6J mice were raised for 8 weeks on either a normal diet (N group), a high-fat diet (HF group), or a high-fat diet with 1.1% decaffeinated (HF+DC group) or 1.1% caffeine-containing instant coffee (HF+CC group). The body weights of mice in the HF+DC and HF+CC groups were mostly intermediate between the N and HF groups, even if there were no difference in the amount of diet consumption in each group. Mesenteric fat weight was lower in the HF+DC group than in the HF group (p < 0.05) and tended to become lower in the HF+CC group than in the HF group. Serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels were significantly lower in the HF+DC and HF+CC groups than in the HF group (p < 0.05). Inflammatory cytokine interleukin (IL)-1beta gene expression in liver was up-regulated in the HF group and significantly down-regulated in the HF+DC and HF+CC groups (p < 0.01), while MCP-1 gene expression in white adipose tissue was also significantly suppressed in the HF+DC group (p < 0.01). The induction of these anti-inflammatory responses by coffee consumption may contribute to reducing the risks of metabolic syndrome.

The HNF-1 target collectrin controls insulin exocytosis by SNARE complex formation.

Defective glucose-stimulated insulin secretion is the main cause of hyperglycemia in type 2 diabetes mellitus. Mutations in HNF-1alpha cause a monogenic form of type 2 diabetes, maturity-onset diabetes of the young (MODY), characterized by impaired insulin secretion. Here we report that collectrin, a recently cloned kidney-specific gene of unknown function, is a target of HNF-1alpha in pancreatic beta cells. Expression of collectrin was decreased in the islets of HNF-1alpha (-/-) mice, but was increased in obese hyperglycemic mice. Overexpression of collectrin in rat insulinoma INS-1 cells or in the beta cells of transgenic mice enhanced glucose-stimulated insulin exocytosis, without affecting Ca(2+) influx. Conversely, suppression of collectrin attenuated insulin secretion. Collectrin bound to SNARE complexes by interacting with snapin, a SNAP-25 binding protein, and facilitated SNARE complex formation. Therefore, collectrin is a regulator of SNARE complex function, which thereby controls insulin exocytosis.

Enhancement of ligand-dependent vitamin D receptor transactivation by the cardiotonic steroid bufalin.

Bufalin, a bufadienolide type cardiotonic steroid that is one of the major components of the toad venom-prepared traditional Chinese medicine called Ch'an Su or Senso, exhibits a cardiotonic action by inhibiting the membranous Na(+),K(+)-ATPase. Bufalin also induces differentiation of leukemia cells alone or in combination with other differentiation inducers including 1alpha,25-dihydroxyvitamin D(3) [1,25(OH)(2)D(3)]. In this study, we performed a transient cotransfection assay using a vitamin D receptor (VDR) expression vector and a luciferase reporter and found that although bufalin did not transactivate the VDR, it effectively enhanced VDR activity induced by 1,25(OH)(2)D(3). Bufalin also augmented VDR activation by bile acid ligands, such as lithocholic acid and 3-ketocholanic acid. Other cardiotonic steroids including ouabain, digitoxigenin and cinobufagin did not enhance VDR activation. Bufalin did not bind directly to VDR but did modulate the interaction of VDR and cofactors, such as steroid receptor coactivator-1 and nuclear receptor corepressor. Bufalin treatment significantly increased the expression of an endogenous VDR target gene, CYP24, in kidney- and monocyte-derived cell lines treated with 1,25(OH)(2)D(3). The data indicate that bufalin-mediated cellular mechanisms such as interaction with Na(+), K(+)-ATPase may affect VDR transcriptional activity. Bufalin may be a useful tool in the investigation of VDR regulation by membrane-originating cellular signals and of pathophysiological mechanisms linking VDR to cardiovascular dysfunction.

Intectin, a novel small intestine-specific glycosylphosphatidylinositol-anchored protein, accelerates apoptosis of intestinal epithelial cells.

Intestinal epithelial cells undergo rapid turnover and exfoliation especially at the villus tips. This process is modulated by various nutrients especially fat. Apoptosis is one of the important regulatory mechanisms of this turnover. Therefore, identification of the factors that control epithelial cell apoptosis should help us understand the mechanism of intestinal mucosal turnover. Here, we report the identification of a novel small intestine-specific member of the Ly-6 family, intectin, by signal sequence trap method. Intectin mRNA expression was exclusively identified in the intestine and localized at the villus tips of intestinal mucosa, which is known to undergo apoptosis. Intectin mRNA expression was modulated by nutrition. Intestinal epithelial cells expressing intectin were more sensitive to palmitate-induced apoptosis, compared with control intestinal epithelial cells, and such effect was accompanied by increased activity of caspase-3. Intectin expression also reduced cell-cell adhesion of intestinal epithelial cells.

Peripheral, but not central, administration of adiponectin reduces visceral adiposity and upregulates the expression of uncoupling protein in agouti yellow (Ay/a) obese mice.

To examine the peripheral and central roles of adiponectin in energy intake and expenditure, we investigated the effects of adiponectin on food intake, adiposity, sympathetic nerve activity (SNA), and mRNA expressions of uncoupling protein (UCP) in the brown adipose tissue (BAT), white adipose tissue (WAT) and skeletal muscle in agouti yellow (A(y)/a) obese mice. Intraperitoneal administration of adiponectin (1.5 mg/kg for 7 days) attenuated body weight gain and reduced visceral adiposity in A(y)/a obese mice compared with PBS-treated controls. In addition, adiponectin treatment increased the expression of UCP1 mRNA in BAT, UCP2 mRNA in WAT, and UCP3 mRNA in skeletal muscle compared with PBS-treated A(y)/a controls. Acute peripheral administration of adiponectin (1.5 mg/kg, one injection) also increased SNA in the BAT accompanied by an increase in rectal temperature. Finally, these above responses as well as expression of c-Fos-like immunohistochemistry in the hypothalamus were not induced by central application of adiponectin (0-15 micro g/kg). Taken together, adiponectin effectively regulated visceral adiposity, SNA, and UCP mRNA expression peripherally, suggesting that this substance can be used as a therapeutic tool, administered peripherally, in the treatment of visceral obesity and related metabolic disorders.

Induction of adiponectin, a fat-derived antidiabetic and antiatherogenic factor, by nuclear receptors.

Adiponectin is a fat-derived hormone with antidiabetic and antiatherogenic properties. Hypoadiponectinemia seen in obesity is associated with insulin-resistant diabetes and atherosclerosis. Thiazolidinediones, peroxisome proliferator-activated receptor-gamma (PPAR-gamma) agonists, have been shown to increase plasma adiponectin levels by the transcriptional induction in adipose tissues. However, the precise mechanism of such action is unknown. In this study, we have identified a functional PPAR-responsive element (PPRE) in human adiponectin promoter. PPAR-gamma/retinoid X receptor (RXR) heterodimer directly bound to the PPRE and increased the promoter activity in cells. In adipocytes, point mutation of the PPRE markedly reduced the basal transcriptional activity and completely blocked thiazolidinedione-induced transactivation of adiponectin promoter. We have also identified a responsive element of another orphan nuclear receptor, liver receptor homolog-1 (LRH-1), in adiponectin promoter. LRH-1 was expressed in 3T3-L1 cells and rat adipocytes. LRH-1 bound specifically to the identified responsive element (LRH-RE). LRH-1 augmented PPAR-gamma-induced transactivation of adiponectin promoter, and point mutation of the LRH-RE significantly decreased the basal and thiazolidinedione-induced activities of adiponectin promoter. Our results indicate that PPAR-gamma and LRH-1 play significant roles in the transcriptional activation of adiponectin gene via the PPRE and the LRH-RE in its promoter.