Adiponectin and adiponectin receptors (AdipoRs) have been found to play significant roles in the etiology of obesity-related chronic disease. Their discovery has been a long and complicated path, ...with many challenges. Developing methods to unravel the molecular secrets has been an informative process in itself. However, with both functional and genetic studies confirming adiponectin as a therapeutic target adipokine, many roles and interactions with certain other biomolecules have been clearly defined. We have found that decreased high molecular weight (HMW) adiponectin plays a crucial and causal role in obesity-linked insulin resistance and metabolic syndrome; that AdipoR1 and AdipoR2 serve as the major AdipoRs in vivo; and that AdipoR1 activates the AMP kinase (AMPK) pathway and AdipoR2, the peroxisome proliferator-activated receptor alpha (PPARα) pathway in the liver, to increase insulin sensitivity and decrease inflammation. Further conclusions are that decreased adiponectin action and increased monocyte chemoattractant protein-1 (MCP-1) form a vicious adipokine network causing obesity-linked insulin resistance and metabolic syndrome; PPARγ upregulates HMW adiponectin and PPARα upregulates AdipoRs; that dietary osmotin can serve as a naturally occurring adiponectin receptor agonist; and finally, that under starvation conditions, MMW adiponectin activates AMPK in hypothalamus, and promotes food intake, and at the same time HMW adiponectin activates AMPK in peripheral tissues, such as skeletal muscle, and stimulates fatty-acids combustion. Importantly, under pathophysiological conditions, such as obesity and diabetes, only HMW adiponectin was decreased; therefore, strategies to increase only HMW adiponectin may be a logical approach to provide a novel treatment modality for obesity-linked diseases, such as insulin resistance and type 2 diabetes. It is hoped that these data will be helpful in developing treatments to counteract the destructive, expensive and painful effects of obesity.
Adiponectin is an adipokine that is specifically and abundantly expressed in adipose tissue and directly sensitizes the body to insulin. Hypoadiponectinemia, caused by interactions of genetic factors ...such as SNPs in the Adiponectin gene and environmental factors causing obesity, appears to play an important causal role in insulin resistance, type 2 diabetes, and the metabolic syndrome, which are linked to obesity. The adiponectin receptors, AdipoR1 and AdipoR2, which mediate the antidiabetic metabolic actions of adiponectin, have been cloned and are downregulated in obesity-linked insulin resistance. Upregulation of adiponectin is a partial cause of the insulin-sensitizing and antidiabetic actions of thiazolidinediones. Therefore, adiponectin and adiponectin receptors represent potential versatile therapeutic targets to combat obesity-linked diseases characterized by insulin resistance. This Review describes the pathophysiology of adiponectin and adiponectin receptors in insulin resistance, diabetes, and the metabolic syndrome.
Aim
To assess the efficacy, safety and dose–response relationship of once‐daily teneligliptin, a novel dipeptidyl peptidase‐4 inhibitor, in Japanese patients with type 2 diabetes mellitus (T2DM) ...inadequately controlled with diet and exercise.
Methods
In this randomized, double‐blind, placebo‐controlled, parallel‐group study, patients (n = 324) were randomized to receive teneligliptin 10, 20 or 40 mg, or placebo, once daily before breakfast for 12 weeks. The primary endpoint was the change in haemoglobin (Hb)A1c from baseline to week 12.
Results
All teneligliptin‐treated groups showed significantly greater reductions in HbA1c and fasting plasma glucose (FPG) than did the placebo group. The differences between the teneligliptin 10, 20 or 40 mg groups and the placebo group for the change in HbA1c were −0.9 least‐squares (LS) mean; 95% confidence interval: −1.0, −0.7, −0.9 (−1.1, −0.7) and −1.0 (−1.2, −0.9)%, respectively (all, p < 0.001). The respective LS means for FPG were −17.8 (−23.4, −12.1), −16.9 (−22.6, −11.2) and −20.0 (−25.7, −14.3) mg/dl (all, p < 0.001). There were no significant differences in HbA1c among the three doses of teneligliptin. The incidence of adverse events and adverse drug reactions was similar in each group. The incidence of hypoglycaemia was not significantly different among the four groups.
Conclusions
Treatment with teneligliptin for 12 weeks provided significant and clinically meaningful reductions in HbA1c and FPG across the dose range studied and was generally well tolerated in Japanese patients with T2DM.
Aims
To assess the efficacy and safety of teneligliptin in combination with glimepiride in Japanese patients with type 2 diabetes mellitus (T2DM) inadequately controlled with glimepiride monotherapy.
...Methods
In the initial 12‐week, double‐blind, placebo‐controlled, parallel‐group period, 194 patients haemoglobin A1c (HbA1c): 8.4 ± 0.8%; fasting plasma glucose (FPG): 164.2 ± 28.1 mg/dl were randomized to either teneligliptin 20 mg or placebo once daily while continuing stable glimepiride therapy. This randomized period was then followed by a 40‐week, open‐label period, where all patients received teneligliptin once daily. The primary endpoint was the change in HbA1c from baseline to week 12.
Results
Teneligliptin reduced HbA1c significantly compared with placebo at week 12. The placebo‐subtracted change in HbA1c was −1.0 ± 0.1% least‐squares (LS) mean ± s.e., p < 0.001. Teneligliptin also significantly reduced FPG and 2‐h postprandial glucose (PPG) as compared with placebo at week 12; the placebo‐subtracted changes were −27.1 ± 3.2 and −49.1 ± 6.2 mg/dl (LS mean ± s.e., both p < 0.001), respectively. The blood glucose‐lowering effects were sustained throughout the 40‐week open‐label period. The incidence rates of adverse events and adverse drug reactions, including hypoglycaemia, during the double‐blind randomized period were similar in both groups. Therefore, teneligliptin was generally well tolerated when used in combination with glimepiride.
Conclusions
The addition of teneligliptin was effective and generally well tolerated in Japanese patients with T2DM inadequately controlled with glimepiride monotherapy. The improvements in glycaemic control were maintained for up to 52 weeks.
Aim
To assess blood glucose control over 24 h and the safety of teneligliptin 10 and 20 mg, a novel dipeptidyl peptidase‐4 inhibitor, in Japanese patients with type 2 diabetes mellitus inadequately ...controlled with diet and exercise.
Methods
Ninety‐nine patients were administered teneligliptin 10 or 20 mg or placebo before breakfast for 4 weeks in a randomized, double‐blind, placebo‐controlled, parallel‐group study.
Results
Both teneligliptin‐treated groups showed significantly smaller 2‐h postprandial glucose (2‐h PPG), 24‐h mean glucose and fasting plasma glucose values than the placebo group. The differences between the teneligliptin 10 mg and placebo groups in changes in 2‐h PPG after each meal were −50.7 ± 7.8, −34.8 ± 9.2 and −37.5 ± 7.5 mg/dl at breakfast, lunch and dinner, respectively least‐squares (LS) means ± standard error (s.e.), all, p < 0.001. The corresponding LS means ± s.e. for teneligliptin 20 mg versus placebo were −38.1 ± 7.8, −28.6 ± 9.2 and −36.1 ± 7.5 mg/dl, respectively (p < 0.001, p < 0.01, p < 0.001, respectively). Both doses of teneligliptin increased postprandial plasma active glucagon‐like peptide‐1 concentrations compared with placebo. The incidence of adverse events and drug‐related adverse events was similar among groups. There were no hypoglycaemic symptoms or serious adverse events.
Conclusions
Once‐daily teneligliptin improved blood glucose levels over 24 h without hypoglycaemia.
Nearly a fourth of all enzymatic activities is attributable to oxidoreductases, and the redox reactions supported by this vast catalytic repertoire sustain cellular metabolism. In many biological ...processes, reduction depends on hydride transfer from either reduced nicotinamide adenine dinucleotide (NADH) or its phosphorylated derivative (NADPH). Despite longstanding efforts to regenerate NADPH by various methods and harness it to support chemoenzymatic synthesis strategies, the lack of product purity has been a major deterrent. Here, we demonstrate that a nanostructured heterolayer Ni-Cu
O-Cu cathode formed by a photoelectrochemical process has unexpected efficiency in direct electrochemical regeneration of NADPH from NADP
. Remarkably, two-thirds of NADP
was converted to NADPH with no measurable production of the inactive (NADP)
dimer and at the lowest reported overpotential - 0.75 V versus Ag/AgCl (3 M NaCl) reference. Sputtering of nickel on the copper-oxide electrode nucleated an unexpected surface morphology that was critical for high product selectivity. Our results should motivate design of integrated electrolyzer platforms that deploy this heterogeneous catalyst for direct electrochemical regeneration of NADH/NADPH, which is central to design of next-generation biofuel fermentation strategies, biological solar converters, energy-storage devices, and artificial photosynthesis.
Aims/hypothesis
Monocyte chemoattractant protein-1 (MCP-1)/chemokine (C-C motif) ligand (CCL) 2 (CCL2) secreted from white adipose tissue (WAT) in obesity has been reported to contribute to tissue ...macrophage accumulation and insulin resistance by inducing a chronic inflammatory state. MCP-1 has been shown to be elevated in the fatty liver of lipoatrophic A-ZIP-transgenic (A-ZIP-Tg) mice. Treatment of these mice with the CC chemokine receptor (CCR) 2 antagonist has been shown to ameliorate the hyperglycaemia, hyperinsulinaemia and hepatomegaly, in conjunction with reducing liver inflammation. However, since CCR2 antagonists can block not only MCP-1 but also MCP-2 (CCL8) and MCP-3 (CCL7), it remains unclear whether MCP-1 secreted from the liver could contribute to hyperglycaemia, hyperinsulinaemia and hepatomegaly in conjunction with liver inflammation, as well as to the M1 and M2 states of macrophage polarisation.
Methods
To address these issues, we analysed the effects of targeted disruption of MCP-1 in A-ZIP-Tg mice.
Results
MCP-1 deficiency alone or per se resulted in a significant amelioration of insulin resistance in A-ZIP-Tg mice, which was associated with a suppression of extracellular signal-regulated protein kinase (ERK)-1/2 and p38 mitogen-activated protein kinase (p38MAPK) phosphorylation in liver. Although MCP-1 deficiency did not reduce the expression of macrophage markers, it increased the expression of the genes encoding M2 macrophage markers such as
Arg1
and
Chi3l3
, as well as significantly reducing the triacylglycerol content of livers from A-ZIP-Tg mice.
Conclusions/ interpretation
Our data clearly indicated that MCP-1 deficiency improved insulin resistance and hepatic steatosis in A-ZIP-Tg mice and was associated with switching macrophage polarisation and suppressing ERK-1/2 and p38MAPK phosphorylation.
Adiponectin (Ad) is a hormone secreted by adipocytes that regulates energy homeostasis and glucose and lipid metabolism. However, the signaling pathways that mediate the metabolic effects of Ad ...remain poorly identified. Here we show that phosphorylation and activation of the 5'-AMP-activated protein kinase (AMPK) are stimulated with globular and full-length Ad in skeletal muscle and only with full-length Ad in the liver. In parallel with its activation of AMPK, Ad stimulates phosphorylation of acetyl coenzyme A carboxylase (ACC), fatty-acid oxidation, glucose uptake and lactate production in myocytes, phosphorylation of ACC and reduction of molecules involved in gluconeogenesis in the liver, and reduction of glucose levels in vivo. Blocking AMPK activation by dominant-negative mutant inhibits each of these effects, indicating that stimulation of glucose utilization and fatty-acid oxidation by Ad occurs through activation of AMPK. Our data may provide a novel paradigm that an adipocyte-derived antidiabetic hormone, Ad, activates AMPK, thereby directly regulating glucose metabolism and insulin sensitivity in vitro and in vivo.
Objective
Transcription factor EB (TFEB) is a master regulator of lysosomal biogenesis and plays an important role in various cancers. However, the function of TFEB in oral squamous cell carcinomas ...has not been examined. The aim of this study was to elucidate the role of TFEB in oral squamous cell carcinomas.
Materials and Methods
Expression levels of TFEB were examined in six different human oral squamous carcinoma cells: HSC2, HSC3, HSC4, SAS, OSC20, and SCC25. Knockdown of TFEB using small interfering RNA in HSC2 and HSC4 cells was performed. Cell morphology was observed by immunofluorescence microscopy. Cell proliferation, invasion, and adhesion were analyzed.
Results
Expression levels of TFEB were high in HSC2, moderate in HSC4 and SCC25, and low in HSC3 and OSC20 cells. Knockdown of TFEB did not affect proliferation of HSC2 and HSC4 cells, but did induced enlargement of lysosomes and endosomes in HSC4 cells. TFEB silencing reduced invasion and migration of these HSC cell squamous carcinoma cells; however, increased cell adhesion was also observed.
Conclusion
TFEB knockdown reduces invasion and migration of cancer cells, likely through lysosomal regulation. Taken together, TFEB influences cell invasion and migration of oral squamous cell carcinomas.
The incidence of coronary heart disease in the United States has declined, and prevalences of several coronary disease risk factors have become comparable to those in Japan. Therefore, the burden of ...coronary atherosclerosis may be closer among younger persons in the 2 countries. We aimed to compare prevalences of coronary atherosclerosis, measured with coronary artery calcium scores, between men in the 2 countries by age group (45-54, 55-64, or 65-74 years). We used community-based samples of Caucasian men in the United States (2000-2002; n = 1,067) and Japanese men in Japan (2006-2008; n = 832) aged 45-74 years, stratifying them into groups with 0, 1, 2, or ≥3 of the following risk factors: current smoking, overweight, diabetes, dyslipidemia, and hypertension. We calculated adjusted odds ratios of US Caucasian men's having Agatston scores of ≥10, ≥100, and ≥400 with reference to Japanese men. Overall, the odds of Caucasian men having each Agatston cutoff point were greater. The ethnic difference, however, became smaller in younger age groups. For example, adjusted odds ratios for Caucasian men's having an Agatston score of ≥100 were 2.05, 2.43, and 3.86 among those aged 45-54, 55-64, and 65-74 years, respectively. Caucasian men in the United States had a higher burden of coronary atherosclerosis than Japanese men, but the ethnic difference was smaller in younger age groups.
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