Biomedical subjects

Ryo Suzuki

Publications and source records attributed to Ryo Suzuki.

At least 19 recordsLinked to original sources

PubMed2026

Long-term safety of oral orforglipron in Japanese participants with type 2 diabetes (ACHIEVE-J): a multicentre, randomised, open-label, parallel-group phase 3 trial.

BACKGROUND: Orforglipron, an oral GLP-1 receptor agonist, requires further evaluation in east Asian populations with type 2 diabetes, given this group's distinct pathophysiological characteristics. This study aimed to assess orforglipron as add-on treatment to diet and exercise alone or to oral antihyperglycaemic medications in Japanese participants with type 2 diabetes. METHODS: This multicentre, randomised, open-label phase 3 study was conducted in 40 medical research centres and hospitals in Japan. Adults with type 2 diabetes and elevated glucose levels managing their condition with diet and exercise alone or with one or two oral antihyperglycaemic medications were assigned (1:1:1) via computer-generated random sequence to receive once-daily oral orforglipron (3 mg, 12 mg, or 36 mg). Randomisation was stratified by background therapy, baseline HbA1c (≤8·5% or >8·5%), and metformin use (yes vs no; applied only to α-glucosidase inhibitors, thiazolidinedione, and glinides). Investigators, participants, and site staff were not masked to treatment. The primary endpoint was safety for 52 weeks, assessed in all randomly assigned participants who received at least one dose of orforglipron. This study is registered with ClinicalTrials.gov, NCT06010004 (ACHIEVE-J). FINDINGS: Between Sept 28, 2023, and June 5, 2025, 450 participants were screened and 401 were randomly assigned to three groups (3 mg, n=132; 12 mg, n=135; and 36 mg, n=134). 352 (88%) completed study treatment. 339 participants (85%, 95% CI 80·7-87·8) had at least one treatment-emergent adverse event (TEAE), more frequently in the 36-mg group (118 [88%, 95% CI 81·5-92·5]) than in the 3-mg (107 [81%, 73·5-86·8]) and 12-mg (114 [84%, 77·4-89·6]) groups. Most TEAEs were of mild (267 [67%, 61·8-71·0]) or moderate (63 [16%, 12·5-19·6]) severity. Discontinuations due to an adverse event occurred in 19 of 134 participants (14%, 95% CI 9·3-21·1) in the 36-mg group compared with seven of 132 (5%, 2·6-10·5) in the 3-mg group and 11 of 135 (8%, 4·6-14·0) in the 12-mg group. Across treatment groups, gastrointestinal symptoms were the most common TEAEs leading to study treatment discontinuation (3 mg: 5 [3·8%, 1·6-8·6]; 12 mg: 8 [5·9%, 3·0-11·3]; and 36 mg: 11 [8·2%, 4·7-14·1]). Level 2 (blood glucose <54 mg/dL) hypoglycaemia events occurred in three of 135 participants in the 12-mg group (2%, 0·8-6·3) and in three of 134 in the 36-mg group (2%, 0·8-6·4) groups. No level 3 (severe) hypoglycaemia events occurred. Outcomes were generally similar across background therapies. INTERPRETATION: Treatment with orforglipron in combination with diet and exercise alone or one or two oral antihyperglycaemic medications for 52 weeks demonstrated an acceptable safety profile in Japanese adults with type 2 diabetes. FUNDING: Eli Lilly. TRANSLATION: For the Japanese translation of the abstract see Supplementary Materials section.

Aged↗

PubMed2007

Analysis of the origin and population dynamics of cardiac progenitor cells in a donor heart model.

Cardiac progenitor (stem) cells have recently been detected in and isolated from the myocardium of neonatal and adult mice, rats, and humans; however, the precise origin and characterization of these cells remain unclear. Using a heterotopic mouse heart transplantation model, we investigated the origin and population dynamics of cardiac progenitor cells. Donor hearts from wild-type C57/BL6 female mice were transplanted into green fluorescent protein (GFP)-transgenic C57/BL6 male mice. The donor hearts were collected 0, 2, 4, 8, and 12 weeks after transplantation. We used quantitative flow cytometry to analyze the number and origin of stem cells in the donor hearts and immunostaining to evaluate the time-related changes in their characteristics. Extracardiac GFP-positive stem cells immigrated into the donor hearts soon after transplantation. Immunostaining revealed that these GFP-positive stem cells in the donor hearts gradually lost expression of the hematopoietic markers of CD45 and CD34 and shifted to express the cardiac-specific transcription factors GATA-4 and NKx2.5. A few of the GFP-positive cells in the donor hearts finally acquired the mature cardiac phenotype in the absence of cell fusion with donor cardiomyocytes. Our discovery provides the first evidence that extracardiac stem cells may be of bone marrow origin, from which they can transform into cardiac progenitor cells in response to myocardial environment cues.

Animals↗

PubMed2007

Glucokinase and IRS-2 are required for compensatory beta cell hyperplasia in response to high-fat diet-induced insulin resistance.

Glucokinase (Gck) functions as a glucose sensor for insulin secretion, and in mice fed standard chow, haploinsufficiency of beta cell-specific Gck (Gck(+/-)) causes impaired insulin secretion to glucose, although the animals have a normal beta cell mass. When fed a high-fat (HF) diet, wild-type mice showed marked beta cell hyperplasia, whereas Gck(+/-) mice demonstrated decreased beta cell replication and insufficient beta cell hyperplasia despite showing a similar degree of insulin resistance. DNA chip analysis revealed decreased insulin receptor substrate 2 (Irs2) expression in HF diet-fed Gck(+/-) mouse islets compared with wild-type islets. Western blot analyses confirmed upregulated Irs2 expression in the islets of HF diet-fed wild-type mice compared with those fed standard chow and reduced expression in HF diet-fed Gck(+/-) mice compared with those of HF diet-fed wild-type mice. HF diet-fed Irs2(+/-) mice failed to show a sufficient increase in beta cell mass, and overexpression of Irs2 in beta cells of HF diet-fed Gck(+/-) mice partially prevented diabetes by increasing beta cell mass. These results suggest that Gck and Irs2 are critical requirements for beta cell hyperplasia to occur in response to HF diet-induced insulin resistance.

Animals↗

PubMed2006

Gene delivery by combination of novel liposomal bubbles with perfluoropropane and ultrasound.

Microbubbles and ultrasound have recently been investigated with a view to improving the transfection efficiency of non-viral gene delivery systems. However, microbubbles are unstable and their targeting ability is insufficient for clinical use. To circumvent these problems, we developed novel polyethyleneglycol (PEG) modified liposomes (Bubble liposomes) containing perfluoropropane, which is an ultrasound imaging gas. Here, we used ultrasound to induce cavitation in Bubble liposomes and then investigated their ability to deliver genes in vitro and in vivo. Bubble liposomes could deliver plasmid DNA to many cell types without cytotoxicity. Additionally, in vivo gene delivery, Bubble liposomes were more effective delivery into femoral artery than lipofection method. Thus, Bubble liposomes might be efficient and novel non-viral tools for gene delivery.

Animals↗

PubMed2006

Overexpression of monocyte chemoattractant protein-1 in adipose tissues causes macrophage recruitment and insulin resistance.

Adipose tissue expression and circulating concentrations of monocyte chemoattractant protein-1 (MCP-1) correlate positively with adiposity. To ascertain the roles of MCP-1 overexpression in adipose, we generated transgenic mice by utilizing the adipocyte P2 (aP2) promoter (aP2-MCP-1 mice). These mice had higher plasma MCP-1 concentrations and increased macrophage accumulation in adipose tissues, as confirmed by immunochemical, flow cytometric, and gene expression analyses. Tumor necrosis factor-alpha and interleukin-6 mRNA levels in white adipose tissue and plasma non-esterified fatty acid levels were increased in transgenic mice. aP2-MCP-1 mice showed insulin resistance, suggesting that inflammatory changes in adipose tissues may be involved in the development of insulin resistance. Insulin resistance in aP2-MCP-1 mice was confirmed by hyperinsulinemic euglycemic clamp studies showing that transgenic mice had lower rates of glucose disappearance and higher endogenous glucose production than wild-type mice. Consistent with this, insulin-induced phosphorylations of Akt were significantly decreased in both skeletal muscles and livers of aP2-MCP-1 mice. MCP-1 pretreatment of isolated skeletal muscle blunted insulin-stimulated glucose uptake, which was partially restored by treatment with the MEK inhibitor U0126, suggesting that circulating MCP-1 may contribute to insulin resistance in aP2-MCP-1 mice. We concluded that both paracrine and endocrine effects of MCP-1 may contribute to the development of insulin resistance in aP2-MCP-1 mice.

Adipose Tissue↗

PubMed2006

Cytokines produced by bone marrow cells can contribute to functional improvement of the infarcted heart by protecting cardiomyocytes from ischemic injury.

It is well known that the implantation of bone marrow mononuclear cells (BM-MNCs) into ischemic hearts can induce angiogenesis and improve cardiac function after myocardial infarction, but the precise mechanisms of these actions are unclear. We hypothesize that the cytokines produced by BM-MNCs play a key role in this cell-based therapy. BM-MNCs from rats were cultured under normoxic or hypoxic (1% O2) conditions for 24 h, and then supernatants were collected for study. ELISA and Western blotting analysis showed that various cytokines, including VEGF, IL-1 beta, PDGF, and IGF-1, were produced from BM-MNCs, some of which were enhanced significantly under hypoxia stimulation. When compared with a control blank medium, the supernatants of BM-MNCs cultured under normoxic or hypoxic conditions inhibited apoptosis significantly and preserved the contractile capacity of isolated adult rat cardiomyocytes in vitro (P < 0.05). Using a rat model of acute myocardial infarction, we injected the supernatants of BM-MNCs or control medium intramyocardially on day 0 and then intraperitoneally on days 2, 4, and 6 after infarction. When compared with the control medium, the supernatants of BM-MNCs cultured under both normoxic or hypoxic conditions increased the microvessel density and decreased the fibrotic area in the infarcted myocardium significantly, contributing to remarkable improvement in cardiac function. Various cytokines were produced by BM-MNCs, and these cytokines contributed to functional improvement of the infarcted heart by directly preserving the contractile capacity of the myocardium, inhibiting apoptosis of cardiomyocytes, and inducing therapeutic angiogenesis of the infarcted heart.

Acute Disease↗

PubMed2006

Synthesis and biological evaluation of boronic acid containing cis-stilbenes as apoptotic tubulin polymerization inhibitors.

A series of boronic acid containing cis-stilbenes as potent inhibitors of tubulin polymerization was synthesized by the introduction of boronic acid as an acceptor-type functional group into the aromatic ring B of the combretastatin framework. High cell-growth inhibition was observed with boron compounds 13 c and 13 d, in which a hydroxy group on the aromatic ring B of combretastatin A-4 was replaced with boronic acid; IC50 values toward B-16 and 1-87 cell lines are 0.48-2.1 microM. Compounds 13 c and 13 d exhibited significant inhibitory activity toward tubulin polymerization (IC50=21-22 microM). The carboxylic acid derivative 17, which can be considered as a mimic of boronic acid 13 c, did not show significant inhibition of cell growth or tubulin polymerization. According to the FACScan analysis using Jurkat cells, apoptosis was induced after incubation for 8 h with 13 c at a concentration of >10(-8) M. Growth inhibitory experiments against a panel of 39 human cancer cell lines revealed 13 c to inhibit growth differently than combretastatin A-4; the correlation coefficient (r) between the two compounds was 0.553 in the COMPARE analysis.

Animals↗

PubMed2006

Pravastatin improves remodeling and cardiac function after myocardial infarction by an antiinflammatory mechanism rather than by the induction of angiogenesis.

BACKGROUND: Recent studies have reported that the 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (or statins) can improve angiogenesis. Using an acute infarction model, we examined the therapeutic merit of statins on angiogenesis, alone and in combination with cell-based therapy. METHODS: Zucker fatty rats, a strain characterized by obesity, hyperglycemia, and hyperlipidemia, were used for this study. After ligating the left anterior descending artery, rats were given oral pravastatin 5 or 50 mg/kg per day, or an intramyocardial injection of a total 2 x 10(7) autologous bone marrow mononuclear cells, or a combination of both. Cardiac function was assessed by echocardiography before treatment, then 7, 14, and 28 days after treatment. Histologic estimation of microvessel density, lymphocyte infiltration, and collagen fiber accumulation in the infarcted myocardium was performed 28 days after treatment. RESULTS: Cardiac function was improved, and collagen deposition was decreased significantly after either cell implantation or pravastatin administration alone, but no synergistic effect was seen by their combination. However, microvessel density in the infarcted myocardium was increased only by implantation of bone marrow mononuclear cells, and not by administration of pravastatin. Pravastatin resulted in significant decreases in the serum levels of interleukin 1beta and tumor necrosis factor-alpha, and also in the infiltration of CD45-positive cells, but not CD117-positive stem cells, in infarcted myocardium. Neither the number of circulating CD34-positive cells nor their endothelial differentiation potency was increased significantly 14 days after oral administration of pravastatin. CONCLUSIONS: Pravastatin can improve cardiac function after myocardial infarction, but through an antiinflammatory mechanism, rather than by induction of therapeutic angiogenesis. No synergistic effect for inducing angiogenesis was found by the combination of pravastatin and implantation of bone marrow mononuclear cells.

Angiogenesis Inducing Agents↗

PubMed2006

Formation and distribution of the sural nerve based on nerve fascicle and nerve fiber analyses.

The formation and distribution of the sural nerve are presented on the basis of an investigation of 31 legs of Japanese cadavers using nerve fascicle and fiber analyses. Nerve fibers constituting the medial sural cutaneous nerve were designated as 'T', whereas those constituting the peroneal communicating branch were designated as 'F'. In 74.2% of cases (23/31), the T and F fibers joined each other in the leg, whereas in 9.7% of cases (3/31) they descended separately. In 16.1% of cases (5/31), the sural nerve was formed of only the T fibers. The sural nerve gave off lateral calcaneal branches and medial and lateral branches at the ankle. The lateral calcaneal branches always contained T fibers. The medial branches consisted of only T fibers, whereas most of the lateral branches consisted of only F fibers (71.0%; 22/31). In addition to the T and F fibers, P fibers, which derived from the superficial and deep peroneal nerves, formed the dorsal digital nerves. The P fibers were entirely supplied to the medial four and one-half toes. However, they were gradually replaced by the T and F fibers in the lateral direction. The 10th proper dorsal digital nerve consisted of T fibers only (38.7%; 12/31), of F fibers only (19.4%; 6/31) or of both T and F fibers (38.7%; 12/31). These findings suggest that the T fibers are essential nerve components for the skin and deep structures of the ankle and heel rather than the skin of the lateral side of the fifth toe. The designation of the medial sural cutaneous nerve should be avoided and only the T fibers are appropriate components for naming as the sural nerve.

Aged↗

PubMed2006

Ontogenetic characteristics of enzyme activities and plasma metabolites in C57BL/6J:Jcl mice deficient in insulin receptor substrate 2.

We have established an inbred line of mice deficient in insulin receptor substrate 2 (IRS2) on a C57BL/6J Jcl genetic background (B6J-IRS2(-/-) mice) as an animal model for typical type 2 diabetes mellitus (DM). We investigated the effect of age and sex on glucose tolerance and insulin resistance and on the activities of enzymes related to lipid metabolism in the liver and skeletal muscle of B6J-IRS2( -/-) mice. Glucose tolerance tests (GTT), insulin tolerance tests (ITT), and sampling for chemical analysis were performed at ages of 6,14, and 24 wk. GTT showed that both genders of B6J-IRs2(-/-) mice had impaired glucose tolerance at the ages of 6 and 14 wk, whereas 24-wk-old female B6J-IRs2(-/-) mice showed glucose tolerance almost comparable to that of wild-type mice; 24-wk-old male B6J-IRs2(-/-) mice still showed impaired glucose tolerance. ITT revealed that both male and female B6J-IRS2(-/-) mice remained insulin-resistant at all time points. Hepatic lipogenetic enzyme activities were higher in B6J-IRS2(-/-) mice than in wild-type mice at 6, 14 and 24 wk of age. In addition, plasma glucose, triglyceride, free fatty acid, total cholesterol, and insulin concentrations in B6J-IRS2(-/-) mice were significantly higher than those in wild-type mice at most time points; plasma triglycerides in 14-wk-old B6J-IRS2(-/-) mice were lower than those of wild-type mice. These findings suggest that young B6J-IRS2(-/-) mice are useful as type 2 DM models.

Animals↗

PubMed2006

[Reexamination of the communicating branch between the sural and tibial nerves].

Reexamination of communicating branches between the sural and tibial nerves ventral to the calcanean tendon was carried out on 52 legs of 26 Japanese cadavers which were used for ordinary dissection practices at the Niigata University School of Medicine. Communicating branches were found in 7 out of 52 dissections (13.5% of cases). In three of the 7 specimens, the communicating branch, the sural nerve and the tibial nerve with the deep crural fascia were removed from the legs and demonstrated by a modified Sihler's staining technique. Three types of communicating branches, Y, U and N, were distinguished on the basis of their shapes. In type Y, a medial branch from the sural nerve and a branch from the tibial nerve joined in Y-shape and become one terminal branch. In type U, the both branches formed a loop between the sural and tibial nerves. The type N communicating branch ran obliquely and medially to reach the tibial nerve distally. Only the Y type appeared in 5 specimens. Both the Y and U type and the Y and N types occurred in one specimen each. We assume that the communicating branch of the N type contains motor fibers which are derived from the sural nerve and innervate some plantar muscles, because this type is correspond to the communication type of some animals in which motor fibers have been demonstrated. Therefore, if the sural nerve biopsy is performed to examine a pure sensory nerve, removal of the more distal part of the sural nerve than a diverging point of a communicating branch is recommended. This study also indicated that the modified Sihler's staining technique is useful to examine distributions of cadaveric peripheral nerves after medical students' dissection course.

Calcaneus↗

PubMed2005

Krüppel-like transcription factor KLF5 is a key regulator of adipocyte differentiation.

Krüppel-like factor 5 (KLF5) is a zinc-finger transcription factor known to play a pivotal role in the pathogenesis of cardiovascular disease. Here, we show that neonatal heterozygous KLF5 knockout mice exhibit a marked deficiency in white adipose tissue development, suggesting that KLF5 is also required for adipogenesis. In 3T3-L1 preadipocytes, KLF5 expression was induced at an early stage of differentiation, and this was followed by expression of PPARgamma2. Constitutive overexpression of dominant-negative KLF5 inhibited adipocyte differentiation, whereas overexpression of wild-type KLF5 induced differentiation even without hormonal stimulation. Moreover, embryonic fibroblasts obtained from KLF5+/- mice showed much attenuated adipocyte differentiation, confirming the key role played by KLF5 in adipocyte differentiation. KLF5 expression is induced by C/EBPbeta and delta. KLF5, in turn, acts in concert with C/EBPbeta/delta to activate the PPARgamma2 promoter. This study establishes KLF5 as a key component of the transcription factor network controlling adipocyte differentiation.

3T3-L1 Cells↗

PubMed2005

Calcium response and FcepsilonRI expression in bone marrow-derived mast cells co-cultured with SCG neurites.

Communication between nerves and mast cells is a prototypic demonstration of neuro-immune interaction. Numerous studies have shown that the stimulation of nerves (or addition of neurotransmitters) can evoke activation of mast cells, and that mast cell-derived mediators can influence neuronal activity. However, it is still unknown whether high affinity IgE receptors (FcepsilonRI) themselves are involved directly in the communication between nerves and mast cells. In the present experiments, we used an in vitro co-culture approach comprising interaction between immune (bone marrow-derived mast cells, BMMCs) and nerve cells (superior cervical ganglia, SCG) to solve the above problem. We found that the intracellular calcium ion concentration ([Ca2+]i) increased much more in BMMCs after antigen (DNP7-BSA) stimulation when they were associated with SCG neurites in the co-culture system. But the [Ca2+]i in BMMCs was less increased when they were not associated with the neurites. Further, the in vitro co-culture approach of BMMCs with SCG neurites for 3 d showed the increases of FcepsilonRI expression occurred on the plasma membranes of BMMCs which were attached to the neurites. On the contrary, N-cadherin molecules which localized on the interface between on the plasma membrane of BMMCs and SCG neurites did not increase with the co-culture for 3 d. All of these results indicated that co-culturing BMMCs with SCG neurites for 3 d promoted not only the calcium response but also the FcepsilonRI expression in BMMCs.

Animals↗

PubMed2005

[Application of the modified Sihler's stain technique to cadaveric peripheral nerves after medical students' dissection course].

The exact ramification and distribution pattern of the peripheral nerves is one of the most important information for anatomists and clinicians. However, it is very difficult to pursue perfectly all of the fine twigs of nerve branches even if we use a stereoscopic microscope. Recently, Liu et al. (Anat. Rec., 247: 137, 1997) applied a modified Sihler's stain technique to study the distribution of intramuscular nerve branches in mammalian skeletal muscles. Then, we attempted to apply this technique to plantar nerves of human foot removed from cadavers which were used for ordinary dissection practices at the School of Medicine. Intrinsic muscles of the foot with motor and sensory nerve branches were removed en bloc from bones of the foot. They were macerated and depigmented in 3% aqueous potassium hydroxide, decalcified in Sihler's solution 1. Then, after staining in Sihler's solution II, they were destained in Sihler's solution I, neutralized in 0.05% lithium carbonate, and cleared in increasing concentrations of glycerin. As a result, each nerve fascicle, which are bundles of nerve fibers invested by the perineurium, was very clearly visualized, since only nerve fibers were stained deep blue-purple, while muscles, the epineurium and the perineurium were made transparent in glycerin. We found an anastomosis between a deep branch of the lateral plantar nerve and the medial plantar nerve, composed of several nerve fascicles. Therefore, the modified Sihler's stain technique can be applied to cadaveric peripheral nerves after medical students' dissection course.

Aged, 80 and over↗

PubMed2004

Expression of DGAT2 in white adipose tissue is regulated by central leptin action.

Acyl-CoA:diacylglycerol acyltransferase (DGAT) enzymes catalyze the final step in mammalian triglyceride synthesis, and their functions are considered to be involved in the mechanisms of obesity, insulin resistance, and leptin resistance. Insulin receptor substrate-2 (IRS-2)-deficient mice exhibit obesity-associated with hypertrophic adipocytes and leptin resistance. Screening for transcripts of genes involved in fatty acid and triglyceride synthesis to investigate the mechanism of the hypertrophic change in the adipocytes showed that expression of DGAT2 mRNA was up-regulated in the white adipose tissue (WAT) of Irs2-/- mice, whereas that of DGAT1 was down-regulated. This reciprocal expression of DGAT1 and DGAT2 was also observed in WAT of leptin-deficient ob/ob mice. A high fat diet also resulted in increased DGAT2 and reduced DGAT1 in the WAT of C57BL/6 mice. Induction of adipocyte hypertrophy in vitro up-regulated both DGAT1 and DGAT2 expression in 3T3-L1 cells, suggesting that adipocyte non-autonomous mechanism in vivo is required for the reciprocal changes in expression of DGAT1 and DGAT2. In fact, intracerebroventricular infusion of leptin reduced DGAT2 expression in WAT of Irs2-/- mice and ob/ob mice, independently of DGAT1 expression. We propose the hypothesis that leptin regulates adipocyte size by altering expression patterns of DGAT via central nervous system to determine the levels of triglyceride synthesis.

3T3-L1 Cells↗

PubMed2004

Adenovirus-encoded hammerhead ribozyme to PDGF A-chain mRNA inhibits neointima formation after arterial injury.

To develop a strategy for gene therapy of restenosis following coronary angioplasty, we examined the effects of a recombinant adenovirus vector encoding a hammerhead ribozyme specific for rat platelet-derived growth factor (PDGF) A-chain mRNA (Ad. Ribozyme) and a control recombinant adenovirus vector encoding the Escherichia coli LacZ gene (Ad.LacZ) on neointima formation in rat carotid artery after balloon injury. Ad. Ribozyme (10(8) PFU/ml) markedly reduced the increased expression of PDGF A-chain mRNA and protein. Ad. Ribozyme significantly decreased the intima/media ratio (68%) of the injured artery, whereas Ad.LacZ had no effect on the intima/media ratio. Most carotid arteries developed thrombi by 14 days after balloon injury, whereas Ad. Ribozyme completely inhibited thrombus formation. Expression of thromboxane A2 (TXA2) receptor mRNA was significantly increased after balloon injury. Ad. Ribozyme significantly decreased the levels of TXA2 receptor. Expression of prostaglandin I2 (PGI2) synthase mRNA was significantly decreased after balloon injury. Ad. Ribozyme significantly increased levels of PGI2 synthase mRNA after balloon injury. The observation that adenovirus-encoded ribozyme to PDGF A-chain inhibits neointima formation may serve as a novel strategy to prevent restenosis after coronary angioplasty. Inhibition of growth factors by genetic approaches may yield new insights into the mechanisms underlying responses to vascular injury and lead to new therapeutic applications.

Adenoviridae↗

PubMed2004

Insulin/Foxo1 pathway regulates expression levels of adiponectin receptors and adiponectin sensitivity.

Adiponectin/Acrp30 is a hormone secreted by adipocytes, which acts as an antidiabetic and antiatherogenic adipokine. We reported previously that AdipoR1 and -R2 serve as receptors for adiponectin and mediate increased fatty acid oxidation and glucose uptake by adiponectin. In the present study, we examined the expression levels and roles of AdipoR1/R2 in several physiological and pathophysiological states such as fasting/refeeding, obesity, and insulin resistance. Here we show that the expression of AdipoR1/R2 in insulin target organs, such as skeletal muscle and liver, is significantly increased in fasted mice and decreased in refed mice. Insulin deficiency induced by streptozotocin increased and insulin replenishment reduced the expression of AdipoR1/R2 in vivo. Thus, the expression of AdipoR1/R2 appears to be inversely correlated with plasma insulin levels in vivo. Interestingly, the incubation of hepatocytes or myocytes with insulin reduced the expression of AdipoR1/R2 via the phosphoinositide 3-kinase/Foxo1-dependent pathway in vitro. Moreover, the expressions of AdipoR1/R2 in ob/ob mice were significantly decreased in skeletal muscle and adipose tissue, which was correlated with decreased adiponectin binding to membrane fractions of skeletal muscle and decreased AMP kinase activation by adiponectin. This adiponectin resistance in turn may play a role in worsening insulin resistance in ob/ob mice. In conclusion, the expression of AdipoR1/R2 appears to be inversely regulated by insulin in physiological and pathophysiological states such as fasting/refeeding, insulin deficiency, and hyper-insulinemia models via the insulin/phosphoinositide 3-kinase/Foxo1 pathway and is correlated with adiponectin sensitivity.

Adenoviridae↗

PubMed2004

Both insulin signaling defects in the liver and obesity contribute to insulin resistance and cause diabetes in Irs2(-/-) mice.

We previously reported that insulin receptor substrate-2 (IRS-2)-deficient mice develop diabetes as a result of insulin resistance in the liver and failure of beta-cell hyperplasia. In this study we introduced the IRS-2 gene specifically into the liver of Irs2(-/-) mice with adenovirus vectors. Glucose tolerance tests revealed that the IRS-2 restoration in the liver ameliorated the hyperglycemia, but the improvement in hyperinsulinemia was only partial. Endogenous glucose production (EGP) and the rate of glucose disappearance (Rd) were measured during hyperinsulinemic-euglycemic clamp studies: EGP was increased 2-fold in the Irs2(-/-) mice, while Rd decreased by 50%. Restoration of IRS-2 in the liver suppressed EGP to a level similar to that in wild-type mice, but Rd remained decreased in the Adeno-IRS-2-infected Irs2(-/-) mice. Irs2(-/-) mice also exhibit obesity and hyperleptinemia associated with impairment of hypothalamic phosphatidylinositol 3-kinase activation. Continuous intracerebroventricular leptin infusion or caloric restriction yielded Irs2(-/-) mice whose adiposity was comparable to that of Irs2(+/+) mice, and both the hyperglycemia and the hyperinsulinemia of these mice improved with increased Rd albeit partially. Finally combination treatment consisting of adenovirus-mediated gene transfer of IRS-2 and continuous intracerebroventricular leptin infusion completely reversed the hyperglycemia and hyperinsulinemia in Irs2(-/-) mice. EGP and Rd also became normal in these mice as well as in mice treated by caloric restriction plus adenoviral gene transfer. We therefore concluded that a combination of increased EGP due to insulin signaling defects in the liver and reduced Rd due to obesity accounts for the systemic insulin resistance in Irs2(-/-) mice.

Adenoviridae↗