Day 2 :
Department of endocrinology of Huashan Hospital Affiliated to Fudan University Institute of Endocrinology and diabetology, at Fudan University
Keynote: Anti inflammatory treatment of diabetes and metabolic syndrome or metabolic inflammatory syndrome
Time : 09:30-10:20
Dr Hu got the M.D and PhD from Shanghai second Medical University in 1973 and 1988. He worked the department of Endocrinology affiliated to University of Chicago during 1988-1990.
Dr Hu finished post doctor training in University of California during 1990-1993 and worked Department of Endocrinology at UCI as an assistant researcher from 1994 to 1996. He worked in Rui Jin Hospital affiliated to Shanghai Second Medical University during 1996-2002 as vice director of Institute of Endocrinogy of Shanghai and vice director of Department of Endocrinogy. He was promoted as a professor in 1999. He was director of Department of Endocrinology of Huashan Hospital affiliated to Fudan University and The Institute of Endocrinology and Diabetology at Fudan University during 2002-2010. Now Dr Hu is director of Institute of Endocrinology and Diabetology at Fudan University and director of Department of Endocrinology of Jinshan Hospital affiliated to Fudan Univesity.
Dr Hu is a council member of Chinese Diabetes association and director of the study group on microvascular complication of CDS. He is vice president of Shanghai association of diabetology. He is Editor in Chief of the Chinese edition of Diabetes Care and editorial board member Journal of Clinic Endocrinology and Metabolism and Chinese Diabetology.
Dr Hu has finished many important research projects such as Important National Nature Science Foundation of china, National High-Tech Project of china(863), National Basic Science Project of china(973), National Nature Science Foundation of china and so on. Dr Hu has published 171 papers including JCI, Diabetes, PNAS and two books in Chinese.
Changes in modern habits and environment produce metabolic products, including FFA and LPS, which polarize macrophages and induce chronic low grade inflammation, which damage tissues and organs and lead to metabolic diseases. Polarized macrophages not only participate in the pathophysiological process of AS, but macrophages can also invade the islets, adipocytes and liver tissues and damage these tissues and participate in the pathophysiological process of type 2 diabetes (T2DM), obesity and nonalcoholic fatty liver (NAFLD). AS, T2DM, NAFLD and obesity are closely related to chronic low grade inflammation and often accumulate, exist, or concurrency. Therefore, researchers compared AS, T2DM, NAFLD and obesity to 4 melons on a vine (chronic low inflammation), and proposed the concept and construction of metabolic inflammatory syndrome (Metabolic Inflammatory Syndrome, MIS). MIS is diagnosed as having 2 or more than 4 metabolic diseases above 4 in adition to the endocrine diseases of the known cause such as Cushing syndrome, Acromegaly and primary hypothyroidism.
The concept of MIS is in line with the theory of system biology and integrated medicine, which is beneficial to the interdisciplinary, basic and clinical combination, and to create a new method for the effective prevention and treatment of metabolic diseases with the same treatment of different diseases and the same treatment with different diseases. MIS is the development of metabolic syndrome (MS). As early as the 60-70 years of twentieth Century, researchers have found that obesity, hypertension, dyslipidemia, and diabetes are more likely to be associated with cardiovascular disease, and the combination of these metabolic risk factors is called metabolic syndrome . In 1998, WHO (WHO) expert group formally named this and put forward the diagnostic standard. Subsequently, various organizations discussed and revised their components. Microalbuminuria, impaired fasting blood glucose, or abnormality of glucose tolerance are still in the first 4 items, and the disputed risk factors include chronic low grade of inflammation (such as CRP, PAI-1), hyperuricemia, nonalcoholic fatty liver, and so on. According to the diagnostic criteria of MS, Cushing syndrome, Acromegaly and primary hypothyroidism and other diseases is also consistent with the diagnosis of MS, suggesting that MS concepts are to be discussed. The concept of MIS can better induce the metabolic diseases caused by chronic low grade inflammation. AS has become a major risk factor for human health. Therefore, screening and early diagnosis of AS is very important. The concept and diagnosis of MIS will encourage and promote T2DM, NAFLD and obese people to screen AS. Therefore, the concept of MIS is helpful for early diagnosis and prevention of AS.
Metformin and GLP-1 analogues are an effective drug for the treatment of diabetes and MIS through the indirect anti-inflammatory effects of hypoglycemic and direct anti-inflammatory effects of STAT3, which not only reduce glucose and have strong weight loss and reduce the risk of cardiovascular disease. Sulfonylureas and non sulfonylurea secretions inhibit ATP sensitive potassium channels to promote insulin secretion, and the ATP sensitive potassium channel plays a role in promoting inflammation, so this hypoglycemic agent also plays a direct and indirect way of reducing inflammation. Thiazolidone two ketones have direct and indirect mechanisms of anti-inflammatory action. Metformin, GLP-1 analogues and thiazolidinetwo can regulate STAT3, which inhibits macrophage polarization.
Dozens of anti inflammatory drugs designed for the design of interleukin, TNF and IKK beta -NF-k beta are being conducted in clinical studies, and some have been used to treat diabetes and get better results. Interleukin -1 (IL-1) receptor antagonist (Anakinra) not only significantly increases insulin secretion, but also decreases HbA1c, CRP and IL-6 in diabetic patients. And it can reduce the risk of cardiovascular events. The decrease of Foxo 1 level is closely related to dedifferentiation of beta cells, and Anakinra can significantly increase the level of Foxo1, suggesting that Anakinra may restore the function of beta cells by regulating dedifferentiation and redifferentiation.
We found that TM4(UBAC2) knockout (KO) mice developed obesity, hepatosteatosis, hypertension, and glucose intolerance under high-fat diet. TM4 counter-regulated Nur77, IKKβ, and NF-kB both in vivo and in vitro. TM4 SNP rs147851454 is significantly associated with obesity after adjusting for age and sex (OR 1.606, 95%CI 1.065-2.422 P=0.023) in 3394 non-diabetic and 1862 type 2 diabetic adults (age ≥ 19) of Han Chinese. TM4 was significantly down-regulated in the visceral fat tissue of patients with obesity who underwent laparoscopic cholecystectomy. The ubiquitin-proteasome inhibitors PS-341 and celastrol could regulate the degradation and function of TM4 and Foxo1 proteins. PS-341 and celastrol induced TM4 expression through inhibition of TM4 and Foxo1 degradation. In db/db mice, PS-341 intervention led to down-regulation of Nur77/IKKβ/NF-κB expression in visceral fat and liver, and alleviation of hyperglycemia, hypertension, and glucose intolerance. Hyperinsulinemic-euglycemic clamp demonstrated that PS-341 improved glucose infusion rate and alleviated insulin resistance in db/db mice. In conclusion, PS-341 and celastrol alleviate chronic low-grade inflammation and improves insulin sensitivity through inhibition of TM4 and Foxo1 degradation. Anti inflammatory reagents such as PS-341 and celastrol may be a candidate for the treatment of metabolic disorders including metabolic syndrome and metabolic inflammatory syndrome.
Associate Professor, Department of Nutrition and Food Sciences, Texas A&M University, Texas 77843, U.S.A.
Keynote: Insulin Signaling, Resistance, and Metabolic Syndrome: Insights from Mouse Models into Disease Mechanisms
Time : 10:20-11:10
Dr. Shaodong Guo is Associate Professor in the Department of Nutrition and Food Science at Texas A&M University College. He received his Ph.D in Physiology from Peking University, China. Then he completed his postdoctoral research training in Genetics, Biochemistry, and Medicine in the Chinese Academy of Sciences, the University of Illinois at Chicago, and Harvard University, respectively. Dr. Guo was an Instructor in Medicine at Children's Hospital Boston and Harvard Medical School for two years prior to joining the faculty at Texas A&M Health Science Center. Currently, Dr. Guo serves as senior editor for the Journal of Endocrinology and Journal of Molecular Endocrinology, two major official journals of Endocrine Society of Europe, UK, and Australia, and he is the textbook chapter writer for Metabolic Syndrome edited by Rexford Ahima and published by Springer in 2016. Dr. Guo lab research focuses on insulin/glucagon and estrogen signal transduction, insulin resistance, gene transcriptional control of nutrient homeostasis, and cardiac dysfunction in diabetes. Dr. Guo has been working on the gene transcriptional regulation of metabolic homeostasis by insulin receptor substrate proteins (IRS) and Forkhead FoxO transcription factors and he has been funded by American Diabetes Association (ADA), American Heart Association, and the National Institute of Health of USA. He is a recipient of ADA junior faculty award, career development award, and Richard R. Lee Award. His work has been published in a number of journals including the JBC, Endocrinology, Hypertension, Diabetes, Circulation Research, AJP, MCB, and Nature Medicine, receiving more than 5,000 citations from the Google Scholar.
Insulin resistance serves as the major mechanism for the development of obesity, which is pandemic in population worldwide over the past decades, largely owing to over nutrition. Excess energy stores in the adipose tissue and other organs as lipids, promoting lipotoxicity and metabolic inflammation, activating intracellular protein kinases to impair insulin signaling components, and resulting in insulin resistance. Insulin resistance is the key etiologic defect that defines “metabolic syndrome”, a group of interrelated disorders, including obesity, hyperglycemia, dyslipidemia, and hypertension. Following insulin resistance, many of patients with the metabolic syndrome eventually developed pancreatic β-cell failure, which triggers the onset of type 2 diabetes mellitus (T2DM) and its complications. Our cell- and animal-based studies demonstrate that insulin and its signaling cascades normally control cell growth, metabolism and survival through activation of mitogen-activated protein kinases (MAPKs) and phosphotidylinositide-3-kinase (PI3K), of which activation of PI-3K-associated with insulin receptor substrate-1 and -2 (IRS1, 2) and subsequent Akt→Foxo1 phosphorylation cascade has a central role in control of nutrient homeostasis and organ survival. Inactivation of Akt and activation of Foxo1, through suppression IRS1 and IRS2 in a variety of organs following over nutrition, lipotoxicity, and inflammation may form a fundamental mechanism for insulin resistance in humans. This seminar discusses the basis of insulin signaling, resistance, and how excess nutrients and lipid signaling from obesity promotes inflammation and insulin resistance, promoting organ failure with emphasis on the IRS and the forkhead/winged-helix transcription factor Foxo1.
Brock University, Canada
Keynote: Antidiabetic properties of Rosemary polyphenols: Carnosol increases skeletal muscle cell glucose uptake via AMPK-dependent GLUT 4 glucose transporter translocation
Time : 11:30-12:20
Dr Tsiani’s research focus is to investigate the biological effects and the mechanism of action of plant-derived polyphenols. She has expertise in muscle metabolism, insulin resistance, cell signaling pathways and cancer biology. Both in vitro cell culture models as well as in vivo, animal models are used in her research studies.
Normal cellular function is maintained by a complex system of signaling molecules (signaling cascades) that coordinate cell response to various stimuli. Defects in cellular signaling can lead to diseases such as diabetes (insulin resistance) and cancer. Understanding cell signaling is of major importance and provides the basis for defining novel tools for targeting signaling molecules and pathways involved in diseases. Dr Tsiani’s research has indicate strong antidiabetic and anticancer properties of plant polyphenols.
Statement of the Problem: Skeletal muscle is highly important in glucose homeostasis since it is quantitatively a major insulin-target tissue. Insulin action in muscle cells activates the phosphatidylinositol-3 kinase (PI3K)/Akt signaling pathway causing the translocation of intracellularly stored GLUT4 glucose transporters to the plasma membrane leading to increased glucose uptake. Impaired insulin action in muscle leads to insulin resistance and type 2 diabetes mellitus (T2DM). AMP-activated kinase (AMPK) is a cellular energy sensor and its activation increases glucose uptake by skeletal muscle cells. Finding AMPK activators is viewed as an effective approach to combat insulin resistance and T2DM. Rosemary extract (RE) has been shown to increase muscle glucose uptake and AMPK activity but the components responsible for these effects have not been identified yet. In the current study, we investigated the effect of carnosol, a polyphenol found in high concentrations in RE.
Methodology: L6 rat muscle cells were used to measure uptake of [3H]-2-deoxy-D-glucose and the signaling molecules involved were investigated by immunoblotting.
Findings: Carnosol stimulated glucose uptake in L6 myotubes in a dose- and time-dependent manner. A response comparable to maximum insulin stimulation (196+9.2 % of control) was seen with 50μM of carnosol (2h) (182+7.8 % of control). Carnosol did not affect Akt phosphorylation while it significantly increased AMPK phosphorylation. Furthermore, the increase in glucose uptake in the presence of carnosol was significantly reduced by the AMPK inhibitor compound C (CC) while it was not affected by the PI3K inhibitor wortmannin. Carnosol increased plasma membrane GLUT4 glucose transporter levels in GLUT4myc overexpressing L6 cells and this response was abolished by the AMPK inhibitor CC.
Conclusion & Significance: Our study is the first to show a significant increase in muscle glucose uptake by carnosol via a mechanism that involves AMPK. Carnosol has potential as a glucose homeostasis regulating agent and deserves further study.