Endocrinology and Metabolic Syndrome

Biography

Biography: Renming Hu

Abstract

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.