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Current Advances in the Biochemical and Physiological Aspects of the Treatment of Type 2 Diabetes Mel 时间:2017-06-14 08:59 来源:未知作者:admin 点击: 次 Abstract:The present review summarizes the current advances in the biochemical and physiological aspects in the treatment of type 2 diabetes mellitus (DM2) with thiazolidinediones (TZDs). DM2 is a metabolic disorder characterized by hyperglycemia, triggering the abnormal activation of physiological pathways such as glucose autooxidation, polyol’s pathway, formation of advance glycation end (AGE) products, and glycolysis, leading to the overproduction of reactive oxygen species (ROS) and proinflammatory cytokines, which are responsible for the micro- and macrovascular complications of the disease. The treatment of DM2 has been directed toward the reduction of hyperglycemia using different drugs such as insulin sensitizers, as the case of TZDs, which are able to lower blood glucose levels and circulating triglycerides by binding to the nuclear peroxisome proliferator-activated receptor gamma (PPARγ) as full agonists. When TZDs interact with PPARγ, the receptor regulates the transcription of different genes involved in glucose homeostasis, insulin resistance, and adipogenesis. However, TZDs exhibit some adverse effects such as fluid retention, weight gain, hepatotoxicity, plasma-volume expansion, hemodilution, edema, bone fractures, and congestive heart failure, which limits their use in DM2 patients.
1. Introduction
The treatment of type 2 diabetes mellitus (DM2) has been directed toward the reduction of hyperglycemia and glycosylated hemoglobin (HbA1c, ≤7%), in order to prevent cardiovascular and other long term risks [1, 2], specially by the usage of insulin sensitizers such as thiazolidinediones (TZDs) [1–5], an effective type of drugs for lowering blood glucose levels as circulating triglycerides [4, 6–9], with adverse effects such as adipocyte differentiation, fluid retention, weight gain, bone loss, and congestive heart failure [6–8, 10–13].
Clinically, pioglitazone is the only available TZD, even though its commercialization has been restricted to a few countries by the US Food and Drug Administration (FDA) since it may cause urinary bladder cancer. The other TZDs, rosiglitazone and troglitazone, show adverse profiles, so they are no longer available in the worldwide market; for example, rosiglitazone was associated with a significant increase in myocardial infarction, heart failure, and death from cardiovascular diseases, so the European Medicines Agency withdrew the approval for this medication in 2010, and the FDA restricted its prescription in the United States [3, 14–17].
In the present review, we summarize the current advances on the biochemical and physiological aspects involved in the treatment of DM2 with TZDs.
Type 2 Diabetes Mellitus (DM2). DM2 is a metabolic disorder characterized by hyperglycemia, which may be due to a defect in insulin secretion of pancreatic β cells, insulin resistance in peripheral tissues, and/or an excessive accumulation of triglycerides and fatty acid derivatives in skeletal muscles. This pathology remains a leading cause of cardiovascular disorders, such as microvascular (retinopathy, nephropathy, and neuropathy) and macrovascular (coronary, cerebrovascular, and peripheral vascular diseases) complications, mainly triggered by the abnormal activation of physiological pathways (Figure 1), and it is also associated with increased risk of cancer, psychiatric illness, cognitive decline, chronic liver disease, and development of arthritis [1–4, 18–24].
The treatment of DM2 is directed toward the reduction of hyperglycemia and HbA1c (≤7%), in order to prevent cardiovascular and other long term risks (Table 1) [1, 2, 5]; there is a wide range of drugs which can be used in order to reduce glycemia, being notable mechanisms such as improving insulin secretion and reducing insulin resistance of peripheral tissues, as the case of TZDs [1–5], which are drugs targeting the peroxisome proliferator-activated receptor gamma (PPARγ).PPARs have emerged as links between lipids, metabolic diseases, and innate immunity as they regulate energy homeostasis [25, 26], and, specifically talking about PPARγ, this receptor is capable of regulating metabolic genes which will be further discussed and improves insulin sensitivity through glucose and lipid uptake and storage in peripheral tissues such as skeletal muscle, liver, and adipose tissue [26].
The relationship between PPARγ and DM2 has been established using both in vitro and in vivo experimentation, since it has been seen that the inactivation of PPARγ in mature adipocytes leads to insulin resistance, as mice lacking the receptor develop hyperlipidemia, hyperglycemia, and/or hyperinsulinemia [26, 27].