Abstract
Diabetes mellitus is a pathology with increasing frequency in society, being one of the main causes of death worldwide. For this reason, new therapeutic targets have been studied over the years. 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) is an enzyme responsible for reducing cortisone to its active form cortisol, which can lead to metabolic changes such as insulin resistance and hyperglycemia. Therefore, 11β-HSD1 inhibition may offer a new therapeutic approach for type 2 diabetes mellitus. This work intends to systematically review the available scientific evidence on this subject. For this, a search was conducted in three databases and 15 clinical and in vivo preclinical studies were included in this review. Despite the high inhibitory and selectivity levels achieved with several molecules and the demonstrated clinical efficacy in diabetes treatment, no phase III clinical trials have yet been conducted. This is important because the long-term effects of 11β-HSD1 inhibitors including the consequences in hypothalamic–pituitary–adrenal axis must be evaluated. However, this enzyme remains a promising target for drug development, including due to its effectiveness in controlling various factors that constitute the metabolic syndrome and its potential for multiple indications in patients with diabetes, including wound healing and weight loss.
Highlights
Type 2 diabetes mellitus (T2DM) is a common chronic disease characterized by increased blood glucose levels, called hyperglycemia, and its prevalence increases with age, affecting both sexes and all age groups [1]
It is not selective, it has shown the ability to increase the sensitivity to hepatic insulin and to decrease glucose production, which is a clear evidence of the potential metabolic benefits of inhibiting 11β-HSD1 in T2DM control [36]
No phase III clinical trials have yet been conducted and there are several challenges to be addressed. For this class of compounds, efficacy assessments are difficult in early-phase clinical studies as it is unclear after which treatment duration 11β-HSD1 inhibitors start to lead to a consistent blood glucose-lowering effect and how long it takes to achieve maximum glucose-lowering efficacy
Summary
Type 2 diabetes mellitus (T2DM) is a common chronic disease characterized by increased blood glucose levels, called hyperglycemia, and its prevalence increases with age, affecting both sexes and all age groups [1]. It is worth highlighting retinopathy (the main cause of blindness in adults), neuropathy (which, in combination with macrovascular dysfunction leads to the appearance of diabetic foot ulcers and, in extreme situations, amputation), and nephropathy (which, in more advanced cases, can cause renal failure) [3]. The most common macrovascular complications are atherosclerosis (which can lead to the development of coronary artery disease or angina pectoris and, in more serious conditions, acute myocardial infarction) and arteriosclerosis (which increases blood pressure, among other problems) [3]. Several criteria may be independently used to establish the diagnosis of T2DM: A 75 g oral glucose tolerance test with a 2 h value of 200 mg/dL (11.1 mmol/L) or higher; a random plasma glucose of 200 mg/dL (11.1 mmol/L) or more with typical symptoms of hyperglycemia; a fasting plasma glucose of 126 mg/dL (7.0 mmol/L) or higher on more than one occasion; or a glycated hemoglobin (HbA1c) value of 6.5% (48 mmol/mol) or more [2]
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