Discovery of novel molecular pathways linked to Insulin Resistance

Introduction

Insulin resistance (IR) is a clinical and major pathological condition that occurs due to inappropriate cell response to insulin hormone and abnormal secretion in the body.

The decrease in insulin sensitivity leads to the progression of many metabolic disorders such as auto-immune diseases, type-1 diabetes mellitus (T1DM), obesity, atherosclerosis, cardiovascular diseases, etc. In some cases recently, insulin resistance has been connected to neurodegeneration and cancer progression (Yaribeygi, Farrokhi, Butler, & Sahebkar, 2019). 

Apart from this, obese people, particularly with high-fat abdominal adipose tissue are more prone to dangerous diseases such as cancer and neurodegeneration, which has recently been concluded by the researchers. 

Although the precise molecular mechanisms are unknown, it is believed that some underlying causes may be oxidative stress, endoplasmic reticulum (ER) stress, mitochondrial dysfunction, mutations and inflammation. The exact cause of IR remains to be understood.

In the process of investigating the therapeutic approach for insulin resistance-based diseases, it is essential to understand the molecular mechanisms and intracellular pathways of important hormones that are related to insulin action such as glucagon-like peptide-1 (GLP-1) and gastric inhibitory polypeptide (GIP). 

GLP-1 promotes insulin secretion from pancreatic beta-cells by regulating blood glucose. It also decreases insulin secretion during low blood glucose levels, hence the risk of hypoglycemia and glycated hemoglobin levels are reduced (Cheng et al., 2019; Vanderheiden et al., 2016).

Therefore, GLP-1 and its analogs are used as an anti-diabetic drug for treatment of insulin-resistance-based disorders.

Common anti-diabetic drug

Liraglutide: It is an acylated analogue of GLP-1, which is the most common antidiabetic drug administrated subcutaneously.  This drug is highly protein bound (98%) due to additional 16-carbon fatty acid and amino acid-based spacer, which plays reversible binding agonist to albumin and increases DPP-4 resistance. It also does not interfere with the cytochrome P450, so it can be eliminated in small peptides through liver and kidneys. 

It shows efficacy in treating Type 2-diabetes mellitus in which it showed significant decreases in glucose, body weight and blood pressure. However, recent clinical studies showed that the treatment with liraglutide is significant but limited (Cummings et al., 2010; Gupta, 2013).

Links between cancer, Alzheimer’s and Insulin resistance

Insulin resistance is the most common age-related problem. There are links between the pathophysiology of both diabetes and Alzheimer’s as insulin shows diverse effects on various pathways in the central nervous system by regulating potential mechanisms such as hyperglycemia, adipokine action and influence of obesity on cerebrovascular disease (Hall et al., 2017; O’Harte, Parthsarathy, Hogg, & Flatt, 2018; Wysocka, Pietraszek-Gremplewicz, & Nowak, 2018). 

Recent studies showed that GLP-1 analogues and incretin-based drugs showed potential risk in breast cancer, pancreatic or thyroid cancer and polycystic ovarian syndrome (PCOS)(Boniol et al., 2018).

Involvement of insulin signaling in carcinogenesis, especially in overexpression of insulin receptor phosphorylation (IRS-1) and altered expression of fatty acid metabolism pathways showed risk in colorectal and endometrial cancer.

In obesity, the adipose tissue and adipocytes play a major role and studies support that these likely have a role in cancer development as they produce many substances such as adiponectin, leptin and apelin. Leptin has cancer stimulating and AD inhibiting properties and adiponectin can inhibit cancer but stimulate AD properties (Orgel & Mittelman, 2013).

So, the effects of liraglutide and novel pathways associated with incretin and insulin signaling pathways and other molecular pathways can be studied and can lead to deeper insights into molecular mechanisms underlying insulin resistance.

Author

Asha Guraka

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