Hypothalamic miR-1983 Targets Insulin Receptor β and the Insulin-mediated miR-1983 Increase Is Blocked by Metformin

Jennifer A Chalmers1, Prasad S Dalvi1, Neruja Loganathan1

  • 1Department of Physiology, University of Toronto, Toronto, Ontario M5S 1A8, Canada.

Endocrinology
|December 17, 2021
PubMed

Insights

A novel microRNA, miR-1983, is elevated in cellular insulin resistance and detectable in human blood. This microRNA may serve as a biomarker and therapeutic target for metabolic diseases.

Area of Science:

  • Neuroendocrinology
  • Metabolic Regulation
  • Molecular Biology

Background:

  • Hypothalamic microRNAs (miRNAs) regulate energy balance and metabolism.
  • Central insulin resistance precedes peripheral insulin resistance.
  • Identifying a hypothalamic miRNA signature for insulin resistance is crucial.

Purpose of the Study:

  • To determine if central insulin resistance generates a specific hypothalamic miRNA signature.
  • To investigate the role of miR-1983 in hypothalamic insulin resistance.
  • To assess miR-1983 as a potential biomarker and therapeutic target for metabolic disease.

Main Methods:

  • In vitro studies using insulin-resistant hypothalamic neuronal models (NPY-expressing).
  • In vivo studies in hyperinsulinemic mice.
  • Detection and correlation analysis of miR-1983 in human blood serum.
  • Assessment of metformin's effect on miR-1983 levels.

Main Results:

  • miR-1983 was upregulated in insulin-resistant hypothalamic models and hyperinsulinemic mice.
  • Insulin receptor β subunit protein decreased, correlating with miR-1983 levels.
  • miR-1983 levels in human serum correlated with insulin and HOMA-IR.
  • Metformin normalized miR-1983 levels in cell culture.

Conclusions:

  • miR-1983 is a unique biomarker for cellular insulin resistance.
  • miR-1983 is a potential therapeutic target for metabolic diseases.
  • Hypothalamic miR-1983 alterations are linked to systemic insulin resistance.

Related Concept Videos

Oral Hypoglycemic Agents: Biguanides and Glitazones01:26

Oral Hypoglycemic Agents: Biguanides and Glitazones

Biguanides, particularly metformin (Glucophage), are insulin sensitizers that enhance glucose uptake, thereby reducing insulin resistance. Unlike sulfonylureas, metformin doesn't prompt insulin secretion, which helps to curb hypoglycemia risk. Metformin is beneficial in treating conditions like polycystic ovary syndrome due to its insulin-resistance reduction capability. The drug's primary action involves curtailing hepatic gluconeogenesis, a significant contributor to high blood...
336
Insulin: The Receptor and Signaling Pathways01:28

Insulin: The Receptor and Signaling Pathways

Insulin action is mediated through a receptor tyrosine kinase, akin to the IGF-1 receptor. The number of receptors per cell varies significantly, from 40 on erythrocytes to 300,000 on adipocytes and hepatocytes. The insulin receptor consists of linked α/β subunit dimers, forming a heterotetramer glycoprotein with two extracellular α subunits and two β subunits spanning the membrane. The α subunits inhibit the inherent tyrosine kinase activity of the β subunits, but...
1.7K
Dipeptidyl Peptidase 4 Inhibitors01:23

Dipeptidyl Peptidase 4 Inhibitors

Dipeptidyl peptidase 4 (DPP-4) is a serine protease widely distributed in the body. It's involved in the inactivation of GLP-1 and GIP hormones, which are crucial for insulin regulation. DPP-4 inhibitors, such as sitagliptin (Januvia), saxagliptin (Onglyza), linagliptin (Tradjenta), alogliptin (Nesina), and vildagliptin (Galvus), help increase the proportion of active GLP-1, enhancing insulin secretion. These inhibitors work by competitively binding to DPP-4. This binding causes a...
282
Glucagon-like Receptor Agonists01:24

Glucagon-like Receptor Agonists

Incretins include glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), which stimulate insulin secretion post-meals. In type 2 diabetes, GIP's efficacy is reduced, making GLP-1 a viable drug target. GIP originates from preproGIP.
GLP-1, when administered in high doses intravenously, triggers insulin secretion, inhibits glucagon release, slows gastric emptying, reduces food intake, and restores normal insulin secretion. However, its rapid inactivation by...
467
Hormones Regulating Blood Glucose01:16

Hormones Regulating Blood Glucose

Insulin is released by beta cells of the pancreas when blood glucose levels are high. It facilitates glucose absorption and utilization in insulin-dependent cells with insulin receptors on their plasma membranes. Insulin promotes glucose uptake by increasing the number of glucose transport proteins in the cell membrane, allowing glucose to enter the cell. As a result, glucose utilization and ATP production are enhanced.
In addition to accelerating glucose uptake and utilization, insulin has...
4.7K
Oral Hypoglycemic Agents: Glinides01:06

Oral Hypoglycemic Agents: Glinides

Repaglinide (Prandin) and Nateglinide (Starlix), known as glinides, are oral insulin secretagogues that stimulate insulin release from pancreatic β cells by closing the ATP-sensitive potassium channels (KATP channel). Repaglinide controls insulin release from pancreatic β cells by managing potassium efflux. It shares two binding sites with sulfonylureas and also has a unique site, indicating overlapping mechanisms of action. With a rapid onset and a 4-7 hour duration, it effectively...
293