Endocrinol Metab.  2012 Mar;27(1):12-19. 10.3803/EnM.2012.27.1.12.

Mechanism of Lipid Induced Insulin Resistance: An Overview

• Bhattacharya S
• Kundu R
• Dasgupta S
• Bhattacharya S

• KMID: 2134812
• DOI: http://doi.org/10.3803/EnM.2012.27.1.12

Abstract

Type 2 diabetes (T2D) is rapidly spreading throughout the world. It's an insidious disease and still treated in an indirect manner without having specific drug target. In majority cases T2D is treated with drugs that address type 1 diabetes, majority of drugs aim to increase insulin release although the root cause for T2D is not the dearth of insulin release, it occurs in the later stage of disease development. T2D silently progressed in the patient; it begins with insulin resistance that takes place due to the loss of insulin sensitivity. Though insulin resistance is the centre of pathogenesis, our treatment of the disease has not yet addressed it. It is now a fact that insulin resistance is manifested by lipid and fatty acids (FAs) play a critical role in blunting insulin sensitivity. Our understanding is still poor in deciphering how lipid impose insulin insensitivity, majority of workers suggest it is because of insulin signaling defects which implements insulin function in inhibiting glucose to the cell from circulation. Number of long chain saturated FA has been shown to produce insulin signaling defects. However, we really need further investigation to find specific target(s) for FA induced damage. In addition to these information, a new dimension of T2D is getting attractive is fetuin-A/alpha2-Heremans-Schmid Glycoprotein, a secretary protein from liver. Its gene locus has been identified as T2D susceptible. Fetuin-A's excess expression occurs by FA and it disrupts adipocyte function. It has been shown to be associated with T2D especially in obesity. In this review, we briefly discuss the present status on the mechanistic understanding of lipid induced insulin resistance that leads to T2D. More we understand the mechanism; opportunity to fight the battle with T2D will be increasing. Since, this field is now vast; we covered a few major events.

Keyword

Alpha-2-HS-Glycoprotein; Fatty acids; HMGA1; Insulin resistance; Lipids; Novel PKCs; Type 2 diabetes

MeSH Terms

Adipocytes
alpha-2-HS-Glycoprotein
Fatty Acids
Glucose
Glycoproteins
Hypogonadism
Insulin
Insulin Resistance
Liver
Mitochondrial Diseases
Obesity
Ophthalmoplegia
Fatty Acids
Glucose
Glycoproteins
Hypogonadism
Insulin
Mitochondrial Diseases
Ophthalmoplegia
alpha-2-HS-Glycoprotein

Figure

• 

  Fig. 1. Schematic representation of insulin signaling pathway. Fatty acid (FA) has been reported to impair this pathway by producing defects on insulin receptor (IR), insulin receptor substrate (IRS1), phosphatidylinositol 3-kinase (PI3K), phophoinositide-dependent kinase1 (PDK1), Akt/protein kinase B (PKB), and glucose transporter 4 (Glut4).

• 

  Fig. 2. Fatty acid (FA) causes insulin receptor (IR) downregulation through pPKCε. FA affected a kinase independent phosphorylation of PKCε through pal-mitoylation in case of palmitate, pPKCε is translocated to nucleus by F-actin where it impairs high mobility group A1 (HMGA1) which regulates IR gene transcription by permitting Sp1 and CCAAT/enhancer-binding protein beta transcription factor to the IR promoter. All these resulted downregulation of IR expression.

• 

  Fig. 3. Fatty acid induced elevated expression of fetuin-A is mediated through NF-κ B. Increase of pNF-κ B level effected enhanced expression of fetuin-A. Since fetuin-A is a secretary protein, it immediately released into the circulation and reaches adipocytes. This causes adipocyte dysfunction as marked by increase of inflammatory cytokines and suppression of adipogenic factors. All together lead to insulin resistance which is evident by decreased glucose uptake along with impaired glucose transporter 4 (Glut4) translocation.

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