Table 1.

Etiology of insulin resistance (IR).

Cause	Gene/Protein	Mechanism	Reference
Reduced insulin quantity or function	-	Autoimmune antibodies	[20]
	INS	Mutations in the insulin gene	[21,22]
Reduced INSR availability	-	Reduced exposure in the membrane	[23,24]
	-	Autoimmune antibodies	[25]
INSR mutations	INSR	Accelerated degradation	[26,27]
		In the ligand-binding domain	[28,29]
		In the tyrosine kinase domain	[27,30]
		Reduced mRNA expression	[31]
Mutations in other elements of the pathway	IRS-1	Impaired insulin signaling	[32,33,34,35]
	PTEN	Impaired end of signaling	[36,37]
	GLUT-4	Reduced glucose internalization in target tissues	[38]
	AKT and its targets	Impaired insulin signaling	[39,40,41,42]
Lipotoxicity	Lipoprotein lipase	Overexpression in muscle	[43]
	IKK and JNK	Endoplasmic reticulum stress by circulating FFA or ceramides	[44,45]
	Serine/threonine (Ser/Thr) kinases (PKC-θ, PKCβII and PKCδ)	DAG-induced activation	[46]
	IKKβ and NFκB	DAG-induced inhibition	[47]
Inflammation	Proinflammatory cytokines (MCP-1, TNF-α, IL1β or IL-6)	Adipocytes and macrophages triggered in obesity Inhibition of several steps of the insulin pathway	[15,48,49,50,51]
Mitochondrial Dysfunction	-	Reduced content and/or biogenesis	[52,53]
	-	Decreased ATP production and phosphocreatine recovery	[54,55,56,57]
	Citrate synthase	Decreased activity	[58]
	-	Lower OxPhos capacity	[59]
	-	Increased ROS	[60,61,62]
Alterations in the zinc metabolism	Zinc transporters (ZnT8, SLC30A8, ZnT7)	Regulation of multiple zinc-dependent effectors	[63,64,65,66,67]

The symbol “-” has been used when no specific gene or protein is related to the mechanism described.