Hereditary severe insulin resistance syndrome: Pathogenesis, pathophysiology, and clinical management

Abstract

Severe insulin resistance has been linked to some of the most globally prevalent disorders, such as diabetes mellitus, nonalcoholic fatty liver disease, polycystic ovarian syndrome, and hypertension. Hereditary severe insulin resistance syndrome (H-SIRS) is a rare disorder classified into four principal categories: primary insulin receptor defects, lipodystrophies, complex syndromes, and obesity-related H-SIRS. Genes such as INSR, AKT2, TBC1D4, AGPAT2, BSCL2, CAV1, PTRF, LMNA, PPARG, PLIN1, CIDEC, LIPE, PCYT1A, MC4R, LEP, POMC, SH2B1, RECQL2, RECQL3, ALMS1, PCNT, ZMPSTE24, PIK3R1, and POLD1 have been linked to H-SIRS. Its clinical features include insulin resistance, hyperglycemia, hyperandrogenism, severe dyslipidemia, fatty liver, abnormal topography of adipose tissue, and low serum leptin and adiponectin levels. Diagnosis of H-SIRS is based on the presence of typical clinical features associated with the various H-SIRS forms and the identification of mutations in H-SIRS-linked genes by genetic testing. Diet therapy, insulin sensitization, exogenous insulin therapy, and leptin replacement therapy have widely been adopted to manage H-SIRS. The rarity of H-SIRS, its highly variable clinical presentation, refusal to be tested for genetic mutations by patients' family members who are not severely sick, unavailability of genetic testing, and testing expenses contribute to the delayed or underdiagnoses of H-SIRS. Early diagnosis facilitates early management of the condition, which results in improved glycemic control and delayed onset of diabetes and other complications related to severe insulin resistance. The use of updated genetic sequencing technologies is recommended, and long-term studies are required for genotype-phenotype differentiation and formulation of diagnostic and treatment protocols.

Keywords: Diabetes; Genetics; Insulin resistance; Lipodystrophy; Pathophysiology; Therapy.

Figure 1

H-SIRS related genes and pathogenesis. (A) Insulin binds to insulin receptor and activates receptor tyrosine kinases, and then followed by IRS/PI3K/AKT act as a complex. GLUT4 moving from the inside to the surface of the cell by GSV, due to the inhabitation of TBCID4 phosphorylation, this is the process of insulin-mediated glucose uptake. (B) The expression of SREBP1c is activated by insulin, induced by AKT and mTORC1, mediating the de novo lipogenesis. (C) Activation of PI3K and PDE3B decreased the concentration of cAMP, and decreased phosphorylation of perilipin (encoded by PLIN1) and recruitment of HSL (encoded by LIPE) to inhibit lipolysis. (D) The process of de novo lipogenesis and the enzymes involved. CIDEC is co-localized with the lipid droplet protein perilipin. Caveolae is the flask-like invaginations of the plasma membrane, Caveolin (encoded by CAV1) is the major protein of Caveolae, Cavin (encoded by PTRF) is peripheral membrane protein of Caveolae. Lamins (Lamin A and Lamin C are encoded by LMNA) are intermediate filaments structural protein underlying the inner nuclear membrane. H-SIRS related genes are embedded with gray boxes. AGPAT: 1-acyl-glycerol-3-phosphate acyltransferase; AKT2: AKT serine/threonine kinase 2; cAMP: cyclic adenosine monophosphate; CAV1: Caveolin 1; CIDEC: cell death-inducing DFFA like effector c; DAG: diacylglycerol; DGAT2: DAG-O-acyltransferase; FA-COA: fat acyl coenzyme A; GLUT4: glucose transporter 4; GPAT: glycerol-3-phosphate acyltransferase; GSV: GLUT4-containing storage vesicles; G3P: glycerol-3-phosphate; HSL: hormone-sensitive lipase; INSR: insulin receptor; IRS: insulin receptor substrate; LIPE: lipase E, hormone-sensitive type; LMNA: lamin A/C; LPA: lysophosphatidic acid; mTORC1: mammalian target of rapamycin complex 1; PA: phosphatidic acid; PAP: phosphatidate phosphatase; PDE3B: phospho-diesterase 3B; PI3K: phosphatidylinositol 3-kinase; PLIN1: Perilipin 1; PKA: protein kinase; TAG: triglyceride; PPARG: peroxisome proliferator-activated receptor Gamma; PTRF: polymerase I and transcript release factor; SREBP1c: sterol regulatory element binding transcription factor 1; TBC1D4: TBC1 domain family member 4.