Review
Copyright ©The Author(s) 2022.
World J Diabetes. Apr 15, 2022; 13(4): 282-307
Published online Apr 15, 2022. doi: 10.4239/wjd.v13.i4.282
Table 2 Various causes of the genetic type of insulin resistance
Site of defect
Type of defect
Clinical features
Insulin receptor: Mutations in the INSR gene (19p13.2) → faulty insulin receptor that cannot transmit signals properlyType A IR syndrome mutation in the INSR gene (19p13.2)Females are more affected than males. Appear during adolescence (delayed menses, 1ry amenorrhea, oligomenorrhea, hirsutism, acanthosis nigricans). Some males may have hypoglycemia & occasionally acanthosis nigricans. Later, they may develop DM
Leprechaunism or Donohue syndrome (extremely rare) autosomal recessiveExtreme insulin resistance with fasting hypoglycemia and postprandial hyperglycemia, low birth weight, distinctive craniofacial features (bulging eyes, protuberant and low-set ears, thick lips, and upturned nostrils), skin abnormalities (hyperkeratosis), enlargement of the breast and clitoris in females and the penis in males, growth delays, & features of other endocrinopathies
Rabson-Mendenhall syndrome (rare) autosomal recessive, also include Donohue syndromeSevere insulin resistance, low birth weight, failure to thrive, lack of subcutaneous fat, muscle wasting, dental abnormalities; hirsutism, polycystic ovaries in females; enlargement of the nipples, genitalia, kidneys, heart, and other organs. Most affected individuals also have acanthosis nigricans, and distinctive facial features include prominent hypertelorism; a broad nose; and large, low-set ears
Polymorphism in PC-1It causes PC-1 overexpression to reduce autophosphorylation of the insulin receptor β-subunit, impairs insulin stimulation of insulin receptor activation & downstream signaling with short at birth, hyperinsulinemia, and high insulin resistance, high prevalence of diabetes, hypertension, and preeclampsia
Defects in fat cell and lipid homeostasis pathwayCongenital generalized lipodystrophy (mutations in BSCL2 on 11q13, & AGPAT2 gene on 9q34)Autosomal recessive, extreme lack of body fat, and severe insulin resistance since birth
Kobberling's syndrome (mutation in the PPAR-δ gene) FPL type 1X-linked dominant, lethal in the hemizygous male. The autosomal dominant form of familial partial lipodystrophy was also described, characterized by the absence of subcutaneous fat, and presence of adipose tissue inside the body cavities and skeletal muscle hypertrophy. Fat loss is generally confined to the arms and legs. Fat loss is usually more prominent on the arms and legs' lower (distal) portions than proximal
Dunnigan's syndrome (LMNA gene mutation) (1q22) FPL type 2An X-linked dominant, lethal in hemizygous males, present with partial lipodystrophy characterized by sparing of the face. The onset of lipodystrophy usually occurs at or around puberty, with improper fat distribution (loss of fat in the limbs and gluteal region and variable regional fat accumulation on the face, neck, and axillary regions giving patients a cushingoid appearance). Females often have a more severe phenotype than males. An increased skeletal muscle volume and mass are also noted. Prominent veins (due to lipoatrophy) are noted in the limbs
Allelic variation in PPAR-δ, PPAR-α, polymorphism of UCP1, UCP2, UCP3 genes & polymorphism of β-2 and β-3 adrenergic receptorAllelic variation in PPAR-δ influences body fat mass by effects on adipocyte; polymorphisms of PPAR-α gene can lead to higher triglyceride and insulin levels; polymorphism of the lipoprotein lipase gene was both linked and associated with insulin resistance; polymorphism of UCP1, UCP2, UCP3 genes are associated with marked adiposity and DM type II; and polymorphism of β-2 and β-3 adrenergic receptors associated with chronic non-communicable disorders, such as cardiovascular diseases, asthma, chronic obstructive pulmonary disease, and obesity, as well as β-agonists and antagonists response and toxicity
Proteases CALP10CALP10 gene polymorphismIt is associated with reduced muscle mRNA levels and insulin resistance, metabolic syndrome, type II DM, and polycystic ovary syndrome
Other hormonal disordersPOMC mutationsCauses mutations in the POMC gene were linked with a clinical phenotype of adrenal insufficiency, red hair pigmentation, early-onset and rapidly progressive obesity, early-onset type 2 diabetes, hypothyroidism, hypogonadism, and growth hormone deficiency
The MC4R gene mutationsMC4R mutations are the most common form of monogenic obesity and have been implicated in 1% to 6% of early-onset severe obesity
The MC3R gene mutationsInactivating mutations in the MC3R gene causes obesity in mice but is not clear in human
Leptin and leptin receptor mutationsHomozygous leptin gene mutations are associated with the early onset of severe obesity and diverse impairment of physiological functions. Recessive leptin receptor mutations are associated with similar pathology in the homozygous state
Ghrelin polymorphismsGhrelin is an orexigenic peptide that stimulates appetite and induces body weight gain and adipogenesis. Ghrelin polymorphisms may be associated with obesity and obesity-related phenotypes
NPY geneNPY gene polymorphism is associated with an increased risk of metabolic syndrome and its related phenotypes, such as central obesity and hyperglycemia
CART polymorphisms CART gene polymorphism is associated with a genetic predisposition to insulin resistance & obesity
ER mutationsER mutations cause impaired insulin sensitivity/glucose intolerance, hyperinsulinemia, and obesity
Prader-Willi syndrome15q11.2–q12, uniparental maternal disomyA key feature of Prader-Willi syndrome is a constant sense of hunger (hyperphagia) that usually begins at about 2 years of age with several physical, mental, and behavioral problems
Alström syndromeMutations in the ALMS1 geneThe ALMS1 gene provides instructions for making a protein whose function is unknown. ALMS1 gene mutants in the hypothalamus might lead to hyperphagia followed by obesity and insulin resistance
Bardet-Biedl syndromeMutations in at least 14 different genes (often called BBS genes)Vision loss is one of the significant features of Bardet-Biedl syndrome. Obesity is another characteristic feature of Bardet-Biedl syndrome. Abnormal weight gain typically begins in early childhood and continues to be an issue throughout life
Cohen syndromeMutations in the VPS13B gene (also called the COH1 gene)Cohen syndrome is an inherited disorder that affects many parts of the body and is characterized by developmental delay, intellectual disability, microcephaly, and weak muscle tone (hypotonia). Obesity develops in late childhood or adolescence
Biemond syndrome IIBiemond syndrome type II is a rare genetic neurological & developmental disorder reported in few patients with a poorly defined phenotype, including iris coloboma, short stature, obesity, hypogonadism, and postaxial polydactyly, and intellectual disability