Trends in Endocrinology & Metabolism
Monogenic forms of insulin resistance: apertures that expose the common metabolic syndrome
Section snippets
The insulin resistance syndrome
The constellation of disturbed carbohydrate and insulin metabolism, together with central obesity, dyslipidemia and hypertension, is variably referred to as the ‘metabolic syndrome’ or the ‘insulin resistance syndrome’ [1]. The resistance or indifference of tissues such as skeletal muscle, adipose tissue and liver to insulin is a defining feature of this syndrome. The phenotype is thought to result from the interaction of environmental factors, such as caloric excess and physical inactivity,
Inherited lipodystrophies: monogenic models of insulin resistance
Lipodystrophy is characterized by loss of adipose tissue stores in some anatomical sites, frequently with excess accumulation of fat in non-dystrophic adipose tissue and such unusual sites as liver and muscle. Several types of lipodystrophy have been characterized at the molecular genetic level (Table 2), including Dunnigan-type familial partial lipodystrophy (FPLD), partial lipodystrophy with mandibuloacral dysplasia, overlap syndromes of partial lipodystrophy with cardiomyopathy and
Dunnigan-type familial partial lipodystrophy
Dunnigan and Koebberling described patients who were normal at birth but who, during puberty, lost subcutaneous fat from extremities and the gluteal region, resulting in prominent, well-defined musculature, together with excess fat deposition within the face and neck, axillae, back, labia majora and intra-abdominally [14]. Non-invasive imaging studies showed absence of subcutaneous fat, but preservation of inter- and intramuscular, intra-abdominal, intrathoracic and bone marrow fat [15]. The
LMNA mutations in other lipodystrophy syndromes
At least seven diseases result from mutant LMNA [21], including some that have partial lipodystrophy as a clinical feature. The extent of lipodystrophy in one of these syndromes, mandibuloacral dysplasia with lipodystrophy (MIM 248370), can be either limited to the extremities or more widely distributed, suggesting genetic heterogeneity. This autosomal recessive phenotype includes mandibular and clavicular hypoplasia, dental abnormalities, stiff joints and ectodermal defects, and results from
PPARG mutations in partial lipodystrophy
PPARG encodes peroxisome proliferator-activated receptor γ (PPAR-γ), a nuclear receptor that induces transcription of genes involved in insulin sensitivity, adipocyte differentiation and inflammation [24]. PPAR-γ mediates the pharmacological enhancement of insulin signaling by thiazolidinedione (TZD) drugs [24]. Because PPAR-γ plays an important role in adipocyte biology, PPARG was a reasonable functional candidate gene for lipodystrophy. Although earlier studies indicated that lipodystrophic
Berardinelli–Seip congenital generalized lipodystrophy
Berardinelli and later Seip described children with absence of subcutaneous fat, muscle hypertrophy, hepatosplenomegaly, acromegaloid features, hyperlipidemia and abnormal carbohydrate metabolism 30, 31. The paucity of adipose tissue and prominent musculature in BSCL are evident from birth 30, 31. Non-invasive imaging studies showed negligible subcutaneous, intra-abdominal and intrathoracic fat, reduced bone marrow fat [32], with preservation of ‘mechanical’ fat in orbits, palms, soles and
Other lipodystrophy syndromes
A BSCL-like syndrome with systemic cystic angiomatosis, subcutaneous angiomas and bone cysts, also called Brunzell syndrome (MIM 272500), was shown to be a variant form of BSCL1 and BSCL2, although mutations were only shown for BSCL2 [38]. Another genetic lipodystrophy syndrome is the distinctive Koebberling variant of partial lipodystrophy, which has an undefined pattern of inheritance, and has been seen in women with loss of limb fat, facial sparing and excess truncal fat. Other rare
Genetics and acquired lipodystrophy
Acquired partial lipodystrophy can be associated with a serum IgG called complement 3 nephritic factor [42], and has been called Barraquer–Simons syndrome, which refers to progressive atrophy of adipose tissue of the upper body. It is also called cephalothoracic lipodystrophy, and the fat repartitioning is the mirror image of that seen in FPLD, in which facial adipose stores are preserved. This condition is not cited in MIM, and no gene mutations have been reported to date. Among the commonly
TZDs and lipodystrophy
TZDs are pharmacological ligands for PPAR-γ that ameliorate the insulin resistance in T2DM and obesity by increasing insulin sensitivity and promoting adipocyte differentiation in vitro [24]. Among patients with FPLD and other lipodystrophy syndromes, troglitazone was given in an open-label, six-month prospective study [44]. Metabolic indices improved, including reductions of glycated hemoglobin, triglycerides and free fatty acids. Body fat increased by ∼3% and magnetic resonance imaging showed
Leptin and lipodystrophy
Plasma concentrations of leptin and adiponectin are reduced in lipodystrophies 19, 45. Leptin replacement alone improved glycemia and plasma lipoproteins among patients with lipodystrophy, suggesting that leptin deficiency contributed to insulin resistance and other metabolic abnormalities in lipodystrophy [46]. Reduction in intramyocellular and hepatic lipid content might partly explain leptin-induced improvement in insulin sensitivity among patients with generalized lipodystrophy [47]. Thus,
Disorders associated with mutant insulin receptors
Although the molecular basis for disorders with mutant insulin receptors was characterized earlier than the basis of the lipodystrophies, the link with biochemical components of insulin resistance and its complications, such as atherosclerosis, is less well established. The insulin receptor is a ligand-activated tyrosine kinase encoded by INSR (MIM 147670). Most INSR mutations cause several syndromes with variable insulin receptor dysfunction. Clinically, these syndromes, leprechaunism (Donahue
Inherited obesity syndromes
A few monogenic obesity syndromes associated with insulin resistance have been solved genetically, specifically Alstrom syndrome and some forms of Bardet–Biedl syndrome (BBS). The insulin resistance seen in these syndromes almost certainly follows from the obesity. However, specific mutations might exert cellular effects at other sites, and might play a more direct role in the metabolic phenotype. The insulin resistance in Alstrom syndrome (MIM 606844) is the best documented.
Alstrom syndrome is
Summary and conclusions
The mutations detected in the genomes of patients with inherited lipodystrophy and other syndromes specify new mechanisms for insulin resistance, with its attendant clinical and metabolic complications. The present challenges include understanding how these particular mutations cause these diseases and their downstream complications, and then using this information to develop new therapies. Some of these diseases have strong documentation of intermediate metabolic disturbances and association
Acknowledgements
I apologize to colleagues whose work could not be cited because of space constraints. I have a Canada Research Chair in Human Genetics and am a Career Investigator of the Heart and Stroke Foundation of Ontario. Support has come from the Canadian Institutes for Health Research, the Canadian Genetic Diseases Network, the Canadian Diabetes Association (in honour of Hazel E. Kerr) and the Blackburn group.
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