Severe Insulin Resistance Syndromes: Clinical Spectrum and Management
Abstract
1. Introduction
2. Characteristics of Severe Insulin Resistance Syndromes
2.1. Insulin Receptor and Insulin Receptor Gene
2.2. Type A Insulin Resistance Syndrome (OMIM 610549)
2.3. Type C Insulin Resistance Syndrome
2.4. Type B Insulin Resistance Syndrome (ORPHA 2298)
2.5. Donohue Syndrome (OMIM 246200)
2.6. Rabson–Mendenhall Syndrome (OMIM 262190)
2.7. Lipodystrophies
2.7.1. Congenital Generalized Lipodystrophies
- Type 1 CGL (CGL1, OMIM 608594)
- Type 2 CGL (CGL2, OMIM 269700)
- Type 3 CGL (CGL3, OMIM 612526)
- Type 4 CGL (CGL4, OMIM 613327)
2.7.2. Congenital Partial Lipodystrophies
- Type 1 FPLD (FPLD1, OMIM 608600)
- Type 2 FPLD (FPLD2, OMIM 151660)
- Type 3 FPLD (FPLD3, OMIM 604367)
- Type 4 FPLD (FPLD4, OMIM 613877)
- Type 5 FPLD (FPLD5, OMIM 615238)
- Type 6 FPLD (FPLD6, OMIM 615980)
- AKT2-linked lipodystrophy
- CAV1-associated lipodystrophy (OMIM 606721)
- Mandibuloacral dysplasia
- SHORT syndrome (OMIM 269880)
- Werner syndrome (OMIM 277700)
2.7.3. Acquired Generalized Lipodystrophy
2.7.4. Acquired Partial Lipodystrophy
- Lipodystrophy associated with HIV therapy
2.7.5. Localized Lipodystrophy Disorders
2.7.6. Other Complex Syndromes of Severe Insulin Resistance
- Subcutaneous insulin resistance syndrome
- Alström syndrome
- Bloom syndrome
- Microcephalic osteodysplastic primordial dwarfism type II
3. Therapy
3.1. Non-Pharmacological Treatment
3.2. Pharmacologic Treatment
4. Summary
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
Abbreviations
AGL | Acquired generalized lipodystrophy |
AKT | Protein kinase B |
APL | Acquired partial dystrophy |
CGL | Congenital generalized lipodystrophy |
DPP-4 | Dipeptidyl peptidase-4 |
DS | Donohue syndrome |
FPLD | Familial partial lipodystrophy |
GIP | Glucose-dependent insulinotropic polypeptide |
GIPR | Glucose-dependent insulinotropic polypeptide receptor |
GL | Generalized lipodystrophy |
GLP-1 | Glucagon-like peptide 1 |
GLP-1R | Glucagon-like peptide 1 receptor |
HAART | Highly active antiretroviral therapy. |
HAIR-AN | Hyperandrogenism, insulin resistance, acanthosis nigricans |
HALS | HIV-associated lipodystrophy |
IGF-1 | Insulin-like growth factor-1 |
INSR | Insulin receptor |
IR | Insulin resistance |
MAD | Mandibuloacral dysplasia |
MAFLD | Metabolic dysfunction-associated fatty liver disease |
MASH | Metabolic dysfunction-associated steatohepatitis |
MOPD II | Microcephalic osteodysplastic primordial dwarfism type II |
PCOS | Polycystic ovary syndrome |
PI3K | Phosphatidylinositol 3-kinase |
PL | Partial lipodystrophy |
PPARγ | Peroxisome proliferator activated receptor-γ |
RETA | Retatruide |
RMS | Rabson-Mendenhall syndrome |
SGLT2 | Sodium-glucose cotransporter 2 |
SIRS | Severe insulin resistance syndrome |
TAIRS | Type A insulin resistance syndrome |
TBIRS | Type B insulin resistance syndrome |
T2DM | Type 2 diabetes mellitus |
TZDs | Thiazolidinediones |
TZP | Tirzepatide |
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Syndrome | Symptoms | Pathogenesis |
---|---|---|
Type A Insulin resistance (TAIRS) OMIM 610549 Prevalence— 1 in 100,000, female predominance. | Symptoms present in adolescence or adulthood. Hyperandrogenism, severe insulin resistance, acanthosis nigricans, hirsutism, oligomenorrhea, polycystic ovaries, acromegaloid features. Occasionally not obese. | Mutations in insulin receptor gene and impaired insulin signaling pathway. Not life-threatening, patients can live beyond middle age. Inheritance—autosomal dominant or autosomal recessive. |
Type B Insulin resistance (TBIRS) ORPHA 2298. Rare, no prevalence reported. | Symptoms are detected in adulthood. Acanthosis nigricans, refractory hyperglycemia, severe insulin resistance, markedly enlarged ovaries, hyperandrogenism, features associated with autoimmunity. | Autoantibody against insulin receptor. Frequently associated with autoimmune disorders. Mortality over 50%. Inheritance—not known. |
Type C Insulin resistance. A variant of type A, the HAIR-AN syndrome. It affects 2–3% of androgen excess patients. | A variant of type A insulin resistance. | Reduced activity of insulin receptor kinase Generally not life-threatening. Inheritance—not known. |
Donohue syndrome (leprechaunism) OMIM 246200. Prevalence— 1 in 1,000,000 live births. | Congenital onset, delayed vertical growth, hyperinsulinemia, acanthosis nigricans, postprandial hyperglycemia, hypotonia, proptosis, infraorbital folds, cardiomegaly, hepatosplenomegaly, hypertrophy of kidneys and ovaries. | Mutations in insulin receptor gene, caused disrupted binding of insulin to its receptor. Death usually during infancy. Inheritance—autosomal recessive. |
Rabson–Mendenhall syndrome OMIM 262190. Prevalence—its exact prevalence has not been assessed; however, it is suggested that its prevalence is less than 1 in 1,000,000 live births. | Congenital onset, growth retardation, wasting of muscles, lack of subcutaneous fat, hyperinsulinemia, polycystic ovaries, acanthosis nigricans, insulin-resistant diabetes, dental abnormality, pineal hyperplasia. | Mutations in insulin receptor gene and impaired insulin signal transduction. Patients survive early childhood, but they have a significantly reduced life expectancy and may die during adolescence or early adulthood. Patients usually survive beyond one year of age. Inheritance—autosomal recessive. |
LIPODYSTROPHIES | ||
---|---|---|
Congenital Generalized Lipodystrophies (CGL)—Seip–Berrardinelli Syndrome (OMIM 269700) | ||
Syndrome | Symptoms | Pathogenesis |
CGL1 OMIM 608594 It has been identified in at least 150 cases. | Lytic bone lesions, cardiomyopathy. The normal adipose tissue deposition is limited to mechanical fat, as well as the mouth, tongue, scalp and perineum. | Mutations in AGPAT2 gene. Deficiency of AGPAT2 impairs signaling pathways of PI3K/AKT and PPARγ, causing affected adipogenesis and reducing the levels of stored triglycerides. Inheritance—autosomal recessive. |
CGL2 OMIM 269700 It has been identified in at least 167 patients. | Absence of body fat with loss of both metabolically active fat and mechanical fat. Since birth, mild mental retardation, dyslipidemia, cardiomyopathy. | Mutations in the BSCL2 gene that codes seipin. It is more severe than CGL1 and features a higher incidence of premature death. Some variants of the BSCL2 gene are fatal, due to encephalopathy in early childhood. Inheritance—autosomal recessive. |
CGL3 OMIM 612526 No prevalence reported. | Impaired function of caveolin may cause lipodystrophy. Short stature, megaesophagus, dyslipidemia, generalized lipodystrophy from birth. | Mutations in the CAV1 gene that codes caveolin-1. Inheritance—autosomal recessive. |
CGL4 Only 21 patients with CGL4 have been reported. | Moderate lipodystrophy, hypertriglyceridemia, cardiomyopathy, cardiac fibrosis. | Mutations in the PTRF gene that codes cavin, a polymerase I and transcript release factor, QT interval prolongation, atlantoaxial instability, gastrointestinal disorders. It can be associated with sudden death. Inheritance—autosomal recessive. |
LIPODYSTROPHIES | ||
---|---|---|
Congenital Partial Lipodystrophies | ||
Familial Partial Lipodystrophies (FPLD) | ||
Syndrome | Symptoms | Pathogenesis |
FPLD1 Köbberling syndrome OMIM 608600 It is predominantly diagnosed in females. | The characteristic clinical features are not completely defined. In patients, the loss of adipose tissue in the extremities is observed, with normal adipose tissue elsewhere. Most affected individuals have diabetes and hypertriglyceridemia that may cause acute pancreatitis. | Little is known about pathophysiological mechanisms. The genetic basis is unknown. A polygenic inheritance is suggested in some patients. |
FPLD2 Dunningan syndrome OMIM 151660 | Loss of subcutaneous tissue from the extremities. Some patients may have acanthosis nigricans, hirsutism, and ovarian hyperandrogenism. Prior to the age of 20, diabetes and hepatic steatosis may develop. | Mutations in LMNA gene that codes lamins A and C. The impaired protein may disrupt the interaction with chromatin or other nuclear lamin proteins, causing apoptosis and the premature death of adipocytes. It may be inherited as an X-linked dominant or autosomal dominant trait. |
FPLD3 OMIM 604367 | Lipoatrophy appears in adulthood. The symptoms are similar to those of FPLD2; however, fat deposition in these patients in the head and neck may be normal. FPLD3 patients have a greater prevalence of hypertriglyceridemia and diabetes. | Mutations in the PPARG gene that participates in adipocyte differentiation and its function. These mutations impair adipocyte differentiation and adipogenesis. Inheritance—autosomal dominant. |
FPLD4 OMIM 613877 It was described in four families. | Loss of subcutaneous fat in the extremities. The syndrome may be associated with severe insulin resistance, diabetes, hypertriglyceridemia, and hepatic steatosis. | Mutations in the PLIN1 gene that codes perilipin-1. It is involved in lipid storage and lipolysis. Inheritance—autosomal dominant. |
FPLD5 OMIM 615238 | Partial lipodystrophy, acanthosis nigricans, severe insulin resistance, diabetes, hepatic steatosis, peripheral lipoatrophy, visceral adiposity. | Mutations in the CIDEC gene. These mutations impair adipocyte differentiation and lipid droplet accumulation. Inheritance—autosomal recessive. |
FPLD6 OMIM 615980 | Distal lipoatrophy, visceral adiposity, and muscular dystrophy. | Mutations in the LIPE gene that codes lipase E. It is involved in the regulation of adipocyte function, and the homeostasis of lipid and glucose. These mutations impair lipolysis, resulting in lipomatosis and partial fat loss. Inheritance—autosomal recessive. |
AKT2-linked lipodystrophy | Insulin resistance, moderate lipodystrophy. | Mutations in the AKT2 gene that codes protein kinase B, a serine/threonine protein kinase. Mutations impair insulin signaling and adipocyte differentiation. Inheritance—autosomal dominant. |
CAV1-associated lipodystrophy OMIM 606721. Only two cases were reported. | Subcutaneous fat loss in the face and upper body, micrognathia, congenital cataracts, diabetes mellitus, hypertriglyceridemia, recurrent pancreatitis. | Mutations in the CAV1 gene that codes caveolin-1, the membrane protein associated with cell metabolism, cell migration, and cell signaling. Inheritance—autosomal dominant. |
Mandibuloacral dysplasia type A OMIM 249370 | Loss of subcutaneous fat from the arms and legs. Skeletal abnormalities, mandibular and clavicular hypoplasia, delayed dentition, progeroid features. | Mutations in the LMNA gene that codes lamin A and C, nuclear lamin proteins. Impaired nuclear functions, causing premature cell death in adipose and skeletal tissue. Inheritance—autosomal recessive. |
Mandibuloacral dysplasia type B OMIM 608612 | Generalized loss of fat, mandibular and clavicular hypoplasia, acrosteolysis, delayed dentition, premature renal failure, progeroid features. | Mutations in the ZMPSTE24 gene that codes zinc and metalloprotease ZMPSTE24, involved in the processing of prelamin A to mature lamin A. Impaired gene may cause the accumulation of the toxic farnesylated form of lamin, resulting in the impaired nuclear function in several tissues. Inheritance—autosomal recessive. |
SHORT syndrome OMIM 269880 | Short stature, hyperextensibility of joins, ocular depression, Riger anomaly, teething delay. | Mutations in the PI3KR1 gene that codes PI3KR1 protein (regulatory p85α subunit). The p85α subunit is associated with the connection and stabilization of the p110 catalytic subunit of the phosphatidyl-inositol 3-kinase (PI3K) protein, which catalyzes the conversion of phosphatidyl phosphate 2 (PIP2) to PIP3, causing the activation of the AKT signaling pathway. The PI3K/AKT signaling pathway regulates cellular functions, such as differentiation, cell survival, and insulin’s biological action. Inheritance—autosomal dominant. |
Werner syndrome OMIM 277700 | Short stature, due to the absence of the pubertal growth spurt, premature aging of features, with onset into the third decade, such as greying and thinning of the hair, bilateral cataracts, scleroderma-like skin changes, premature atherosclerosis, and development of early-onset cancers. These patients may suffer premature muscle loss from the limbs or sarcopenia. Diabetes mellitus, fatty liver disease and dyslipidemia are also commonly reported. | Biallelic variants in the WRN gene that codes a dual DNA helicase/exonuclease enzyme. Inheritance—autosomal recessive. |
LIPODYSTROPHY | ||
---|---|---|
Acquired Generalized Lipodystrophy (AGL)—Lawrence Syndrome | ||
Syndrome | Symptoms | Pathogenesis |
Lawrence syndrome It was described in approximately 80 patients. Predominantly occurs in females. | It usually develops during childhood, adolescence or adulthood. In most patients, the loss of fat begins in adolescence, and occurs variably over a period of weeks, months, or years. Low levels of leptin and very low levels of adipokines may be associated with metabolic complications, such as type 2 diabetes mellitus, hypertriglyceridemia, metabolic dysfunction-associated steatotic liver disease (MASCD), and severe insulin resistance. | Its pathogenesis is unknown, although it is suggested that previous infection or autoimmune diseases, such as Hashimoto thyroiditis, rheumatoid arthritis, hemolytic anemia, chronic, active hepatitis, panniculitis, Sjögren syndrome, juvenile-onset dermatomyosities, systemic sclerosis, and systemic lupus erythematosus, may be relevant. In 50% of patients with autoimmune- or panniculitis-associated AGL, anti-perilipin (anti-PLIN1) antibodies were detected. Therefore, it is suggested that a pathogenic role of anti-PLIN1 is involved in the development of the Lawrence syndrome. It is suggested that autoantibodies and proinflammatory cytokines, such as TNF-α and IL-6, are involved in AGL, causing impaired fat uptake, the differentiation of adipocyte, adipogenesis, and the increased apoptosis of adipocytes/pre-adipocytes. |
LIPODYSTROPHIES | ||
---|---|---|
Acquired Partial Lipodystrophy | ||
Syndrome | Symptoms | Pathogenesis |
Barraquer–Simons syndrome OMIM 608709 One of the most commonly acquired types of lipodystrophy, approximately 250 cases have been reported. Its higher prevalence was detected in females, often after a fertility illness. | It begins in childhood or adolescence. Fat loss usually occurs over a period of months or years. A loss of adipose tissue from the face and upper trunk is detected, while in the rest of the body increased adiposity may be observed. In patients, autoimmune disorders have been reported, such as dermatomyositis, hypothyroidism, pernicious anemia, rheumatoid arthritis, temporal arteritis, or mesangiocapillary glomerulonephritis. Most patients with this syndrome have a circulating autoantibody called C3 nephritic factor and low complement component 3 (C3) levels. C3 nephritic factor plays an important role, stabilizing the C3 convertase enzyme by increasing the half-life of the convertase by blocking the degradation of C3. A result is the excessive activation of C3. In some patients the development of membrane-proliferative glomerulonephritis (MPGN) is observed, which occurs on average 8 to 10 years after initial diagnosis. In patients hyperinsulinemia may be detected, but without severe insulin resistance. The prevalence of diabetes mellitus in these patients is much lower as compared to other types of lipodystrophy. | The etiology of Barraquer–Simons syndrome remains unclear; however, the autoimmune-mediated destruction of adipocytes is suggested. |
LIPODYSTROPHY | ||
---|---|---|
Lipodystrophy Associated with HIV Therapy | ||
Syndrome | Symptoms | Pathogenesis |
HIV-associated lipodystrophy syndrome (HALS). It is the most common type of partial lipodystrophy. | HALS is detected in approximately 40% of patients, who are treated with highly active antiretroviral therapy (HAART), especially HIV-1 protease inhibitors and nucleoside analogue reverse transcriptase inhibitors. HALS depends on the duration of HAART treatment. The drugs used can develop lipodystrophy, and these drugs may be the cause of lipodystrophy. Reduced subcutaneous adipose tissue is associated with a low concentration of leptin, while decreased levels of adipokine are associated with excess visceral fat. | There are different mechanisms of these associations suggested, such as the increased apoptosis of adipocytes, the inhibition of preadipocytes differentiation, and the suppression of adipogenesis. These mechanisms also include the changed expression of adipogenic transcriptors, such as PPARγ, CCAAT/enhancer-binding protein-α (C/EBO-α), CCAAT/enhancer-binding protein-β (C/EBP-β), and sterol regulatory element-binding protein 1 (SREBP-1). Metabolic and clinical manifestations, as well as the severity of HALS, may be dependent on inflammation processes. |
LIPODYSTROPHY | ||
---|---|---|
Localized Lipodystrophy Disorders | ||
Syndrome | Symptoms | Pathogenesis |
Localized lipodystrophy disorders | These disorders are characterized by small amounts of subcutaneous fat loss from small areas of the body, and do not cause insulin resistance. There are no observed metabolic abnormalities, as the amount of fat loss is minimal. A rare cause of localized lipodystrophy is lipodystrophia centrifugalis abdominalis infantilis. In this lipodystrophy disorder, a centrifugal loss of subcutaneous fat is observed in the abdomen with erythematous and scaly changes at the periphery. It usually occurs before the age of three years. As a related abnormality, we may cite localized lipodystrophy, i.e., a lack of fat in small areas of trunks or parts of limbs. | Localized lipodystrophy disorders include lipodystrophy caused by drug injections, lipodystrophy semicircularis, centrifugal lipodystrophy, and panniculitis-associated lipodystrophy. Drug-induced lipodystrophy at the site of injection is associated with insulin therapy. The use of purified human insulin means that this disorder is rare now. Localized lipodystrophy may also be caused by glucocorticoids and antibiotics. |
Other Complex Syndromes of Severe Insulin Resistance | ||
---|---|---|
Syndrome | Symptoms | Pathogenesis |
Subcutaneous insulin resistance syndrome | Resistance to the action of subcutaneous insulin. | This syndrome occurs due to increased insulin-degrading enzyme activity in the subcutaneous tissue. |
Alström syndrome | Endocrine, cardiac renal and hepatic complications, and complications with vision and hearing, may be observed. | It is caused by a mutation in the ALMS1 gene. |
Bloom syndrome | In patientsgrowth retardation, photosensitive skin, compromised immune system, insulin resistance, and a high predisposition of cancer are observed. The mean age of death is 26, most commonly caused by malignancies. | It is caused by a mutation in the BLM gene. |
Microcephalic osteodysplastic primordial dwarfism type II | Pre- and post-natal growth failure with microcephaly, characteristic facial features, skeletal dysplasia, abnormal dentition, insulin resistance and truncal obesity are observed. | This syndrome is caused by a mutation in the pericentrin PCNT gene. |
Medications | Mechanism of Action and Effects |
---|---|
Metformin | Decreases gluconeogenesis, stimulates peripheral glucose uptake, and causes weight loss. In patients with lipodystrophies, especially with HALS, it improves insulin sensitivity, increases the activation of insulin receptor tyrosine kinase, and enhances the synthesis of glycogen. |
IGF-1 | Improves metabolic control in SIRS caused by mutations in the gene, increases life span, regulates glucose homeostasis, reduces hepatic gluconeogenesis and increases glucose uptake in peripheral tissues. |
GLP-1RAs | Stimulates insulin secretion, activates GLP-1 receptor, increases the secretion of insulin, inhibits the secretion of glucagon and inhibits insulin resistance. |
Sulfonylureas | Activates insulin receptors, increases the amount of glucose transporters, increases insulin sensitivity and improves insulin resistance. |
DPP-4 inhibitors | Improves insulin sensitivity, stimulates the activity of endogenous GLP-1 and insulinotropic polypeptide. |
SGLT2 inhibitors | Decrease blood glucose levels, stimulates insulin secretion and increases the excretion of urinary glucose, reducing blood glucose levels. Reduce insulin resistance and body weight. |
Metreleptin | This is recommended for treating congenital generalized lipodystrophies. It improves glycemic control and alleviates hypertriglyceridemia. |
Immunosuppressant | There are different and controversial results. |
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Pliszka, M.; Szablewski, L. Severe Insulin Resistance Syndromes: Clinical Spectrum and Management. Int. J. Mol. Sci. 2025, 26, 5669. https://doi.org/10.3390/ijms26125669
Pliszka M, Szablewski L. Severe Insulin Resistance Syndromes: Clinical Spectrum and Management. International Journal of Molecular Sciences. 2025; 26(12):5669. https://doi.org/10.3390/ijms26125669
Chicago/Turabian StylePliszka, Monika, and Leszek Szablewski. 2025. "Severe Insulin Resistance Syndromes: Clinical Spectrum and Management" International Journal of Molecular Sciences 26, no. 12: 5669. https://doi.org/10.3390/ijms26125669
APA StylePliszka, M., & Szablewski, L. (2025). Severe Insulin Resistance Syndromes: Clinical Spectrum and Management. International Journal of Molecular Sciences, 26(12), 5669. https://doi.org/10.3390/ijms26125669