Insulin resistance is a condition wherein cells fail to adequately respond to insulin. It is a prevalent medical condition associated with several diseases, such as type 2 diabetes mellitus, metabolic syndrome, hypertension, obesity, and polycystic ovary syndrome. Insulin resistance may be involved in metabolic disturbances, such as hyperglycemia, hyperinsulinemia, dyslipidemia, hyperuricemia, endothelial dysfunction, elevated inflammatory markers, and a prothrombotic state. Severe insulin resistance syndromes are a heterogeneous group of rare disorders. These disorders are characterized by profound insulin resistance, substantial metabolic abnormalities, and different clinical manifestations and complications. They may be hereditary or acquired, caused by defects in insulin action and cellular responsiveness to insulin. Severe insulin resistance syndromes may also be due to aberrations in adipose tissue function and development. The majority of these disorders are associated with an increased risk of severe complications and mortality. This review aims to summarize the current knowledge on the epidemiology, pathophysiology, complications and prognosis of severe insulin resistance syndromes, as well as to categorize these syndromes by disease process, including defects in insulin receptor, intracellular insulin signaling defects, lipodystrophies, etc.

Lipodystrophy syndromes comprise a group of rare diseases characterized by loss of adipose tissue without nutritional or catabolic causes. As the rarity of these conditions necessitates collaboration, the European Consortium of Lipodystrophies (ECLip) established an international, longitudinal registry for patients with all forms of lipodystrophy (excluding HIV-associated cases). From December 2017 to November 2023, 19 centers from 13 countries recruited 631 patients into the ECLip Registry. Cross-sectional data were analyzed using descriptive statistics. Prospective data were available for 467 patients (82.7% female; 86.5% adults; median age 44.0 years). Familial partial lipodystrophy (FPLD) was the most common subtype (57.4%), especially FPLD2 (37.9%). However, in men, congenital generalized lipodystrophy was nearly as common as FPLD (33.3% vs. 35.8%). Symptoms at onset varied by subtype, with loss of adipose tissue being the most frequent. More than 70% of the patients suffered from metabolic complications, particularly dyslipidemia (59.0%) and diabetes (48.4%), but prevalence and severity varied between subtypes (prevalence of diabetes, eg, 76.9% in patients with acquired partial lipodystrophy vs. 8.7% in acquired localized lipodystrophy). Metreleptin, the only disease-specific treatment, was used by 11.6% of all patients. Thirty-four deaths were documented, primarily due to cardiovascular events and cancer. Patients with generalized forms of lipodystrophy died earlier compared to patients with partial forms (median age at death 27.0 vs. 72.0 years). This study describes the largest cohort of patients with lipodystrophy reported to date. The dataset offers a comprehensive view of the epidemiology, clinical presentation, and associated comorbidities of lipodystrophy.

Lipodystrophy syndromes comprise a group of rare endocrine disorders characterized by the generalized or partial loss of adipose tissue. Affected individuals frequently display absolute or relative reductions in leptin, a key adipokine regulator of hunger-satiety signaling, and are predisposed to a range of metabolic and end-organ complications, often from a young age. The presentation and severity of lipodystrophy syndromes is largely dependent on the extent of adipose tissue loss while comorbidities often deteriorate with age. In this regard, optimizing care for children and adolescents with lipodystrophy syndromes is a pivotal step in supporting them into adulthood. To assist clinicians with limited experience of managing young patients with lipodystrophy syndromes, we describe our clinical approach to a series of pediatric patients with these rare diseases. The clinical history, diagnosis, disease management and follow-up care of 10 international pediatric patients with lipodystrophy syndromes are presented. Teaching points from each case study are also provided. Most of these cases are based on patients from our clinics with certain details changed to protect privacy. Others represent hypothetical scenarios based on our clinical experience supported by review of the medical literature and are included here for educational purposes. Our patients illustrate the broad phenotypic spectrum of lipodystrophy syndromes that can manifest early in life. We highlight the importance of timely and accurate diagnosis in guiding early disease management strategies to help reduce the risk of comorbidities. The challenges faced by clinicians managing pediatric patients with lipodystrophy syndromes and how these challenges may differ from adult patients are also explored. The cases presented in this manuscript may assist clinical teams to promptly diagnose and holistically manage young patients with lipodystrophy syndromes and help optimize clinical outcomes as they transition to adult care.

Acquired partial lipodystrophy (APL) is an ultra-rare disorder characterized by unique loss of subcutaneous fat affecting mostly the face, neck, trunk, and upper extremities. The precise prevalence of metabolic derangements and other comorbidities among patients with APL is not clear. We report clinical features and metabolic and autoimmune derangements in a large cohort. A total of 86 participants (77 female, 9 male; median age 40 years [range 8-78 years]) with APL from 2 US tertiary referral centers, UT Southwestern and National Institute of Diabetes and Digestive and Kidney Diseases, were recruited into prospective observational studies. Demographic, health history, and laboratory data at the initial evaluation and follow-up were systematically collected and analyzed. The median age of onset of lipodystrophy was 7 years (range, 2-51 years). About 15% had autoimmune diseases, 38% had either diabetes mellitus or glucose intolerance, 43% had hypertriglyceridemia, and 61% had fatty liver or metabolic dysfunction-associated steatohepatitis (MASH). A total of 71% of patients had low serum complement 3 (C3) levels, 8% had membranoproliferative glomerulonephritis, while drusen occurred in 62% of those with fundus examination (n = 21). Patients with C3 hypocomplementemia, compared to those with normal serum C3 level, reported earlier onset of diabetes or glucose intolerance (median age 36 vs 56.5 years, P = .007), hypertriglyceridemia (30 vs 48 years, P = .03), and drusen (33 vs 60 years, P = .14). Our data reveal high risk of metabolic comorbidities and drusen in patients with APL, with earlier onset of these complications in those with C3 hypocomplementemia.

Acquired partial lipodystrophy is a late complication of total body irradiation (TBI) performed during hematopoietic stem cell transplantation. Diagnosing this condition remains challenging due to its rarity and limited clinical awareness. Long-term patient observation is essential since this type of lipodystrophy develops more than a decade post-TBI. We present a unique case of a patient with acquired lipodystrophy who underwent TBI for leukemia treatment in 2003 and was diagnosed with diabetes in 2013, but standard diabetes therapies proved ineffective. By 2018, the patient exhibited distinctive features, i.e. hirsutism, reduced lean mass, cutaneous alterations (including an umbilical psoriatic plaque), barrel chest, hepatomegaly, lipoatrophy of upper and lower limbs, acanthosis nigricans in the axillae and Cushingoid facies. In 2020, she was diagnosed with breast cancer, followed by liver, ovarian and pancreatic metastases in 2021. In addition to this case report, we reviewed the literature on acquired lipodystrophy cases following TBI to compare their clinical features and phenotypes with those of our patient. This comparison aims to aid clinical practice by facilitating earlier diagnosis and treatment of lipodystrophy. TBI can lead to acquired lipodystrophy, which is associated with severe comorbidities. Due to its diagnostic complexity, expert clinicians and a multidisciplinary approach are essential for early identification and appropriate treatment according to etiologic aspects. We hypothesize that this condition may serve as a model for studying metabolic dysfunction in fat-related diseases.