Lipodystrophy can be caused by metabolic abnormalities due to genetic issues. These are often characterized by insulin resistance and are associated with metabolic syndrome.

People with Laron syndrome have strikingly low rates of cancer and diabetes, although they appear to be at increased risk of accidental death due to their stature.

The condition is transmitted as an autosomal recessive trait, and often affects children of consanguineous parents. The physical findings and symptoms vary greatly among each individual.

Genetic diseases are determined by two genes, one from the mother and one from the father. Recessive genetic disorders occur when an individual inherits the same abnormal gene for the same trait from each parent. If one of the inherited genes is normal, while the other is for the disease, the person will only be a carrier and will not display any symptoms.

The risk for two carrier parents to both pass the defective gene and, therefore, have an affected child is 25 percent with each pregnancy. The risk to have a child who is a carrier like the parents is 50 percent with each pregnancy. The chance for a child to receive normal genes from both parents and be genetically normal for that particular trait is 25 percent.

Researchers have determined that the Rabson–Mendenhall syndrome is caused by mutations of the insulin receptor gene. The insulin receptor gene is located on the short arm (p) of chromosome 19. Mutations of the insulin-receptor gene lead to an alteration of structure or reduced number of insulin receptors. This results in reduced binding of insulin, and may also lead to abnormalities in the post-receptor pathway.

Individuals with Rabson-Mendenall syndrome will need ways to compensate for their insulin resistance, and may do this by increasing insulin secretion. This can lead to excessive insulin levels in the blood (hyperinsulinemia), which can be responsible for multiple symptoms. Definitive genotype–phenotype correlation for insulin receptor defects is difficult to establish primarily due to the rarity of these syndromes. However, researchers believe more severe phenotype changes are due to a mutation in the alpha subunit of the receptor.

Rabson–Mendenhall syndrome is a rare autosomal recessive disorder characterized by severe insulin resistance. The disorder is caused by mutations in the insulin receptor gene. Symptoms include growth abnormalities of the head, face and nails, along with the development of acanthosis nigricans. Treatment involves controlling blood glucose levels by using insulin and incorporating a strategically planned, controlled diet. Also, direct actions against other symptoms may be taken (e.g. surgery for facial abnormalities) This syndrome usually affects children and has a prognosis of 1–2 years.

Lipodystrophies can be a possible side effect of antiretroviral drugs. Other lipodystrophies manifest as lipid redistribution, with excess, or lack of, fat in various regions of the body. These include, but are not limited to, having sunken cheeks and/or "humps" on the back or back of the neck (also referred to as buffalo hump) which also exhibits due to excess cortisol. Lipoatrophy is most commonly seen in patients treated with thymidine analogue nucleoside reverse transcriptase inhibitors like zidovudine (AZT) and stavudine (d4T).

PPID shares similarities to Equine Metabolic Syndrome, which also causes regional adiposity, laminitis, and insulin resistance. Treatment and management may differ between the two endocrinopathies, making differentiation important. However, it is important to keep in mind that horses with EMS may develop PPID, therefore both diseases may occur simultaneously.

Cortisol inhibition, and as a result, excess androgen release can lead to a variety of symptoms. Other symptoms come about as a result of increased levels of circulating androgen. Androgen is a steroid hormone, generally associated with development of male sex organs and secondary male sex characteristics The symptoms associated with Cortisone Reductase Deficiency are often linked with Polycystic Ovary Syndrome (PCOS) in females. The symptoms of PCOS include excessive hair growth, oligomenorrhea, amenorrhea, and infertility. In men, cortisone reductase deficiency results in premature pseudopuberty, or sexual development before the age of nine.

AGL with autoimmune origin is responsible for about 25% of all AGL reports. Those with autoimmune origin stems from other autoimmune diseases, most commonly with juvenile dermatomyositis and autoimmune hepatitis, but also occurs with rheumatoid arthritis, systemic lupus erythematous, and Sjogren syndrome.

There is no known cause for this disease; however, three origins of AGL are generally suspected: panniculitis-associated, autoimmune-associated, and idiopathic AGLs. Triggers may include infections that aggravate the panniculitis, or any disease state that can induce autoimmunity. Overlap between panniculitis and autoimmune types also exists. Another theory suggest that AGL is an autoimmune disease itself, as panniculitis can be described as an autoimmune disease, however its triggering factors remains to be unknown. Underlying genetic factor may be associated; however neither confirmed nor rejected.

Molecular genetic investigations have shown that this disorder is mainly associated with mutations in the gene for the GH receptor. These can result in defective hormone binding to the ectodomain or reduced efficiency of dimerization of the receptor after hormone occupancy. There are exceptionally low levels of insulin-like growth factor (IGF-1) and its principal carrier protein, insulin-like growth factor binding protein 3.

A related condition involving postreceptor insensitivity to growth hormone has been associated with STAT5B.

Frailty is a common geriatric syndrome. Estimates of frailty's prevalence in older populations may vary according to a number of factors, including the setting in which the prevalence is being estimated – e.g., nursing home (higher prevalence) vs. community (lower prevalence), and the operational definition used for defining frailty. Using the widely used frailty phenotype framework proposed by Fried et al. (2001), prevalence estimates of 7–16% have been reported in non-institutionalized, community-dwelling older adults.

The occurrence of frailty increases incrementally with advancing age, and is more common in older women than men, and among those of lower socio-economic status. Frail older adults are at high risk for major adverse health outcomes, including disability, falls, institutionalization, hospitalization, and mortality.

Epidemiologic research to date has led to the identification of a number of risk factors for frailty, including: (a) chronic diseases, such as cardiovascular disease, diabetes, chronic kidney disease, depression, and cognitive impairment; (b) physiologic impairments, such as activation of inflammation and coagulation systems, anemia, atherosclerosis, autonomic dysfunction, hormonal abnormalities, obesity, hypovitaminosis D in men, and environment-related factors such as life space and neighborhood characteristics. Advances about potentially modifiable risk factors for frailty now offer the basis for translational research effort aimed at prevention and treatment of frailty in older adults. A recent systematic review found that exercise interventions can increase muscle strength and improve physical function; however, results are inconsistent in frail older adults living in the community.

Several associated risk factors include the following:

- Genetic factors (inherited component):

- Family history of type 2 diabetes

- Insulin receptor mutations (Donohue syndrome)

- LMNA mutations (familial partial lipodystrophy)

- Cultural variables, such as diet varying with race and class; factors related to stress, socio-economic status and history have been shown to activate the stress response, which increases the production of glucose and insulin resistance, as well as inhibiting pancreatic function and thus might be of importance, although it is not fully corroborated by the scientific evidence.

- Particular physiological conditions and environmental factors:

- Age 40–45 years or older

- Obesity

- The tendency to store fat preferentially in the abdomen (also known as "abdominal obesity)", as opposed to storing it in hips and thighs

- Sedentary lifestyle, lack of physical exercise

- Hypertension

- High triglyceride level (hypertriglyceridemia)

- Low level of high-density lipoprotein (also known as HDL cholesterol or "good cholesterol")

- Prediabetes, blood glucose levels have been too high in the past, i.e. the patient's body has previously shown slight problems with its production and usage of insulin ("previous evidence of impaired glucose homeostasis")

- Having developed gestational diabetes during past pregnancies

- Giving birth to a baby weighing more than 9 pounds (a bit over 4 kilograms)

- Pathology:

- Obesity and overweight (BMI > 25)

- Metabolic syndrome (hyperlipidemia + HDL cholesterol level 2.82 mmol/L), hypertension (> 140/90 mmHg), or arteriosclerosis

- Liver pathologies

- Infection (Hepatitis C)

- Hemochromatosis

- Gastroparesis

- Polycystic ovary syndrome (PCOS)

- Hypercortisolism (e.g., Cushing's syndrome, glucocorticoid therapy)

- Medications (e.g., glucosamine, rifampicin, isoniazid, olanzapine, risperidone, progestogens, glucocorticoids, methadone, many antiretrovirals)

Diagnosis of cortisone reductase deficiency is done through analysis of cortisol to cortisone metabolite levels in blood samples. As of now, there is no treatment for cortisone reductase deficiency. Shots of cortisol are quickly metabolised into cortisone by the dysregulated 11β-HSD1 enzyme; however, symptoms can be treated. Treatment of hyperandroginism can be done through prescription of antiandrogens. They do so by inhibiting the release of gonadotropin and luteinizing hormone, both hormones in the pituitary, responsible for the production of testosterone.

This test may also be referred to as a ‘’resting ACTH’’, ’’endogenous ACTH’’, or ‘’basal ACTH’’. The majority of ACTH produced in normal horses comes from corticotrope cells in the pars distalis, with only 2% thought to come from melanotropes in the pars intermedia. In horses with PPID, melanotropes produce abnormally high levels of ACTH. Basal plasma ACTH concentrations, which measure the blood levels of circulating ACTH, can therefore be useful in diagnosing the disease.

ACTH levels naturally fluctuate in healthy horses, with a significant rise occurring the in autumn (August through October) in North American horses. Horses with PPID have a similar, but much more significant, rise in the autumn. Therefore, a seasonally adjusted reference range must be used that correlates with the time of year the sample is taken. Failure to use a seasonally adjusted reference range may lead to false-positive results in normal horses if they are sampled in the fall. Autumnal testing is thought to be more sensitive and specific than testing at other times of the year, so is preferred. Basal plasma ACTH levels may increase if the horse is severely ill or under great stress or pain, such as if it has laminitis. However, such events must be fairly significant to confound the results. Additionally, ACTH levels may not be significantly increased early on in the disease, leading to false negatives.

Glucocorticoid deficiency 1 (FGD or GCCD) is an adrenocortical failure characterized by low levels of plasma cortisol produced by the adrenal gland despite high levels of plasma ACTH. This is an inherited disorder with several different causes which define the type.

FGD type 1 (FGD1 or GCCD1) is caused by mutations in the ACTH receptor (melanocortin 2 receptor; MC2R). FGD type 2 is caused by mutations in the MC2R accessory protein (MRAP). These two types account for 45% of all cases of FGD.

Some cases of FGD type 3 are caused by mutations in the steroidogenic acute regulatory protein (StAR), with similarity to the nonclassic form of lipoid congenital adrenal hyperplasia. In this case, a general impairment in not just adrenal steroid production, but gonadal steroid production can affect sexual development and fertility.

The causes of other cases of FGD type 3 not due to StAR are currently unknown.

Sedentary lifestyle increases the likelihood of development of insulin resistance. It has been estimated that each 500 kcal/week increment in physical activity related energy expenditure, reduces the lifetime risk of type 2 diabetes by 9%. A different study found that vigorous exercise at least once a week reduced the risk of type 2 diabetes in women by 33%.

Donohue syndrome (also known as leprechaunism) is an extremely rare and severe genetic disorder. "Leprechaunism" derives its name from the fact that people with the disease often have elfin features and are smaller than usual. Affected individuals have an insulin receptor with greatly impaired functionality.

TOFI (thin-outside-fat-inside) is used to describe lean individuals with a disproportionate amount of fat (adipose tissue) stored in their abdomen. The figure to illustrate this shows two men, both 35 years old, with a BMI of 25 kg/m. Despite their similar size, the TOFI had 5.86 litres of internal fat, whilst the healthy control had only 1.65 litres.

Subjects defined as TOFI with body mass index (BMI) <25 kg/m have increased levels of many of the risk factors associated with the metabolic syndrome. This phenotype is a further refinement of “metabolically-obese normal-weight" (MONW).

Subjects defined as TOFI have been described as being at higher risk of developing insulin resistance and type II diabetes due to the fact that they have reduced physical activity/VOmax, reduced insulin sensitivity, higher abdominal adiposity, and a more atherogenic lipid profile. Another important characteristic observed in this cohort is elevated levels of liver fat. It is shown that overconsumption of fructose can lead to TOFI by inducing inflammation associated cortisol release.

This is difficult to establish in the general population since the necessary imaging examinations are time consuming and expensive; however, in a recent research study it was estimated that 14% of the men and 12% of the women scanned with a BMI 20–25 kg/m were classified as TOFI.

It has been suggested that the biological underpinnings of frailty are multifactorial, involving dysregulation across many physiological systems. A proinflammatory state, sarcopenia, anemia, relative deficiencies in anabolic hormones (androgens and growth hormone) and excess exposure to catabolic hormones (cortisol), insulin resistance, glucose levels, compromised altered immune function, micronutrient deficiencies and oxidative stress are each individually associated with a higher likelihood of frailty. Additional findings show that the risk of frailty increases with the number of dysregulated physiological systems in a nonlinear pattern, independent of chronic diseases and chronologic age, suggesting synergistic effects of individual abnormalities that on their own may be relatively mild. The clinical implication of this finding is that interventions that affect multiple systems may yield greater, synergistic benefits in prevention and treatment of frailty than interventions that affect only one system.

Associations between specific disease states are also associated with and frailty have also been observed, including cardiovascular disease, diabetes mellitus, renal insufficiency and other diseases in which inflammation is prominent. To the extent that dysregulation across several physiologic systems underlie the pathogenesis of the frailty, specific disease states are likely concurrent manifestations of the underlying impaired physiologic function and regulation. It is possible that clinically measurable disease states can manifest themselves or be captured prior to the onset of frailty. No single disease state is necessary and sufficient for the pathogenesis of frailty, since many individuals with chronic diseases are not frail. Therefore, rather than being dependent on the presence of measurable diseases, frailty is an expression of a critical mass of physiologic impairments.

Metabolic syndrome affects 60% of the U.S. population older than age 50. With respect to that demographic, the percentage of women having the syndrome is higher than that of men. The age dependency of the syndrome's prevalence is seen in most populations around the world.

Various strategies have been proposed to prevent the development of metabolic syndrome. These include increased physical activity (such as walking 30 minutes every day), and a healthy, reduced calorie diet. Many studies support the value of a healthy lifestyle as above. However, one study stated these potentially beneficial measures are effective in only a minority of people, primarily due to a lack of compliance with lifestyle and diet changes. The International Obesity Taskforce states that interventions on a sociopolitical level are required to reduce development of the metabolic syndrome in populations.

The Caerphilly Heart Disease Study followed 2,375 male subjects over 20 years and suggested the daily intake of a pint (~568 ml) of milk or equivalent dairy products more than halved the risk of metabolic syndrome. Some subsequent studies support the authors' findings, while others dispute them. A systematic review of four randomized controlled trials found that a paleolithic nutritional pattern improved three of five measurable components of the metabolic syndrome in participants with at least one of the components.

The cause of the disease is the lack of a fully functional insulin receptor, which has a profound effect during fetal development and thereafter. In one case, it was found (by culturing pancreatic cells) that the receptor produced by the mutant allele is only about 15% as effective as the normal receptor. The beta cells in the pancreas, which make and store insulin and release it on an as-needed basis, are often found to be very large or numerous.

In some patients, particularly those who are longer-lived, unusual bone changes are sometimes seen, and there may be excessive body hair and

velvety hyperpigmentation of the skin.

The prognosis is quite dire, with early death usual. In fact, most patients die in their first year except in milder forms of the disease, but few are known to have lived longer. The variation is unsurprising given the diversity of mutations causing the disease.

Many of the problems associated with Donohue syndrome may be due to the insulin receptor binding the insulin-like growth factor, regulating the growth of the embryo, in addition to its well-known

role in the regulation of blood sugar.

Endocrine syndromes associated with acanthosis nigricans can develop in many conditions, particularly:

- starts with insulin resistance, such as diabetes mellitus and metabolic syndrome

- excess circulating androgens, particularly Cushing's disease, acromegaly, polycystic ovarian disease

- Addison's disease and hypothyroidism

- Rare diseases, including pinealoma, leprechaunism, lipoatrophic diabetes, pineal hyperplasia syndrome, pituitary basophilism, ovarian hyperthecosis, stromal luteoma, ovarian dermoid cysts, Prader-Willi syndrome, and Alstrom syndrome.

Acanthosis nigricans associated with endocrine dysfunction is more insidious in its onset, is less widespread, and the patients are often concurrently obese.

Familial acanthosis may arise as a result of an autosomal dominant trait, presenting at birth or developing during childhood.