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Lipodystrophy is a disorder of the subcutaneous adipose tissue. It can occur in two forms--partial and total. Gorlin and Goldman (1970) suggested that facial lipodystrophy can only occur bilaterally, and should it occur unilaterally, then it is hemifacial atrophy. A case is reported to illustrate that partial lipodystrophy can occur unilaterally.
A female patient with the following symptoms has been observed: complete absence of subcutaneous fat on the arms and legs, well developed adipose tissue on the trunk and face, severe hyperlipidemia, eruptive xanthomas, insulin resistant diabetes mellitus with lack of ketoacidosis, hepatomegaly and elevated basal metabolic rate. The patient thus exhibited all characteristics of lipatrophic diabetes (Lawrence type of diabetes). The mother and a sister of the patient were found to have the same peculiar appearance and a slight hyperlipidemia but no diabetes mellitus. The combination of this type of partial lipodystrophy with severe hyperlipidemia, insulin resistant diabetes mellitus without ketoacidosis and elevated basal metabolic rate was further observed in 2 unrelated patients without known familial occurrence. Thus partial lipodystrophy of the extremities is another, previously undescribed, syndrome associated with the Lawrence type of diabetes mellitus. In the 1 family the syndrome of lipodystrophy and hyperlipidemia is dominantly inherited. Besides the autosomal recessively inherited syndrome of congenital generalized lipodystrophy there is a heterogenous group of dominantly inherited syndromes with various types of lipodystrophy.
Patients with congenital generalized lipodystrophy are extremely insulin resistant. To ascertain whether this resistance is due to an insulin receptor defect, we tested four young patients with congenital generalized lipodystrophy and seven healthy persons of comparable age for the binding of 125I insulin to mononuclear leukocytes isolated from peripheral blood. Mononuclear leukocytes from patients with congenital generalized lipodystrophy bound significantly less insulin than cells from normal subjects (P less than 0.01). When patients with lipodystrophy fasted for 60 hours, the insulin binding increased. Altered insulin receptors may be responsible for the pronounced insulin resistance and the decreased synthesis of triglycerides in congenital generalized lipodystrophy.
Lipoatrophic diabetes has been produced in rabbits by injection of a fraction prepared from the urine from patients with congenital generalized lipodystrophy. Both these conditions are considered to be hypothalamic syndromes. The animals, and a patient with congenital generalized lipodystrophy and latent diabetes were treated with the dopamine receptor blocker, pimozide, for 4 and 17 months, respectively. The results were discouraging even though the patient got a daily dose of 16 mg pimozide. Fenfluramine has a lowering effect on brain serotonin, and peripheral effects on glucose and triglyceride metabolism. This drug improved the general condition of the rabbits with lipoatrophic diabetes, as well as that of the patient with congenital generalized lipodystrophy. The rabbits became normoglycaemic and insulin sensitive. In the patient a normalization of the urinary excretion of the serotonin metabolite 5-OH-indole acetic acid was observed. His voracious hunger and profuse perspiration were reduced, the hyperkeratotic layer of the skin peeled off, and the pigmentations of the skin decreased. There was observed an improvement of ALAT and ASAT, normalization of the fasting blood glucose, and increased sensitivity to exogenous insulin. After 11 months of 200 mg fenfluramine daily addtitional administration of 2 g clofibrate per day produced normalization of the serum triglyceride concentration and a marked reduction of the resistance to insulin. Three more patients with congenital generalized lipodystriphy, two of whom have manifest diabetes, have now started treatment with fenfluramine and are improving. The rabbits got relapse of their lipoatrophic diabetes when the fenfluramine treatment was stopped. It is suggested that a disturbance in the serotonin metabolism of the central nervous system may be of pathogenetic importance in congenital generalized lipodystrophy.
Lipodystrophy, which may be subdivided into a partial and a total form, is not a commonly reported disorder. One patient is presented in whom the lipodystrophy was not only confined to the face but even to one side. Progressive hemifacial atrophy was excluded by roentgencephalometric analysis and electromyography. It is suggested that the reported entity be considered as a separate group under the name of hemifacial lipodystrophy.
Two patients suffering from partial lipodystrophy, pancreatitis, and recurrent eosinophilia are described. In one patient the duodenum and the terminal ileum were narrowed, the appearances suggesting eosinophilic gastroenteritis: bilateral hydronephrosis was also present without ureteric obstruction. An association between lipodystrophy and renal disease is recognized; it is possible that there is also an association between lipodystrophy and pancreatitis, and eosinophilia with or without an intestinal lesion may be a further association.
A patient with nephrotic syndrome in association with partial lipodystrophy is reported. The features of partial lipodystrophy are well recognized and the renal lesion is a mesangiocapillary glomerulo-nephritis of a dense deposit type with an associated depression of C3. This type of kidney involvement is becoming increasingly recognized as common in the syndrome of partial lipodystrophy.
Renal involvement is found in 20 to 50% of cases of Partial lipodystrophy (PLD). We report 8 cases of PLD of which 6 had a glomerular nephropathy and 2 had no renal disease but all had persistent hypocomplementemia and 5 had circulating nephritic factor (C3NeF). The analysis of these cases and of all the cases reported in the literature shows the specificity of the glomerular involvement. Membranoproliferative glomerulonephritis (MPGN) with dense intramembranous deposits is a constant finding in PLD with renal involvement. This variety of MPGN is well known for being associated with persistent hypocomplementemia. However, the presence of hypocomplementemia and C3NeF in patients with PLD but without nephritis raises the question of the interrelationship between alternative pathway complement activation and the development of MPGN with or without lipodystrophy. There is no valid explanation in the present state of knowledge for the association of partial lipodystrophy hypocomplementemia, and MPGN. From the answer to this problem should emerge a better understanding of the role of complement in renal disease and in particular in the unusual form of glomerular injury seen in MPGN.
Hyperglycemia, glucose intolerance, hyperinsulinemia and resistance to exogenous insulin were found in a 10-year-old Japanese boy diagnosed as having congenital generalized lipodystrophy. Studies on insulin receptors of circulating mononuclear leucocytes indicated that insulin-resistant diabetes combined with congenital generalized lipodystrophy may be due to disturbance of insulin binding to membrane receptors. No insulin-binding antibody or antibody that impairs insulin-receptor binding was found. Plasma glucagon showed an exaggerated response to L-arginine before treatment. After treatment with a controlled diet and an oral sulfonylurea (500 mg/day) for 4 weeks, there was improvement in the plasma glucagon response to L-arginine. Improvement in the hyperglycemia, hyperinsulinemia and acanthosis nigricans was also observed. On the other hand, on completion of a 7-day high-fat diet, a marked increase in serum free fatty acids, triglycerides and beta-lipoproteins was observed. The total plasma post-heparin lipolytic activity during the high fat diet was within the normal range. However, the level of protamine-inactivated activity was 3 times that of the control.
The course of disease of a patient with membranoproliferative glomerulonephritis and partial lipodystrophy is described. The case is further characterized by a deficiency of C3 and C3- activator, by normal values of C4, by evidence of the nephritogenic factor, by raised fibrin degradation products and by an unselective proteinuria. The course of the glomerulonephritis runs parallel to a pronounced susceptibility to infection (at first varicella, tonsillitis and measles, later pneumonia, meningitis, encephalitis and hepatitis). On account of a nephrotic syndrome and an initative impairment of the renal function, a cytostatic treatment was begun, which although raising the C3 level did not influence the further course of the disease. As the patient has a healthy identical twin sister without lipodystrophy, who shows no reduction in C3 and no nephritogenic factor, this case proves that these diseases are acquired and not genetically determined.
A case of partial lipodystrophy with C3 nephritic factor was found to be associated with mesangiocapillary glomerulonephritis although all clinical parameters of renal function were normal. Diagnosis of mesangiocapillary glomerulonephritis required renal biopsy. Nephriti factor obtained from this patient was immunochemically related to nephritic factor isolated from the serum of patients with typical mesangiocapillary glomerulonephritis without partial lipodystrophy.
A previously unreported patient with partial (cephalothoracic) lipodystrophy is described. Glucose tolerance and plasma lipids were normal, but plasma insulin increased to 340 muU/ml during an oral glucose tolerance test. Plasma free fatty acids were appropriately suppressed by oral glucose, insulin, and nicotinic acid, and were increased by infusion of norepinephrine. The lipolytic responses was also normal in response to two stimuli for endogenous catecholamine release: upright posture and 2-deoxyglucose infusion. There was a gradual development of postural hypotension in response to upright posture despite appropriate reflex tachycardia. Anhidrosis was present over the lower half of the body during this test, in a distribution corresponding to the area of adipose tissue hypertrophy. Anhidrosis was also seen in this region in response to warm ambient temperature. Adipose cells from the atrophic area were smaller than those from the hypertropic area, but the atrophic cells were only 65% of the volume of the hypertrophic cells by two different methods. Thus, loss of cells occurred. Glucose-1(-14)C utilization and in vitro lipolysis were similar in the two cell preparations; the difference were explicable by cell size and did not suggest a metabolic abnormality. Counts of unmyelinated nerves were similar in the two areas. These findings indicate that in this patient the lipodystrophy was associated with normal fat cells and an autonomic dysfunction. However, the findings cannot completely explain the pathogenesis of her disorder. Loss of fat cells, rather than symmetrical shrinkage, occurred in the upper half of the body.
Basal free fatty acid (FFA) turnover was found to be elevated or at the upper limit of normal in a patient with total lipodystrophy. The decrease in plasma FFA concentration which occurred after intravenous administration of insulin was shown to be primarily due to a fall in the inflow of FFA into the circulation. These results provide support for the suggestion that adipocytes in total lipodystrophy are able to synthesize triglycercide, but that they are unable to store it because of rapid lipolysis.
Adipocyte hypertrophy during obesity triggers chronic inflammation, leading to metabolic disorders. However, the role of adipocyte-specific inflammatory signaling in metabolic syndrome remains unclear. The linear ubiquitin chain assembly complex, LUBAC, is an E3-ligase that generates nondegradative linear ubiquitination (Lin-Ub). LUBAC regulates NF-κB/MAPK-driven inflammation and prevents cell death triggered by immune receptors like TNF receptor-1. Here, we show that mice lacking HOIP, the Lin-E3 ligase catalytic subunit of LUBAC, in adipocytes (HoipA-KO) display lipodystrophy and heightened susceptibility to obesity-induced metabolic syndrome, particularly metabolic dysfunction-associated steatotic liver disease (MASLD). Mechanistically, loss of HOIP attenuates TNF-induced NF-κB activation and promotes cell death in human adipocytes. Inhibiting caspase-8-mediated cell death is sufficient to prevent lipodystrophy and MASLD in HoipA-KO obese mice. HOIP expression in adipose tissue positively correlates with metabolic fitness in obese individuals. Overall, our findings reveal a fundamental developmental role for Lin-Ub in adipocytes by mitigating cell death-driven adipose tissue inflammation and protecting against obesity-related metabolic syndrome.
This report describes the occurrence of cephalothoracic lipodystrophy in one of 7-yr-old identical twin sisters. The affected twin had classical loss of sc fat from her face, upper arms, and trunk as well as associated hypocomplementemia, microscopic hematuria, and a borderline oral glucose tolerance test without hyperinsulinism. The unaffected twin had a normal urinalysis, serum complement, and oral glucose tolerance. Both twins, when challenged iv with LRH or TRH, showed appropriate FSH and LH or TSH and PRL responses, respectively. This report, in conjunction with another similar twin pair recently described in the German literature, makes a simple, single gene genetic etiology untenable and supports the view that cephalothoracic lipodystrophy in an acquired disease.
A 15-year-old girl is described with the sicca syndrome of keratoconjunctivitis and xerostomia. There was no associated rheumatoid arthritis or other connective tissue disorder, but total lipodystrophy had been present since the age of 9 years. Marked hyperreactivity of the humoral immune system and suppression of cell-mediated immunity was shown. The association of sicca syndrome with total lipodystrophy has not previously been reported.
Two patients with congenital generalized lipodystrophy have been studied at rest, and during and after long-term exercise at different carefully measured work loads. The two patients represented different stages of diabetes development. Both patients derived most of their energy used during muscular exercise from carbohydrate, and comparatively little from fat. FFA levels remained low throughout the period of observation in contrast to normal individuals and patients with juvinile diabetes. The data presented seem to show that deposition of glucose and free fatty acids (FFA) as triglyceride, must be impaired and are not compatible with the concept of increased triglyceride turnover in the adipocytes. The fall in blood glucose concentration (BCG) was less than in normal individuals and juvenile diabetes during exercise, and the glucose tolerance remained unchanged following work stop in both patients (k-values unchanged), in contrast to normal persons and patients with juvenile diabetes. Both patients showed significant falls in circulating immuno-reactive insulin (IRI) levels during exercise irrespective of a rise or fall in BGC. Thus, the exercise itself might activate endogenous mechanisms which could, on the one hand increase the circulating BGC, and at the same time force circulating IRI to decrease, thus disturbing the well-known relationship between circulating glucose and IRI levels as has been exhibited in normal subjects. The high IRI levels, also during exercise in these patients, indicate a relative insulin resistance in the muscles, but less marked than the insulin resistance in the adipose tissue. The IRI response after glucose infusion did not change significantly with increasing work loads with one exception. Exercose did not alter significantly the human growth hormone (HGH) levels in either the diabetic or the non-diabetic patient indicating an abnormal regulation of the HGH secretion in congenital lipodystrophy.
1. Suppressible and non-suppressible insulin-like activities (ILA) of plasma from 3 patients with congenital generalized lipodystrophy have been studied, employing isolated fat cells from rat epididymal adipose tissue. 2. In all 3 patients the fasting ILA was markedly increased compared with the normal controls. In one of the patients (I.T.) total ILA rose to about 800 muU per ml during an iv glucose tolerance test. 3. The observed total ILA was in all cases (controls included) equal to or slightly higher than the previously determined immunoreactive plasma insulin (IRI). The exact determination of ILA was, however, hampered by a dilution effect, which was present even at high plasma dilutions. 4. In 2 of the patients addition of insulin antiserum inhibited plasma ILA by about 50%. In the third patient (I.T.), who exhibited the highest insulin level, at least 85% of the activity was suppressed by insulin antibodies. The levels of non-suppressible ILA were higher than in the controls in terms of muU per ml, but lower than in the controls when related to total ILA. 5. These findings strongly support our previous conclusion that the elevated plasma insulin seen in congenital generalized lipodystrophy is mainly due to true pancreatic insulin. 6. Since the effect of plasma insulin on isolated fat cells were freely expressed, i.e. suppressible ILA was equal to or slightly lower than IRI, the presence of a circulating insulin antagonist in this disease may be excluded.