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Insulin resistance is emerging as a key, and possibly primary, abnormality in a variety of seemingly unrelated diseases1.
A Caucasian woman aged 30 was referred because of uncontrolled hypertension and proteinuria. She had a 4-year history of insulin-requiring diabetes mellitus, which was difficult to control; she was taking cyproterone acetate and ethinyloestradiol for infertility attributed to polycystic ovary syndrome (PCOS). Over the preceding 5 years she had noticed a gradual change in her appearance, with her face, hands and feet becoming thinner. On examination, there was striking loss of the subcutaneous fat from her cheeks and limbs, with increased fat deposition under her chin and over her upper back (Figure 1 a,Figure 1 b,Figure 1 c). She also had androgenic alopecia with facial hirsutism and minimal breast development, as well as peripheral acrocyanosis; she complained of severe Raynaud's phenomenon. Her blood pressure was 188/114 mmHg lying and 194/120 mmHg standing; she had heavy proteinuria (6.1 g/24 h) but no peripheral oedema; plasma albumin concentration was normal. Plasma urea and electrolytes, creatinine clearance, serum complement and immunoglobulins, and an autoantibody screen all gave normal results. When exogenous insulin was withheld, basal plasma insulin concentration was 906 pmol/L (normal range 11-86)—a finding consistent with underlying insulin resistance. Serum trigylceride concentration ranged between 3 and 5 mmol/L (normal < 1.8) and her total cholesterol was between 5 and 6 mmol/L (ideal < 5.2). An ultrasound scan of her abdomen showed kidneys of normal size and texture but fatty infiltration of the liver (which is commonly associated with insulin resistance). Renal artery stenosis as a cause of her hypertension was excluded by magnetic resonance angiography. Because of her heavy proteinuria in the absence of diabetic retinopathy or neuropathy, and the lack of improvement on lowering of blood pressure, she underwent renal biopsy. There were no features of diabetic renal disease; rather, the appearance was typical of focal and segmental glomerulosclerosis (FSGS) (Figure 2) without immune complex deposition (except in scarred areas due to ‘trapping’ of immunoglobulins): electron microscopy revealed foot process fusion, a feature of this condition. A skin biopsy taken from her forearm showed normal epidermis and dermis but complete absence of subcutaneous fat.
Lipodystrophy may be partial or total2. The patient we describe has partial lipodystrophy, which may be familial (autosomal dominant) or sporadic3. In the sporadic form, females are more frequently affected than males and subcutaneous fat is progressively lost from the upper body and face. The aetiology of the lipodystrophies is unknown. The partial form has been found in various other disorders, some autoimmune4,5,6. All forms of lipodystrophy are associated with insulin resistance and dyslipidaemia; other common features include hirsutism, acanthosis nigricans, menstrual abnormalities and PCOS7. Indeed, primary insulin resistance is now thought to underlie isolated PCOS and associated hyperandrogenism8.
There is a recognized association between partial lipodystrophy and a particular form of renal disease known as type II mesangiocapillary glomerulonephritis (MCGN)9. It is due to abnormal complement activation and C3 consumption triggered by an autoantibody, ‘C3 nephritic factor’, which may also be the cause of adipocyte loss by cell lysis10,11. Partial lipodystrophy almost always precedes the development of MCGN10, which can be precipitated by pregnancy or the contraceptive pill12. Unusually, our patient has FSGS and not MCGN (moreover she did not have detectable C3-nephritic factor). FSGS may be primary, and of unknown aetiology, or secondary to focal renal injury and scarring, resulting in reduced nephron mass and hyperfiltration (which also occurs in insulin-dependent diabetes, morbid obesity with insulin resistance and metabolic syndrome X)13. Renography in our patient did not reveal any cortical scarring.
An acquired form of partial lipodystrophy, again with insulin resistance, is that due to HIV protease inhibitors such as indinavir14. The mechanism is unknown, but the insulin resistance is thought to be primary and a cause, rather than a consequence, of adipocyte loss and redistribution. Moreover, there is evidence that these drugs directly inhibit the uptake of glucose by insulin-sensitive tissues such as fat and skeletal muscle15. HIV nephropathy can resemble (especially in those of African origin) FSGS, which may improve on protease inhibitor therapy16; but this only serves to underline the currently descriptive nature of this ill-understood form of glomerular injury. The inherited forms of lipodystrophy are not associated with mutations of candidate genes for insulin resistance such as those for the insulin receptor and adipocyte determination factor PPARγ17. Recent studies have localized the defect to chromosome 13 and a positional cloning approach has disclosed mutations in the gene encoding the nuclear envelope protein lamin A/C18, the function of which remains speculative. Interestingly, heterozygotes for one reported mutation are more likely than those with no mutation to have hypertension, dyslipidaemia and insulin resistance19.
Our patient exemplifies the variety of clinical and metabolic consequences that can be linked to insulin resistance and the importance of targeting therapy at this underlying defect. Indeed, since we began trying to reduce insulin resistance with metformin and rosiglitazone, her lipodystrophy has improved. This case highlights the need for a multidisciplinary approach to insulin resistance in all its guises and the importance of studies to determine: (1) adipocyte function and its relationship to insulin resistance; (2) the significance of lamin A/C mutations and normal adipocyte function; and (3) the role of insulin resistance per se in the pathogenesis of FSGS.
We thank Dr M Griffiths for reporting the renal histology and for providing Figure 2.