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Where does insulin resistance in lipodystrophic HIV-1-positive subjects come from?

Schmidt, Hartmut H.-J.

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From the Medizinische Klinik Gastroenterologie, Hepatologie und Endokrinologie, Charité, Berlin, Germany.

Correspondence to Hartmut H-J Schmidt, M.D., Med. Klinik Gastroenterologie, Hepatologie und Endokrinologie, Charité, D - 10098 Berlin, Germany. Tel: +49 30 450 514102; fax: +49 30 450 514916; e-mail: hartmut.schmidt@charite.de

Received: 18 June 2001; accepted: 26 June 2001.

The rapid introduction of protease inhibitors has substantially improved the survival of HIV-1-infected patients. Alterations in lipid and glucose metabolism and in distribution of fatty tissue have been increasingly observed in patients treated with protease inhibitors [1–3]. Because of the increased survival of HIV-1-infected patients, therapy-induced development of diabetes mellitus and dyslipemia is of potential concern, as both disorders are closely associated with increased risk for cardiovascular disease [4,5]. In extension to the clinical importance of protease inhibitor-induced metabolic alterations, this phenomenon may also provide an excellent opportunity for examining the pathogenesis of altered glucose and lipid metabolism.

In this issue of AIDS, van der Valk et al. examined the insulin sensitivity and the endogenous glucose production and glucose uptake in lipodystrophic HIV-1 positive subjects receiving protease inhibitors [6]. Although this study did not focus on the intra-individual follow up of HIV-1-infected subjects before and after treatment with protease inhibitors, they convincingly show for the first time in these patients, that endogenous glucose production at basal insulin concentrations is increased in protease inhibitor-treated patients. In addition, endogenous glucose production and insulin secretion was less suppressable, during an hyperinsulinaemic euglycaemic clamp, and insulin-stimulated glucose disposal was decreased. The latter observations define the term insulin resistance. The question then arises, what stimulates the endogenous glucose production and why does this observed insulin resistance develop? To further elucidate the mechanism they determined the concentration of unesterified fatty acids in plasma, and showed that there was an increased basal concentration and a less suppressable concentration, during an hyperinsulinaemic euglycaemic clamp. Furthermore, fasting serum triglyceride concentrations were significantly increased in comparison with the studied control group, despite the fact that there was no significant differences in body mass index, lean body mass and fat mass between the groups. Elevations of serum triglycerides in the fasting state usually result from upregulated hepatic synthesis of apolipoprotein B and very-low-density lipoprotein particles, which in turn may result from the observed increased serum concentrations of unesterified fatty acids in the studied patients [7]. Decreased intravascular lipolytic activity (lipoprotein lipase and hepatic lipase) may also contribute to the observed hypertriglyceridaemia [7] : therefore, these data nicely fit with the current understanding of glucose and lipid metabolism.

It is well known that insulin resistance can occur in the chronic hypertriglyceridaemic state and, vice versa, that hypertriglyceridaemia can occur in diabetic patients. The question remains what comes first and what triggers these diseases. Although the link between hyperinsulinaemia due to insulin resistance and hypertriglyceridaemia are presumably unesterified fatty acids, it is still not known, where the regulatory step begins and why only some patients develop diabetes and/or hypertriglyceridaemia.

Insulin resistance is the opposite of insulin sensitivity and reflects the upregulated insulin secretion by the pancreatic β-cells compensating for a decreased biological response to circulating insulin [8]. Decompensation results in hyperglycaemia called diabetes mellitus. Insulin resistance has been associated with android obesity, hypertriglyceridaemia, genetic predisposition, aging, drug toxicity, and sedentary lifestyle. Decreased insulin response results in reduced uptake of glucose in muscle, increased intracellular lipolysis, and subsequent increased release of unesterified fatty acids. Raised serum concentration of unesterified fatty acids stimulates hepatic glucose production, reduces glucose utilization in muscle, and enhances insulin secretion; thus exacerbating the state of hyperinsulinaemia. This complex interactive system between insulin, glucose, and unesterified fatty acids seems to be regulated by liver, muscle and adipose tissue.

An additional important feature of this phenomenon is the variable presence of lipodystrophy, the altered localization of adipose tissue. Lipodystrophy is very heterogenous in HIV-1-treated patients and ranges from lipatrophy to regional increase of adipose tissue. Therefore, a more precise clinical description of lipodystrophy in these patients is ideally required in the future for a better understanding of these variable metabolic states. More generally speaking, lipodystrophy may also stand for android and gynoid obesity. Android obesity relates to the metabolic syndrome, also called syndrome X, which interestingly presents with similar features, such as insulin resistance, increased serum concentrations of unesterified fatty acids and dyslipaemia. The understanding of the metabolic disturbance in HIV-1-treated patients may, therefore, serve as a model for better understanding of the metabolic syndrome.

The observation of these variable, but similar symptoms raises the question of the regulatory elements for determining flux of unesterified fatty acids and glucose, insulin release and response, lipoprotein synthesis, as well as for intracellular and intravascular lipolysis. We know from the identification of the genetic defect in familial partial lipodystrophy, a rare inherited syndrome associated with lipodystrophy, myopathy, dyslipemia, and insulin-resistant diabetes mellitus, that the nuclear envelope protein lamin A/C plays an important role in mediating altered glucose and lipid metabolism [9–11]. Other factors such as retinoic acid, its binding proteins, and peroxisome proliferator-activated receptor-γ may play also a role in this context [12].

In conclusion, we are still not able to fully define the exact mechanism causing lipodystrophy, insulin resistance, and dyslipemia: however, the precise analysis of metabolic parameters in HIV-1 patients before and after treatment with protease inhibitors serves as an excellent model to improve our understanding of the pathogenesis of these metabolic diseases.

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References

1. Behrens G, Dejam A, Schmidt HH-J. et al. Impaired glucose tolerance, beta cell function and lipid metabolism in HIV-patients treated with HIV-protease inhibitors. AIDS 1999, 13: 63–70.
2. Carr A, Cooper DA. Adverse effects of antiretroviral therapy. Lancet 2000, 356: 1423–1430.
3. Schmidt HH-J, Behrens G, Genschel J. et al. Lipid evaluation in HIV-1 positive patients treated with protease inhibitors. Antiviral Ther 1999, 4: 163–170.
4. Henry K, Melroe H, Huebsch J. et al. Severe premature coronary artery disease with protease inhibitors [letter]. Lancet 1998, 351: 1328.1328.
5. Behrens G, Schmidt H, Meyer D, Stoll M, Schmidt RE. Vascular complications associated with use of HIV protease inhibitors [letter]. Lancet 1998, 351: 1958.1958.
6. Van der Valk M, Bisshop PH, Romijn JA. et al. Lipodystrophy in HIV-1 subjects is associated with insulin resistance in multiple metabolic pathways. AIDS 2001, 15: 2093–2100.
7. Ascaso JF, Real JT, Carmena R. Insulin resistance and familial dyslipidemias. Diabetes, Obesity and Metabolism 1999, 1: 323–330.
8. Saltiel AR. New perspectives into the molecular pathogenesis and treatment of type 2 diabetes. Cell 2001, 104: 517–529.
9. Shackleton S, Lloyd DJ, Jackson SNJ. et al. LMNA, encoding lamin A/C, is mutated in partial lipodystrophy. Nat Genet 2000, 24: 153–156.
10. Behrens G, Schmidt HH-J, Schmidt RE, Trembath RC. Lessons from lipodystrophy – LMNA encoding lamin A/C, in HIV-therapy associated lipodystrophy. AIDS 2000, 14: 1854–1855.
11. Schmidt HH-J, Genschel J, Baier P. et al. Dyslipemia in familial partial lipodystrophy caused by a R482W mutation in the LMNA gene. J Clin Endocrinol Metab 2001, 86: 2289–2295.
12. Willson TM, Lambert MH, Kliewer SA. Peroxisome proliferator-activated receptor gamma and metabolic disease. Annu Rev Biochem 2001, 70: 341–367.
Keywords:

lipodystrophy; insulin resistance; diabetes mellitus; HIV-1; protease inhibitor; hyperlipidaemia

© 2001 Lippincott Williams & Wilkins, Inc.