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Abnormalities of Glucose Metabolism, Including Insulin Resistance
Michael Dube, MD, University of Indiana and ACTG researcher
The 3rd International Workshop on Adverse Drug Reactions and Lipodystrophy in HIV included some important new insights into the mechanisms behind insulin resistance in ARV drug-treated patients with HIV. There is an increasing recognition that there are 2 important factors contributing to the insulin resistance seen among treated patients, that due to the protease inhibitors and that due to fat redistribution itself. Both need to be considered in practice and in future research into potential interventions. Lesser progress has occurred with specific therapies that address insulin resistance, but insight into mechanisms is nonetheless very important into deciding what types of interventions are likely to be effective.
Importance of insulin resistance: Insulin resistance is the term used when the body needs more insulin than normal to control the blood sugar. Only when the pancreas can no longer produce sufficient insulin to overcome the resistance does diabetes occur, so testing the blood sugar alone will not be enough to estimate insulin resistance. Unfortunately, an exact measure of it does not truly exist, it is just not as straightforward as measuring something like a cholesterol level. It is unclear exactly what degree of insulin resistance is acceptable for an individual to experience without harm. This is just as true for the general population as it is for those with HIV, and presumably varies from person to person. It is also true that the amount of increase in cholesterol levels that an individual can safely experience will vary from person to person. But it is clear that insulin resistance is undesirable, even if the blood sugar remains relatively normal (i.e. in the non-diabetic range). It causes an increase in cardiovascular disease risk and abnormalities in blood vessel function and lipid levels. Interventions that address insulin resistance all tend to improve cardiovascular risk factors.
(editorial comment: you can perform an insulin resistance test to evaluate whether or not you are developing insulin resistance, which can preceed seeing sugar elevations in the blood and diabetes. Performing the insulin resistance test is a way to perhaps identify a potential problem before sugar in your blood is elevated).
PIs and insulin resistance: Studies in both rats (Hruz et al) and humans (Noor et al) both documented that insulin resistance occurs rapidly, that is with just a single dose, of indinavir. As suspected from clinical experience, this insulin resistance appears to be rapidly reversible. New insights into the exact cellular site of insulin resistance were provided by Murata et al, who reported that indinavir inhibited the function of Glut-4, the intracellular glucose transporter that is stimulated by insulin to come to the surface of the cell to facilitate glucose entry into muscle and fat cells. Their report, which expanded on their published paper from the Journal of Biologic Chemistry in 2000, that this function was inhibited by concentrations of indinavir that are present during treatment in humans. Caron et al, following up on their recently published report from the journal Diabetes in June 2001, reported that development of adipocytes (fat cells) and the function of certain proteins important to lipid metabolism (SREBP-1 and PPAR-gamma), as well as a measure of apoptosis (cell death) were adversely affected more by indinavir than nelfinavir, and the least by amprenavir. They found that a cellular mechanism, apart from the Glut-4 effect noted above, may also be responsible for insulin resistance due to protease inhibitors. This effect on early insulin signaling events was again most marked for indinavir. Importantly, they found that the drug rosiglitazone, an insulin-sensitizing drug that augments the activity of PPAR-gamma, reversed almost all of the adverse effects seen with PIs in these fat cells. Whether this drug will be effective for treating lipodystrophy (in humans) remains to be seen (see below).
(Edit. Note: Hruz suggested that the effects he saw may be due to direct binding between indinavir and the Glut-4 transporter molecule. The inhibitory effect occurs within the therapeutic range achieved in vivo in humans [same dose humans take]. He suggests the inhibition of Glut-4 is direct and likely directly contributes to the insulin resistance observed in PI treated patients. And further he said the in vitro testing of drugs in development or being considered for HIV treatment could be tested to see if they inhibit Glut-4. Hruz reported that Glut-4 is the primary mediator of stimulated glucose uptake in vivo; Hruz suggested that indinavir induced peripheral insulin resistance. Haugaardıs paper discussed below also reports peripheral glucose disposal rate (peripheral insulin resistance) was decreased in patients with lipodystrophy. He suggests hepatic insulin resistance occurred in patients with lipodystrophy. Hruz also said that PI drug levels at the time of glucose tolerance testing may be critical to the measurement of insulin resistance. Noor suggested a PI drug should be taken before blood is drawn to accurately assess effect on insulin sensitivity and glucose metabolism. As I stated in a previous report, indinavir was the only PI for which data was reported, but during question & answer the speakers said they had looked at all protease inhibitors and they suggested other protease inhibitors show similar effects but perhaps there are differences in the degree of effect between the different protease inhibitors
In the Noor study a single 1200 mg oral dose of indinavir achieved standard steady plasma concentrations (10 uM) acutely reduced insulin stimulated glucose disposal by average of 34% in the 6 HIV-negative subjects. Although Haugaard reported not finding peripheral or hepatic insulin resistance associated with PI or NRTI, Yarasheski (abstract 6) reported HIV associated glucose intolerance is characterized by a greater duration of HIV perhaps meaning a greater duration to antiretroviral therapy).
A report from Dube et al in HIV-infected patients on amprenavir-based therapy tended to support Caron's findings. We reported no significant insulin resistance during the first 24 weeks of treatment with abacavir-3TC-amprenavir in 14 (edit. Note: mostly Hispanic) subjects (2 of whom received d4T instead of 3TC). However, subjects gained trunk fat, lipids rose, and had evidence of insulin resistance at week 48, although peripheral fat loss was not seen. This study suggested that amprenavir lacks the acute effects of indinavir on insulin resistance and might be a better PI choice where insulin resistance is a particular concern. The lack of peripheral lipoatrophy was an interesting finding, that might be related to the particular PI used or to the nucleosides used. With amprenavir seldom used as a sole PI anymore, usually combined with ritonavir, the clinical implications of this study are less clear. Further work is clearly needed with identifying PIs with the least effects on glucose and lipid metabolism.
Scientists from Bristol-Myers-Squibb, makers of the investigational PI atazanavir (formerly known as BMS-232632) which appears to have lesser lipid effects than some of the PIs currently in use, displayed a poster reporting the effects of various PIs on fat (adipocyte) and liver (hepatocyte) cells in vitro, although amprenavir was not included. They studied atazanavir, ritonavir, indinavir, nelfinavir, and saquinavir, but only reported the effects of ritonavir (which was said to be the worst of the PIs) and atazanavir on glucose uptake. They found a significant reduction in insulin-stimulated glucose uptake (roughly comparable to insulin resistance) with ritonavir but not atazanavir. Further clarification of their results and methods are needed, but these results suggest that atazanavir may have a lesser tendency to provoke insulin resistance in patients. Clinical studies of this drug in insulin resistance are needed.
Pathophysiology of insulin resistance: The site in the body of insulin resistance were further described at this conference. It has been shown previously that muscle cells become insulin resistant during PI treatment. But insulin also acts on the liver cells which produce glucose when there is no glucose available from a recent meal or from glycogen, in a process called gluconeogenesis. Normally, when there is enough glucose around, insulin signals the liver to slow down gluconeogenesis. Haugaard et al reported that the liver also is insulin resistant among subjects with lipodystrophy, requiring greater concentrations of insulin to signal it to stop gluconeogenesis. Whether this effect was primarily due to PIs or to the fat redistribution itself is not clear. A study by Behrens et al in subjects on HAART (most of whom had a loss of fat) suggested that, in addition to a defect in how Glut-4 transports glucose into the cell, that once glucose gets into the cell it is not phosphorylated normally, further impairing energy utilization and insulin resistance. Formation of stored glucose, in the form of glycogen, may be impaired as well.
Steve Grinspoon reported data from his group (Hadigan et al) regarding the role of lipolysis (breakdown of fat) in lipodystrophy and insulin resistance. In HIV-infected men with abdominal obesity, an increased rate of lipolysis was found. This correlated with visceral fat (fat accumulation in belly) measured by CT and with insulin resistance, suggesting increased lipolysis contributes to insulin resistance. Then, a group of male subjects with severe insulin resistance and central obesity were given a dose of the drug acipimox, which acutely inhibits lipolysis. This resulted in a marked decrease in free fatty acids and an improvement in insulin resistance. While this type of response would also be expected in an HIV-uninfected person with visceral obesity and insulin resistance, it provides a rationale to test interventions targeted at inhibiting lipolysis and reducing free fatty acid levels in patients with lipodystrophy.
Interventions for insulin resistance: Rosiglitazone and pioglitazone are thiazolidenedione (TZD) drugs used clinically to treat type 2 diabetes mellitus. They act by increasing insulin sensitivity (which is analogous to reducing insulin resistance) and the activity of PPAR-gamma (protein or gene), which is critical in the development and function of adipocytes. There is hope that these drugs will not only improve insulin sensitivity, but also increase subcutaneous fat like they do in diabetics, and thus improve lipoatrophy in HIV patients without diabetes. Few trials have been done in non-diabetic individuals. Two small studies (one with rosi and one with pio) reported no significant objective improvement with either drug. These results should not be considered either definitive or discouraging, and a real answer awaits larger, properly controlled trials. No problems with toxicity were reported. Use of these drugs in HIV, except where used for treating established diabetes, remains investigational and is not generally recommended. A large ACTG trial comparing rosiglitazone and metformin, alone and in combination, is currently underway and enrolling subjects with high fasting insulin levels and abdominal obesity.
Hadigan et al reported that the benefits of metformin in reducing abdominal obesity, insulin resistance, and impaired fibrinolysis (impaired ability to lyse blood clots) were sustained out to 9 months of therapy. This was a follow-up report for their important JAMA paper from 2000 which showed improvements during metformin treatment as compared to placebo, among HIV subjects with abdominal obesity and high fasting insulin levels. How the drug works when high fasting insulin levels are not present is not known, and there is concern that lipoatrophy might worsen. However, lactic acidosis was not seen with metformin, which has been an important concern.
(Edit. Note: statistically significant reductions in body mass index, waist circumference, and waist-to-hip ratio were seen in response to metformin. Metformin was reportedly well-tolerated, no one discontinued due to side effects, and there were no increases in lactate levels).
Where does this all take us? Quite obviously, there remains a great deal of work to be done in the area of insulin resistance and HIV. I am encouraged by the progress to date, including an emerging understanding of the cellular mechanisms and pathophysiology of the problems. Some progress is being made in identifying the kinder, gentler antiretroviral therapies as well as interventions to address insulin resistance in this population. As always, additional clinical trials, both in the HIV infected and uninfected, will be of tremendous importance.
Until more data is available from clinical trials, it continues to be reasonable to recommend those measures that are recommended among the general population, particularly for those at high risk of insulin resistance and diabetes. Loss of weight for the obese, and the use of regular aerobic exercise, are reasonable non-drug measures that can be expected to be effective at reducing insulin resistance that can be recommended for all patients suffering from HIV infection. This would be particularly true for those with pre-existing lipodystrophy, who are taking PIs, who have traditional risk factors for type 2 diabetes such as positive family history, obesity, high-risk ethnicity (Hispanic, black, native American, Asian-American, or a Pacific Islander), age >45 years, history of gestational diabetes or impaired glucose tolerance, hypertension, or abnormal lipids. As you might imagine, this probably covers a majority of those living with HIV.
(Edit. Note: it has been reported from study that weight reduction due to exercise may result in fat loss in belly but might exascerbate fat loss in the periphery, so caution is recommended).
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