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Insulin Resistance in Healthy Volunteers Taking IDV/rtv & Reyataz/r; TH9507, a new growth hormone releasing fact
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From Jules Levin
I'm at the 6th Lipodystrophy Workshop in Wash DC. If you think there will be an answer to what causes body changes at this meeting there won't be. And if you think there will be a way to avoid body changes or to reverse them after they occur on HAART, the answer to that is not at this meeting either. There appears to be a lull in research at this time. I think answers to these questions are much more difficult to find than many thought. Several years ago I thought it would be awfully hard to find what causes lipodystrophy and how to reverse it, if possible at all. My thinking is not different today, but perhaps I'm wrong. So what's interesting at this meeting from today's sessions?
"Insulin Resistance in Healthy Volunteers Administered Single Dose Ritonavir Boosted Indinavir and Atazanavir Regimen"
Dominic Doran (Research Institute for Sports and Exercise Sciences, Liverpool, John Moores University, Liverpool, UK) reported on this study in an oral talk today. The results from this study support the notion that boosting ATV with 100 mg of RTV may not have a negative effect on insulin resistance. Preliminary studies in patients show similar results, but further studies in patients are planned and are needed to confirm these suggestions. Another important study should examine the effect of ATV & ATV/rtv on glucose in patients who already have developed diabetes to see if improvement is possible.
The aim of the study is to determine the impact of RTV boosted IDV and atazanavir (ATV, Reyataz) on insulin sensitivity following an acute bout of exercise. To observe the mechanisms of observed insulin resistance. BACKGROUND: Single dose IDV induces insulin resistance in HIV-negative men presumably by blockade of the insulin responsive glucose transporter GLUT4. By contrast, ATV has not been associated with altered lipid or glucose metabolism nor with inhibition of GLUT4 in vitro. In this 3-arm study, investigators compared the effects of a single dose of boosted ATV/rtv, IDV/rtv, and placebo on insulin and exercise stimulated glucose disposal, GLUT4 mRNA and protein expression.
18 healthy male volunteers (25 yrs old) were randomized to a single dose of placebo (n=6), ATV/rtv (300/100) (n=6), IDV/rtv (800/100) (n=6). One hour after drug administration, subjects performed 60 minutes of cycling at 70% of VO2 max. They then underwent a 180 minutes euglycemic hyperinsulemic clamp to assess the effects on insulin sensitivity, glucose disposal and free fatty acids (FFA). At baseline, 60 minutes and post-exercise a percutaneous needle muscle biopsy was performed.
RESULTS: There were no significant differences in plasma glucose, insulin and FFA between placebo, IDV/rtv or ATV/rtv at baseline or during the clamp. ATV and IDV plasma concentrations were within the expected range at 60 minutes and remained so until the end of the clamp. Insulin-stimulated glucose disposal per unit of insulin (M/I) was significantly reduced in the IDV/rtv group (8.19±0.3) when compared with both the placebo (12.1±1.0 mg/kg/min-1 per μU/ml, p<0.05) and ATV/rtv (14.58±1.0 mg/kg/min-1 per μU/ml, p<0.05) arms.
The non-oxidative component of total glucose disposal (storage) was lower in the IDV/rtv group (3.74±0.42 mg/kg/min-1), when compared with the placebo (5.62±0.60 mg/kg/min-1) and ATV/rtv arms (5.40±0.53) P<0.01.
Total GLUT4 mRNA and protein did not decrease in either IDV/rtv or ATV/rtv groups when compared with placebo.
AUTHOR CONCLUSIONS:
--IDV/rtv, but not ATV/rtv, acutely induces insulin resistance, an effect which is not mediated by direct inhibition of GLUT4. The effect of these drugs in vivo (patients) on the intrinsic activity of GLUT4 warrants further investigation.
--The PI combination IDV/rtv exerts rapid inhibitory effect on glucose utilization via reduced glycogen storage.
--The PI ATV/rtv had no effect on glucose utilization in line with data from un-boosted studies and long-term trials.
--The mechanism appears not to be mediated via defects in GLUT4 mRNA or protein expression.
--AMPK in the insulin signaling cascade is up-regulated in response to exercise and drug-induced stress possibly as a response to a reduction in energy charge within the muscle.
In another oral presentation results from a study were reported on 7 healthy HIV-negative men who were given a single dose of 800 mg RTV or placebo two hours before a euglycemic-hyperinsulinemic clamp. The single dose of 800 mg RTV acutely decreased insulin-mediated glucose disposal and non-oxidized glucose disposal during the clamp. Therapeutic drug levels were achieved during the clamp study. Free fatty acids were equally suppressed during the clamp study. There was a trend towards an increase in HOMA insulin resistance index and fasting serum glucose. The clamp findings are consistent with an acute blockade of GLUT4 by RTV. There was a 21% decrease in insulin-mediated glucose disposal, which is less than the 34% decrease in insulin-mediated disposal with a single dose of IDV. In vitro studies suggest that RTV & IDV induce insulin resistance to a similar degree.
"Effects of TH9507, a Growth Hormone Releasing Factor (GRF) Analog, on Body Composition in Patients with Abdominal Fat Accumulation Associated with HIV Lipodystophy Syndrome"
Steve Grinspoon (Mass General Hospital, Boston, MA) reported results from this early study in an oral talk today. The preliminary results appear promising. Grinspoon said there will be a public announcement soon of plans for the next study.
BACKGROUND: This is a drug that stimulates release of GH. TH9507 has a longer half-life than the natural peptide, has been shown to increase IGF-1 levels within the physiologic range and to safely improve body composition in non-HIV infected patients. Grinspoon also said accumulation of visceral adipose tissue (VAT, abdominal fat) may increase risk of cardiovascular diseases, which is related to increased metabolic factors. In HIV GH levels are reduced and are inversely correlated with accumulation of VAT. Pharmacologic doses of GH are able to reduce truncal fat and VAT but are associated with insulin resistance and side effects of GH excess. This drug is well tolerated at single doses up to 2 mg/day including with regard to glycemic control in type 2 diabetic patients.
Grinspoon reported results from a multi-center, randomized, double-blind, placebo controlled study of 12-week treatment of TH9507 at 1 mg or 2 mg by single daily s.c. injection. Patients were male and female. Stable on HAART for at least 8 weeks. Had abdominal fat accumulation: WC >95 cm and WHR>0.93 for males, WC >94 cm & WHR>0.87 for females. (WC=WAIST CIRCUMFRANCE). Fasting glucose <150 mg/dL. He stressed that patients had elevated glucose up to 150 showing that mild diabetes was studied. Stable lipid-lowering agents permitted.
BASELINE CHARACTERISTICS: age 44-46 yrs; 18 men ineach arm and 1-3 females. CD4 was 525-570. BMI: 28-20 kg/m2. WHR 1.0.
At week 12, serum IGF-1 levels increased over baseline by 59% (p=0.002) and 80% (p=0.0001) at 1 mg (n=17) and 2 mg (n=15), respectively.
There was a decrease in visceral fat of -15.7% for the 2 mg group (p<0.05) vs baseline, -5.4% for the placebo group, NS vs baseline, whereas subcutaneous fat was preserved. There was no difference when comparing placebo to the 2 mg group between baseline & week 12, but there was a decrease in abdominal fat from baseline in the patients receiving 2 mg at week 12. 11 patients taking 2 mg experienced nervous system adverse events (headaches, patestthesis), 7 patients experienced GI disorders, and patients also experienced arthralgia, and other side effects. The drug did not adversely affect lipids and was well tolerated with regards to glucose. Change in glucose parameters: glucose (mmol/L) 0.2 placebo; 0.1, 1 mg; 0.1, 2 mg; 2-h glucose (mmol/L): 0.6, placebo; 0.1, 1 mg; 0.7, 2 mg; insulin (mmol/L): 5.1, placebo; -2.8, 1 mg; 7.4, 2 mg. Although insulin increased, glucose did not.
Grinspoon conluded:
once daily dosing at 2 mg over 12 weeks-
--increased IGF-1 levels within the physiologic range
--decreased trunk fat and visceral fat with no significant effect on subcutaneous fat (limb fat)
--increased lean body mass
--improved lipid profile
--was well tolerated with no AEs on glucose
This was an initial study & only 12 week treatment. Unlike other HGH, glucose was not adversely affected even with mildly insulin resistant patients included in the study, and lipids were not adversely affected. Compared to placebo the 2 mg dose did not show improvement, but patients who received 2 mg showed reduced abdominal fat at week 12 compared to baseline. Researchers at the meeting felt the drug has promise but data is preliminary.
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