In vitro studies have shown that insulin and IGF-1 releases the fibrinolytic inhibitor plasminoge... more In vitro studies have shown that insulin and IGF-1 releases the fibrinolytic inhibitor plasminogen activator inhibitor-1 (PAI-1) from cells of hepatic origin. To investigate the effects of IGF-1 on fibrinolysis: 1) cultured hepatoma cells were grown in the presence of IGF-1 and media collected for secreted PAI-1 and cells probed for PAI-1 mRNA, 2) 8 hypopituitary patients were treated with recombinant human growth hormone (rhGH) and 3) 5 type 2 diabetic patients were treated with recombinant human IGF-1 (rhIGF-1). Treatment of Hep G2 cells with IGF-1 (1000 ng/ml) increased secretion of PAI-1 from a median value of 80 ng/10(6) cells (range 21-91) to 144 ng/10(6) cells (range 128-169) after 24 h (p < 0.01). Synthesis of PAI-1 mRNA increased in a similar fashion. Treatment of hypopituitary patients with rhGH led to an increase in circulating IGF-1 from a mean value of 166 (range 41-324) ng/ml at baseline to 322 (77-575) ng/ml at 4 weeks and 259 (104-533) ng/ml after 8 weeks (p < 0.02). Despite this, no changes in circulating PAI-1 or fibrinolysis occurred. Type II diabetic patients treated with rhIGF-1 showed an increase in circulating IGF-1 from a mean value of 120 ng/ml (range 109-196), at baseline to 823 ng/ml (585-894) after 5 days. This also was not associated with changes in circulating PAI-1 or in fibrinolysis. The results confirm that IGF-1 induces the synthesis of PAI-1 in Hep G2 cells.(ABSTRACT TRUNCATED AT 250 WORDS)
TO THE EDITOR: Fortmann and colleagues meta-analysis (1) showed that vitamin and mineral suppleme... more TO THE EDITOR: Fortmann and colleagues meta-analysis (1) showed that vitamin and mineral supplementation provides little benefit and does not aid cognition (2) or prevent cardiovascular events (3). The authors concluded that supplements have no value. However, data constraints limit interpretation to a narrower conclusion: Supplementation in well-nourished persons does not affect the end points studied but may have other benefits or abolish signs and symptoms of unrecognized deficiencies, which are surprisingly common. Many studies of vitamin supplements are flawed, including Fortmann and colleagues review, because vitamin concentrations at enrollment are usually not measured. It is predictable that study populations include those with low concentrations of vitamins, subclinical deficiencies, or both and others who are vitamin replete. These groups are distinguishable only if baseline, and preferably postsupplementation, vitamin concentrations are measured. Without measurement, assuming that all participants are vitamin and mineral replete is unsafe. Benefits in one group may be hidden by no effect in the other. Measurement of vitamin concentrations before and after supplementation will allow distinct effects to be recognized. For example, 22% and 7% of U.S. adults are considered vitamin C insufficient (serum vitamin C concentrations <28 mol/L) or deficient (<11 mol/L), respectively (4). Only those with concentrations less than 5 mol/L may exhibit scurvy. In contrast, vitamin C concentrations of approximately 50 to 60 mol/L are predictable in persons consuming the recommended dietary allowance of vitamin C; additional vitamin C intake increases concentrations only modestly at best among these persons. To put the problem in perspective, studies to test antihypertensive therapy would not be done without measuring blood pressure at enrollment. To treat everyone regardless of blood pressure would be illogical. However, this strategy has been persistently pursued in evaluating vitamin supplements. Vitamin and mineral supplements may benefit persons with marginal deficiencies. For example, patients with plasma vitamin C concentrations less than 20 mol/L report lassitude, a symptom that precedes scurvy (5). However, lassitude is common and nonspecific, and marginal vitamin C deficiency is difficult to recognize. Marginal vitamin and mineral deficiencies, even without obvious clinical disease, may decrease quality of life or have long-term adverse effects. This factor may be an adequate reason for supplement use, even if it does not prevent diseases other than deficiency states. Meticulous attention to the design and conduct of clinical trials, many study participants, and meta-analyses cannot compensate for fundamental physiologic oversights about vitamin doses and concentrations. Perhaps vitamin and mineral supplementation has little value in the general population, but these studies are inadequate to show it.
In vitro studies have shown that insulin and IGF-1 releases the fibrinolytic inhibitor plasminoge... more In vitro studies have shown that insulin and IGF-1 releases the fibrinolytic inhibitor plasminogen activator inhibitor-1 (PAI-1) from cells of hepatic origin. To investigate the effects of IGF-1 on fibrinolysis: 1) cultured hepatoma cells were grown in the presence of IGF-1 and media collected for secreted PAI-1 and cells probed for PAI-1 mRNA, 2) 8 hypopituitary patients were treated with recombinant human growth hormone (rhGH) and 3) 5 type 2 diabetic patients were treated with recombinant human IGF-1 (rhIGF-1). Treatment of Hep G2 cells with IGF-1 (1000 ng/ml) increased secretion of PAI-1 from a median value of 80 ng/10(6) cells (range 21-91) to 144 ng/10(6) cells (range 128-169) after 24 h (p < 0.01). Synthesis of PAI-1 mRNA increased in a similar fashion. Treatment of hypopituitary patients with rhGH led to an increase in circulating IGF-1 from a mean value of 166 (range 41-324) ng/ml at baseline to 322 (77-575) ng/ml at 4 weeks and 259 (104-533) ng/ml after 8 weeks (p < 0.02). Despite this, no changes in circulating PAI-1 or fibrinolysis occurred. Type II diabetic patients treated with rhIGF-1 showed an increase in circulating IGF-1 from a mean value of 120 ng/ml (range 109-196), at baseline to 823 ng/ml (585-894) after 5 days. This also was not associated with changes in circulating PAI-1 or in fibrinolysis. The results confirm that IGF-1 induces the synthesis of PAI-1 in Hep G2 cells.(ABSTRACT TRUNCATED AT 250 WORDS)
TO THE EDITOR: Fortmann and colleagues meta-analysis (1) showed that vitamin and mineral suppleme... more TO THE EDITOR: Fortmann and colleagues meta-analysis (1) showed that vitamin and mineral supplementation provides little benefit and does not aid cognition (2) or prevent cardiovascular events (3). The authors concluded that supplements have no value. However, data constraints limit interpretation to a narrower conclusion: Supplementation in well-nourished persons does not affect the end points studied but may have other benefits or abolish signs and symptoms of unrecognized deficiencies, which are surprisingly common. Many studies of vitamin supplements are flawed, including Fortmann and colleagues review, because vitamin concentrations at enrollment are usually not measured. It is predictable that study populations include those with low concentrations of vitamins, subclinical deficiencies, or both and others who are vitamin replete. These groups are distinguishable only if baseline, and preferably postsupplementation, vitamin concentrations are measured. Without measurement, assuming that all participants are vitamin and mineral replete is unsafe. Benefits in one group may be hidden by no effect in the other. Measurement of vitamin concentrations before and after supplementation will allow distinct effects to be recognized. For example, 22% and 7% of U.S. adults are considered vitamin C insufficient (serum vitamin C concentrations <28 mol/L) or deficient (<11 mol/L), respectively (4). Only those with concentrations less than 5 mol/L may exhibit scurvy. In contrast, vitamin C concentrations of approximately 50 to 60 mol/L are predictable in persons consuming the recommended dietary allowance of vitamin C; additional vitamin C intake increases concentrations only modestly at best among these persons. To put the problem in perspective, studies to test antihypertensive therapy would not be done without measuring blood pressure at enrollment. To treat everyone regardless of blood pressure would be illogical. However, this strategy has been persistently pursued in evaluating vitamin supplements. Vitamin and mineral supplements may benefit persons with marginal deficiencies. For example, patients with plasma vitamin C concentrations less than 20 mol/L report lassitude, a symptom that precedes scurvy (5). However, lassitude is common and nonspecific, and marginal vitamin C deficiency is difficult to recognize. Marginal vitamin and mineral deficiencies, even without obvious clinical disease, may decrease quality of life or have long-term adverse effects. This factor may be an adequate reason for supplement use, even if it does not prevent diseases other than deficiency states. Meticulous attention to the design and conduct of clinical trials, many study participants, and meta-analyses cannot compensate for fundamental physiologic oversights about vitamin doses and concentrations. Perhaps vitamin and mineral supplementation has little value in the general population, but these studies are inadequate to show it.
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