endocrine fashion, and their bioactivity is greatly modulated Hyperinsulinemic euglycemic clamps were performed by their binding proteins. Thus, GH, which reduces sensitivon six patients with compensated alcoholic cirrhosis and ity to insulin, normally stimulates the secretion of IGF-I, on six normal comparison subjects. As in previous studwhich increases insulin sensitivity. ies, glucose uptake in the cirrhotic patients was only Several roles have been suggested for the six IGF-binding 21% of the comparison value. The cirrhotic patients had proteins (IGFBPs) identified thus far. These include limiting high growth hormone (GH) and low insulin-like growth the bioactivity of the IGFs to protect against hypoglycemia, factor-I (IGF-I) levels, with low insulin-like growth facregulation of the stability or clearance rate of the IGFs, and tor-binding protein (IGFBP)-3 levels, but surprisingly modulation of the action of the IGFs at a cellular level. 2 high IGFBP-1 levels (26.8 { 8.4 mgH vs. 3.2 { 0.2 mg/L, P IGFBP-3 is the most abundant in serum and binds 95% of รต .001). The log IGFBP-1 level was inversely correlated circulating IGF-I and -II in a ternary complex that is highly with the log insulin sensitivity (r ร
0.95). The clamps stable and probably serves to limit the bioavailability of the were repeated with a somatostatin infusion to suppress IGFs. IGFBP-3 is produced by the liver and by most other GH secretion. IGFBP-1 increased in both groups, espetissues in response to IGF-I and GH. 2 IGFBP-1 is produced cially in the cirrhotic subjects. Insulin sensitivity inmainly by the liver and is the only IGFBP that displays rapid creased in the normal subjects but was unchanged in regulation with serum levels that vary rapidly in response the cirrhotic patients. Following GH treatment (0.13 U/ to meals. Levels of IGFBP-1 are high in fetal life, fall precipikg/d for 5 days), the clamps were repeated. GH, IGF-I, tously at gestation, and then show a progressive age-related and IGFBP-3 levels were now similar in the two groups;
decline in normal individuals. High levels have been found IGFBP-1 levels decreased in the cirrhotic patients but in prolonged fasting, prolonged exercise, in anorexia nervosa, remained fivefold higher than the comparison value in intensive care patients, in chronic renal failure, and in (10.6 { 3.7 vs. 2.1 { 0.4, P รต .05). Glucose uptake in the insulin-dependent diabetes mellitus. 4 IGFBP-1 levels are cirrhotic patients remained only 29% of the comparison lowered by insulin. Low levels have been found in obesity value, but the change in their insulin sensitivity was and polycystic ovary syndrome. IGFBP-1 is thought to limit inversely correlated with the change in their IGFBP-1 the bioactivity of IGF-I by preventing its binding to cell memlevels (r ร
0.84). These results suggest an important role branes. 4 Less is known about the other binding proteins. for IGFBP-1 in modulating insulin sensitivity in cirrho-IGFBP-2 may provide an intermediate level of regulation of sis. (HEPATOLOGY 1996;24:127-133.)
IGF availability and may be important under conditions in which there is insufficient IGFBP-3 to carry all available Growth hormone (GH) is essential for normal growth, but IGFs. It may be specifically induced by IGF-II. 2 its role in the adult remains uncertain. Its secretion is in-
The GH/IGF-I axis is deranged in cirrhosis 5 ; GH levels are creased by stress, starvation, and in diseases such as poorly raised and increase further in response to insulin and glucontrolled diabetes mellitus, cirrhosis, and acromegaly. In cose, as opposed to the normal decrease. Despite the high GH, each of these conditions, high levels of GH are associated IGF-I levels in cirrhosis are low. Cirrhotic patients exhibit with insulin resistance. Indeed, infusions of GH in the short marked basal hyperinsulinemia and insulin resistance, but and long term have been shown to induce insulin resistance. 1 the relationship between the GH/IGF-I abnormalities and One of the main effects of GH is to stimulate production of the metabolic abnormalities is unclear. It is possible that the insulin-like growth factor-I (IGF-I). IGF-I and -II are polypepimbalance between GH and IGF-I that exists in cirrhosis tides with structural homology to proinsulin that regulate leads to insulin resistance. However, suppression of GH with proliferation and differentiation, but only IGF-I is dependent somatostatin does not improve insulin sensitivity in cirrhoon GH. 2 Like insulin, they exert insulin-like metabolic effects sis, 6 and these data are now extended with IGFBP measureand increase insulin sensitivity. 3 Unlike insulin, IGFs are ments. In an attempt to ''equalize'' GH and IGF-I levels beproduced by most tissues of the body and are abundant in tween the cirrhotic and comparison subjects, both groups the circulation. They function in an autocrine, paracrine, and were treated with GH. Thus, insulin sensitivity was measured using hyperinsulinemic euglycemic clamps under three conditions: 1) control clamps; 2) somatostatin infusion to suppress GH secretion; and 3) following 5 days of treatment with Abbreviations: GH, growth hormone; IGF-I, insulin-like growth factor-I; IGFBP, insulinlike growth factor-binding protein; NEFA, nonesterified fatty acid; SRIH,.