It is proposed that an intracellular cycle exists to limit or terminate the insulin signal. The cycle involves increased synthesis of sn-1,2-diacylglycerol (DAG) in response to insulin. The DAG activates protein kinase C (PKC) which phosphorylates glycogen synthase either directly or through other protein kinases to render it inactive. Protein kinase C may also inhibit the insulin receptor by phosphorylation of receptor serine residues. Insulin resistance could then arise as a consequence of a persistent increase in DAG levels. Such an increase could occur in three different ways. Chronic hyperinsulinaemia could increase DAG levels by de-novo synthesis from phosphatidic acid, by hydrolysis of phosphatidylcholine, or by hydrolysis of glycosyl-phosphatidylinositol; DAG is also formed by hydrolysis of phosphatidylinositol 4,5-biphosphate (PIP2). This reaction, known as the 'PI response,' may be the connection between hypertension and insulin resistance. A third mechanism for an increase in DAG involves neural abnormalities. Thus, muscle denervation in the rat is characterized both by a profound insulin resistance and a large increase in DAG. It is possible that a similar increase occurs in humans and may explain the association between denervation, inactivity, and insulin resistance.
1endocrine 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 õ .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 Å 0.95). The clamps stable and probably serves to limit the bioavailability of the were repeated with a somatostatin infusion to suppressIGFs. 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 õ .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 Å 0.84). These results suggest an important role branes. 4 Less is known about the other binding proteins.
We examined whether elevated plasma nonesterified fatty acid (NEFA) levels exert a direct effect on protein metabolism by measuring [2H5]phenylalanine skeletal muscle exchange and whole body turnover. [2H5]phenylalanine was infused (0.5 mg.kg-1 x h-1) for 300 min in seven healthy subjects on two occasions. Intralipid (10%; 30 ml/h) or 0.154 mol/l NaCl was infused in random order from 120 min. Measurements were taken during basal (90-120 min) and infusion (270-300 min) periods. Intralipid infusion increased plasma NEFA levels [1.31 +/- 0.13 vs. 0.49 +/- 0.05 (SE) mmol/l; P < 0.05] and forearm NEFA uptake [45 +/- 76 vs. -51 +/- 44 nmol . 100 ml forearm-1 x min-1; P < 0.05]. Serum insulin and blood ketone body levels were similar with the two treatments. Elevated plasma NEFA levels were associated with a comparable decrease in forearm phenylalanine uptake (11 +/- 2 vs. 17 +/- 2 nmol x 100 ml forearm-1 x min-1; lipid vs. control, P < 0.05) and release (20 +/- 2 vs. 26 +/- 3 nmol x 100 ml forearm-1 x min-1; lipid vs. control, P < 0.05). However, there were no significant changes in net forearm phenylalanine exchange and whole body phenylalanine turnover. Therefore, elevated plasma NEFA levels were associated with a comparable decrease in the rates of skeletal muscle protein synthesis and breakdown but did not appear to influence overall protein balance, as assessed using [2H5]phenylalanine.
Cirrhosis is characterized by paradoxical growth hormone secretion in response to glucose and insulin infusion. To ascertain whether this abnormality contributes to insulin resistance, euglycemic hyperinsulinemic glucose clamps were performed on six patients with cirrhosis and six normal control subjects. Each patient with cirrhosis underwent two clamps in random order, a clamp with somatostatin (250 micrograms/hr) together with insulin and glucagon replacement, and a control clamp without somatostatin. The normal subjects underwent the control clamp only. During the control clamp, growth hormone levels were considerably higher in the patients with cirrhosis (6.1 +/- 0.4 vs. 0.5 +/- 0.4 mU/L, p < 0.02), and glucose uptake was considerably lower (3.29 +/- 0.56 vs. 9.52 +/- 1.14 mg/kg/min, p < 0.001). Indirect calorimetry indicated that the defect was accounted for by lower nonoxidative glucose disposal (1.23 +/- 0.45 vs. 6.00 +/- 0.73, p < 0.001). Peripheral glucose uptake, exemplified by forearm glucose uptake (0.27 +/- 0.04 vs. 1.22 +/- 0.42 mg/100 ml/min, p < 0.02), and calculated insulin sensitivity (24 +/- 8 vs. 114 +/- 20 microliters/kg/min per mU/L) were particularly diminished. In the patients with cirrhosis somatostatin suppressed growth hormone levels (6.1 +/- 1.2 to 1.2 +/- 0.4 mU/L, p < 0.05). However, no significant changes occurred in whole-body glucose uptake (3.29 +/- 0.56 vs 3.01 +/- 0.54 mg/kg/min), forearm glucose uptake (0.27 +/- 0.04 vs 0.30 +/- 0.01 mg/100 ml/min) or insulin sensitivity (24 +/- 8 vs, 35 +/- 10 microliters/kg/min/mU/L, p = 0.42).(ABSTRACT TRUNCATED AT 250 WORDS)
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