Effects of hyperglycaemia and hyperinsulinaemia on plasma amino acid levels in obese subjects with normal glucose tolerance

Abstract

OBJECTIVE: To investigate the effects of hyperglycaemia and hyperinsulinaemia on amino acid disposal in human obesity. DESIGN: Four sequential experimental conditions: (1) overnight fasting; (2) hyperglycaemia with hyperinsulinaemia (2 h hyperglycaemic clamp at 11 mmolal); (3) hyperglycaemia with basal insulin (1 h hyperglycaemic clamp during somatostatin infusion), (4) hyperglycaemia with resuming hyperinsulinaemia (1 h hyperglycaemic clamp after somatostatin discontinuation). SUBJECTS: Seven non-obese and seven obese non-diabetic, normo-insulinaemic subjects. MEASUREMENTS: Glucose infused to maintain steady-state hyperglycaemia. Plasma insulin, glucagon, free fatty acid and amino acid concentrations in the last 20 min of the four experimental conditions. Net rates of plasma amino acid disappearance and appearance (m mmolal per hour), calculated as the slopes of the regression of amino acid concentration on time. RESULTS: The amount of glucose infused to maintain hyperglycaemia was reduced by nearly 50% in obese subjects. During hyperinsulinaemia, FFA suppression was lower in obese subjects. In all experimental conditions plasma amino acid levels were slightly, non-signi®cantly higher in obese than in non-obese subjects. In both groups plasma amino acids decreased slightly with ongoing fasting, decreased remarkably during hyperglycaemia ± hyperinsulinaemia, rose promptly when insulin concentration was suppressed by somatostatin infusion, and declined again after somatostatin discontinuation. Also the time-course of plasma branched-chain amino acids, which paralleled that of total amino acids, was similar in the two groups. The net rates of amino acid disappearance from plasma did not differ in obese and non-obese subjects both at fasting and during hyperglycaemia ± hyperinsulinaemia. Also plasma amino acid appearance during hyperglycaemia with basal insulin was not different in the two groups. CONCLUSION: The net traf®c of amino acids to and from plasma in relation to insulin drive and prevailing glucose is not impaired in obese subjects with normal glucose tolerance, in spite of a decreased insulin sensitivity of glucose and lipid metabolism.

Obesity-related elevations in plasma leucine are associated with alterations in enzymes involved in branched-chain amino acid metabolism

“…We found elevated plasma BCAAs in ob/ob mice and high-fat diet-induced obesity in mice and in Zucker fatty rats, in agreement with previous reports in obese humans and Zucker fatty rats (4,5,11,12,37,46,48,49,52,56). These elevations were associated with reductions in the activity or amount of enzymes involved in the early steps of BCAA metabolisms in selective tissues, including liver and fat.…”

“…obesity; mitochondrial branched chain amino acid transaminase; branched chain keto acid dehydrogenase; branched chain keto acid dehydrogenase kinase; ob/ob mice; Zucker rats; bariatric surgery; humans PLASMA CONCENTRATIONS of branched-chain amino acids (BCAAs) are elevated in humans and animal models of obesity (4,11,12,31,37,46,48,52,56). Although the plasma levels of other amino acids may also change in obesity, the rises in the BCAAs are of particular interest because they appear to have unique obesity-related effects.…”

Leucine and Protein Metabolism in Obese Zucker Rats

“…Adipose tissue has been suggested to be quantitatively important for whole-body BCAA catabolism [32], [37], [38] and in obesity a consistent finding has been decreased gene expression of BCAA catabolic enzymes in adipose tissue [27], [30], [33], [39]. In contradistinction, some studies, e.g., [21], but not all, e.g., [14], have reported increased Leu oxidation in obesity.…”

“…Indeed, using [1- 13 C]-Leu and gas-chromatography mass spectrometry (GC-MS), elevated protein turnover and proteolysis in obese humans has been reported [14], [15], [16], [17], [18], [19]. However this too has not always been observed [20], [21] and seems inconsistent with the findings that aminoacidemia in lean animals and in obesity activates mTOR kinase activity. In lean animals, such signaling by BCAAs increases protein synthesis and inhibits muscle protein degradation as measured by changes in 3-methylhistidine (3-MeHis) [10], [22], [23].…”

Impact of Src Homology 2-Containing Inositol 5′-Phosphatase 2 on the Regulation of Insulin Signaling Leading to Protein Synthesis in 3T3-L1 Adipocytes Cultured with Excess Amino Acids

“…The rapamycin-sensitive pathway via mammalian target of rapamycin (mTOR) is known to be a target activated by the nutrient, which controls the mammalian translation machinery via activation of p70 S6 kinase (S6K1) and inhibition of the eukaryotic initiation factor (eIF)4E inhibitor, 4E-BP1 (also known as PHAS-I) (15)(16)(17)(18). In addition to the physiological role of amino acids, previous studies have shown that fasting plasma amino acid concentrations are elevated both in rodents and human subjects with obesity (19,20). Thus, the chronic elevation of amino acid concentrations appears to be associated with the pathological state including the insulin resistance syndrome (19).…”