Pancreatic hormones and amino acid levels following liver transplantation

Glucose intolerance, hyperinsulinemia, peripheral insulin resistance and hyperglucagonemia are common in patients with advanced liver disease. These abnormalities in the plasma levels of the pancreatic hormones, insulin and glucagon have been thought to be responsible, at least in part, for the abnormal plasma ratio of branched‐chain amino acids to aromatic amino acids. To evaluate this issue, plasma levels of glucose, insulin, glucagon, C‐peptide and the branched‐chain and aromatic amino acids were measured before and serially after orthotopic liver transplantation in 9 humans and 5 dogs. The abnormal plasma amino acid levels rapidly improved and achieved normal levels following orthotopic liver transplantation. Insulin levels also became normal following orthotopic liver transplantation, despite enhanced insulin secretion documented by an even further increased level of C‐peptide. In contrast, the baseline abnormal plasma glucagon levels which are commonly seen in cirrhotics became even more abnormal following orthotopic liver transplantation. Despite this progressive increase in the abnormally elevated plasma glucagon levels, plasma amino acid levels, both branched‐chain and aromatic, became normal. These data demonstrate that before and after orthotopic liver transplantation, there is: (i) no relationship between the changes in plasma levels of glucagon and changes observed in the plasma level of amino acids; and (ii) plasma insulin and amino acid levels change in the same direction. In addition, these changes in plasma insulin and amino acid levels following orthotopic liver transplantation occur despite enhanced secretion of insulin evidenced by the progressive increase in plasma levels of C‐peptide. Copyright © 1987 American Association for the Study of Liver Disease

Circulating free fatty acids, insulin, and glucose during chemical stimulation of hypothalamus in rats

The aim of this study was to investigate plasma free fatty acids (FFA), insulin, and blood glucose during chemical stimulation of the lateral and ventromedial hypothalamic areas (LHA and VMH) in rats. Therefore male Wistar rats were implanted with bilateral cannulas in the LHA or the VMH and into the left and right jugular veins. Freely moving rats were then infused into the LHA and VMH with norepinephrine (NE), epinephrine (E), or acetylcholine or intravenously with NE or E. Before, during, and after the infusions, simultaneous blood samples were taken without disturbing the animals. Infusion of NE into the LHA resulted in a decrease of plasma FFA and a simultaneous increase of insulin. NE infusion in the VMH elicited an increase of plasma FFA, plasma insulin, and blood glucose. E infusion into the LHA did not lead to a change of plasma FFA, whereas insulin and glucose showed an increase. E infusion into the VMH evoked increases of plasma FFA and insulin. Peripheral administration of NE led to a sharp increase of FFA, whereas plasma insulin and blood glucose did not change. E in the periphery elicited an augmentation of plasma FFA and blood glucose and a suppression of insulin during infusion. After termination of E infusion, plasma FFA and glucose levels decreased, whereas plasma insulin showed a sharp increase. It is concluded 1) that the effects produced by administration of NE and E are dependent on hypothalamic localization and local receptor population characteristics; 2) that there are striking differences regarding the effects on the investigated blood parameters between hypothalamically infused NE and E and peripherally infused NE and E; and 3) that the LHA and VMH are able to alter plasma FFA levels independently of blood glucose and insulin levels.

Adiponectin, in contrast to leptin, is not associated with body mass index, waist circumference and HOMA-IR in subjects of a west-African population

Factors associated with plasma levels of adiponectin and leptin were studied in adult subjects without diabetes from Cotonou in Benin (West‐Africa). Seventy (70) men and 45 women were included in the study. Anthropometric variables were measured and a venous blood sample was drawn from each subject, after an overnight fasting period, for measurement of plasma glucose, insulin, leptin, and adiponectin levels. HOMA‐IR was determined to assess insulin resistance. Adiponectin and leptin levels were higher in women than in men (with adiponectin 18.48 ± 12.77 vs.7.8 ± 10.39 μg/mL, P < 0.0001, and leptin 30.77 ± 19.16 vs. 8.66 ± 8.24 ng/mL, P < 0.0001). Fasting insulin level and HOMA‐IR were also higher in the females. Hyperleptinemia was observed in 66,96% of subjects and hypoadiponectinemia was present in 44.35% of subjects. In both men and women, leptin correlated with age (r = 0.2; P = 0.02), BMI (r = 0.572; P < 0.0001), waist circumference (r = 0.534; P < 0.0001), fasting insulin (r = 0.461; P < 0.001), and HOMA‐IR (r = 0.430; P < 0.0001). No significant correlation was observed for adiponectin levels with these variables. Only in women, adiponectin was inversely correlated with fasting glucose (r = −0.423; P < 0.004). These data confirm previous descriptions of leptin but suggest that variations in factors determining serum adiponectin levels observed between ethnicities could also been seen between populations from the same ethnicity

Plasma free fatty acids do not provide the link between obesity and insulin resistance or β-cell dysfunction: results of the Reading, Imperial, Surrey, Cambridge, Kings (RISCK) study

Aims To investigate the relationship between adiposity and plasma free fatty acid levels and the influence of total plasma free fatty acid level on insulin sensitivity and β-cell function. Methods An insulin sensitivity index, acute insulin response to glucose and a disposition index, derived from i.v. glucose tolerance minimal model analysis and total fasting plasma free fatty acid levels were available for 533 participants in the Reading, Imperial, Surrey, Cambridge, Kings study. Bivariate correlations were made between insulin sensitivity index, acute insulin response to glucose and disposition index and both adiposity measures (BMI, waist circumference and body fat mass) and total plasma free fatty acid levels. Multivariate linear regression analysis was performed, controlling for age, sex, ethnicity and adiposity. Results After adjustment, all adiposity measures were inversely associated with insulin sensitivity index (BMI: β = −0.357; waist circumference: β = −0.380; body fat mass: β = −0.375) and disposition index (BMI: β = −0.215; waist circumference: β = −0.248; body fat mass: β = −0.221) and positively associated with acute insulin response to glucose [BMI: β = 0.200; waist circumference: β = 0.195; body fat mass β = 0.209 (P values <0.001)]. Adiposity explained 13, 4 and 5% of the variation in insulin sensitivity index, acute insulin response to glucose and disposition index, respectively. After adjustment, no adiposity measure was associated with free fatty acid level, but total plasma free fatty acid level was inversely associated with insulin sensitivity index (β = −0.133), acute insulin response to glucose (β = −0.148) and disposition index [β = −0.218 (P values <0.01)]. Plasma free fatty acid concentration accounted for 1.5, 2 and 4% of the variation in insulin sensitivity index, acute insulin response to glucose and disposition index, respectively. Conclusions Plasma free fatty acid levels have a modest negative association with insulin sensitivity, β-cell secretion and disposition index but no association with adiposity measures. It is unlikely that plasma free fatty acids are the primary mediators of obesity-related insulin resistance or β-cell dysfunction

Acute effect of electroacupuncture at the Zusanli acupoints on decreasing insulin resistance as shown by lowering plasma free fatty acid levels in steroid-background male rats

<p>Abstract</p> <p>Background</p> <p>Insulin sensitivity has been enhanced by electroacupuncture (EA) in rats, but the EA phenomenon in an insulin resistant state is still unclear. This study reports the use of a large dose of prednisolone to evaluate the effects of EA in a state of insulin resistance.</p> <p>Methods</p> <p>The plasma levels of free fatty acids (FFAs) were estimated in steroid-background rats (SBRs) and compared with those in healthy rats treated with normal saline. In addition, plasma glucose and endogenous insulin levels were assayed to calculate the homeostasis model assessment (HOMA) index. Intravenous glucose tolerance test (IVGTT) was carried out to compare glucose tolerance. The SBRs were randomly divided into EA-treatment and non-EA treatment groups and 15-Hz EA was applied to the bilateral Zusanli acupoints to investigate its effects on insulin resistance. In addition to an insulin challenge test (ICT) and IVGTT, the plasma levels of FFAs were measured and western blot was performed to help determine the effects of EA on the insulin resistant state.</p> <p>Results</p> <p>The plasma levels of FFAs increased markedly in SBRs, the HOMA index was markedly higher, and glucose tolerance was impaired. EA improved glucose tolerance and insulin sensitivity by decreasing the plasma levels of FFAs. Further, the insulin signaling proteins (IRS1) and glucose transporter isoform protein (GLUT4) in skeletal muscle inhibited by prednisolone recovered after EA.</p> <p>Conclusion</p> <p>Insulin resistance was successfully induced by a large dose of prednisolone in male rats. This insulin resistance can be improved by 15 Hz EA at the bilateral Zusanli acupoints, as shown by decreased plasma levels of FFAs.</p

Adiponectin Expression from Human Adipose Tissue: Relation to Obesity, Insulin Resistance, and Tumor Necrosis Factor-α Expression

Adiponectin is a 29-kDa adipocyte protein that has been linked to the insulin resistance of obesity and lipodystrophy. To better understand the regulation of adiponectin expression, we measured plasma adiponectin and adipose tissue adiponectin mRNA levels in nondiabetic subjects with varying degrees of obesity and insulin resistance. Plasma adiponectin and adiponectin mRNA levels were highly correlated with each other (r = 0.80, P \u3c 0.001), and obese subjects expressed significantly lower levels of adiponectin. However, a significant sex difference in adiponectin expression was observed, especially in relatively lean subjects. When men and women with a BMI2were compared, women had a twofold higher percent body fat, yet their plasma adiponectin levels were 65% higher (8.6 ± 1.1 and 14.2 ± 1.6 μg/ml in men and women, respectively; P \u3c 0.02). Plasma adiponectin had a strong association with insulin sensitivity index (SI) (r = 0.67, P \u3c 0.0001, n = 51) that was not affected by sex, but no relation with insulin secretion. To separate the effects of obesity (BMI) from SI, subjects who were discordant for SI were matched for BMI, age, and sex. Using this approach, insulin-sensitive subjects demonstrated a twofold higher plasma level of adiponectin (5.6 ± 0.6 and 11.2 ± 1.1 μg/ml in insulin-resistant and insulin-sensitive subjects, respectively; P \u3c 0.0005). Adiponectin expression was not related to plasma levels of leptin or interleukin-6. However, there was a significant inverse correlation between plasma adiponectin and tumor necrosis factor (TNF)-α mRNA expression (r = -0.47, P \u3c 0.005), and subjects with the highest levels of adiponectin mRNA expression secreted the lowest levels of TNF-α from their adipose tissue in vitro. Thus, adiponectin expression from adipose tissue is higher in lean subjects and women, and is associated with higher degrees of insulin sensitivity and lower TNF-α expression

Deletion of Gpr27 in vivo reduces insulin mRNA but does not result in diabetes.

Gpr27 is a highly conserved, orphan G protein coupled receptor (GPCR) previously implicated in pancreatic beta cell insulin transcription and glucose-stimulated insulin secretion in vitro. Here, we characterize a whole-body mouse knockout of Gpr27. Gpr27 knockout mice were born at expected Mendelian ratios and exhibited no gross abnormalities. Insulin and Pdx1 mRNA in Gpr27 knockout islets were reduced by 30%, but this did not translate to a reduction in islet insulin content or beta cell mass. Gpr27 knockout mice exhibited slightly worsened glucose tolerance with lower plasma insulin levels while maintaining similar insulin tolerance. Unexpectedly, Gpr27 deletion reduced expression of Eif4e3, a neighboring gene, likely by deleting transcription start sites on the anti-sense strand of the Gpr27 coding exon. Our data confirm that loss of Gpr27 reduces insulin mRNA in vivo but has only minor effects on glucose tolerance

Association of Plasma Levels of Resistin with Subcutaneous Fat Mass and Markers of Inflammation but not with Metabolic Determinants or Insulin Resistance

The aim of the present study was to investigate the relationship of plasma resistin levels with determinants of the metabolic syndrome (MetS) and anthropometric parameters in healthy Korean subjects. Plasma resistin levels were determined in 276 subjects. In subjects with MetS, the plasma resistin levels were not significantly increased compared to those without MetS (8.3±4.3 ng/mL vs. 8.5±3.6 ng/mL, respectively, P=0.84). In addition, the plasma resistin levels were not correlated with the body mass index, the waist circumference, homeostasis model assessment-insulin resistance (HOMA-IR), fasting plasma glucose or insulin levels. However, the plasma resistin levels were positively correlated with the abdominal subcutaneous fat (r=0.18, P<0.01) in all subjects and correlated with TNF α(r=-0.16, P<0.05) and hsCRP (r=0.15, P<0.05) in subjects without MetS but not with MetS. With multiple linear regression analysis, these linear associations remained to be significant. The results of this study show that plasma resistin levels in humans were not associated with markers of insulin resistance, obesity or other determinants of the MetS

Insulin-like growth factor-1 is a negative modulator of glucagon secretion

Glucagon secretion involves a combination of paracrine, autocrine, hormonal, and autonomic neural mechanisms. Type 2 diabetes often presents impaired glucagon suppression by insulin and glucose. Insulin-like growth factor-I (IGF-1) has elevated homology with insulin, and regulates pancreatic β-cells insulin secretion. Insulin and IGF-1 receptors share considerable structure homology and function. We hypothesized the existence of a mechanism linking the inhibition of α-cells glucagon secretion to IGF-1. Herein, we evaluated the association between plasma IGF-1 and glucagon levels in 116 nondiabetic adults. After adjusting for age gender and BMI, fasting glucagon levels were positively correlated with 2-h post-load glycaemia, HOMA index and fasting insulin, and were negatively correlated with IGF-1 levels. In a multivariable regression, the variables independently associated to fasting glucagon were circulating IGF-1 levels, HOMA index and BMI, explaining 20.7% variation. To unravel the molecular mechanisms beneath IGF-1 and glucagon association, we investigated whether IGF-1 directly modulates glucagon expression and secretion in an in vitro model of α-cells. Our data showed that IGF-1 inhibits the ability of low glucose concentration to stimulate glucagon expression and secretion via activation of the phosphatidylinositol-3-kinase/Akt/FoxO1 pathway. Collectively, our results suggest a new regulatory role of IGF-1 on α-cells biological function

Aldosterone status associates with insulin resistance in patients with heart failure-data from the ALOFT study

&lt;b&gt;Background&lt;/b&gt;: Aldosterone plays a key role in the pathophysiology of heart failure. In around 50% of such patients, aldosterone 'escapes' from inhibition by drugs that interrupt the renin-angiotensin axis; such patients have a worse clinical outcome. Insulin resistance is a risk factor in heart failure and cardiovascular disease. The relationship between aldosterone status and insulin sensitivity was investigated in a cohort of heart failure patients. &lt;b&gt;Methods&lt;/b&gt;: 302 patients with New York Heart Association (NYHA) class II-IV heart failure on conventional therapy were randomized in ALiskiren Observation of heart Failure Treatment study (ALOFT), designed to test the safety of a directly acting renin inhibitor. Plasma aldosterone and 24-hour urinary aldosterone excretion as well as fasting insulin and Homeostasis model assessment of insulin resistance (HOMA-IR) were measured. Subjects with aldosterone escape and high urinary aldosterone were identified according to previously accepted definitions. &lt;b&gt;Results&lt;/b&gt;: Twenty per-cent of subjects demonstrated aldosterone escape and 34% had high urinary aldosterone levels. At baseline, there was a positive correlation between fasting insulin and plasma(r=0.22 p&#60;0.01) and urinary aldosterone(r=0.19 p&#60;0.03). Aldosterone escape and high urinary aldosterone subjects both demonstrated higher levels of fasting insulin (p&#60;0.008, p&#60;0.03), HOMA-IR (p&#60;0.06, p&#60;0.03) and insulin-glucose ratios (p&#60;0.006, p&#60;0.06) when compared to low aldosterone counterparts. All associations remained significant when adjusted for potential confounders. &lt;b&gt;Conclusions&lt;/b&gt;: This study demonstrates a novel direct relationship between aldosterone status and insulin resistance in heart failure. This observation merits further study and may identify an additional mechanism that contributes to the adverse clinical outcome associated with aldosterone escape