Voice outcomes after thyroidectomy without superior and recurrent laryngeal nerve injury: VoiSS questionnaire and GRBAS tool assessment.

Voice symptoms are frequently reported early after thyroidectomy, even in the absence of laryngeal nerves injury. We evaluated the short-term outcomes of these functional alterations. Thirty-nine patients were enrolled in a prospective observational trial, evaluating voice function before and 3 months after uncomplicated thyroidectomy, using VoiSS as assessed using a validated patient rated questionnaire; and perceptual voice analysis using GRBAS scale (Grade, Roughness, Breathiness, Asthenia, Strain). Impact of dysphonia on patient's life using VoiSS questionnaire revealed differences between pre- and postoperative assessment. There was statistically significant worsening in the impairment subgroup of VoiSS (p = 0.027). GRBAS evaluation was consistent between the three independent raters but showed differences between pre- and postoperative voice assessment. Age, TSH and a preoperative finding of laryngopharyngeal reflux significantly predicted quality of voice after thyroid surgery (all p < 0.004), as identified by the GRBAS assessment tool, but not type of surgery, gender or smoking status; although prediction of total variance in changes of voice was modest (r 2 = 0.07). Voice changes may occur after thyroidectomy without evident laryngeal nerve injury. Patients should be made aware of possible mild changes in voice even after uncomplicated thyroid surgery and this might be considered to be part of the informed consent.

Fetuin A is a Predictor of Liver Fat in Preoperative Patients with Nonalcoholic Fatty Liver Disease.

BACKGROUND: Nonalcoholic fatty liver disease (NAFLD) and steatohepatitis (NASH) are frequent comorbidities in perioperative patients. However, the predictive role of the hepatokine fetuin A was not evaluated in this collective. OBJECTIVE: To study fetuin A as predictor of NAFLD/NASH in preoperative patients. METHODS: 58 subjects were included. Fetuin A was studied in patients undergoing open abdominal surgery and in a subset with acute liver failure. Blood and liver specimens were sampled. NAFLD was histologically evaluated. Liver fat was additionally analyzed by an enzymatic approach, circulating fetuin A by enzyme linked-immunosorbent assay, fetuin A mRNA by reverse-transcription PCR. RESULTS: Univariate correlation studies linked fetuin A to liver steatosis (r = 0.40, p = .029) and hepatocellular ballooning degeneration (r = 0.34, p = .026). Compared to non-NAFLD subjects fetuin A was increased in NAFLD (p = .009) and in NASH (p = .029). However, when corrected for main confounders by linear modeling, fetuin A remained related to hepatic steatosis, but not to ballooning degeneration or other NAFLD features. In support of this, biochemically analyzed liver lipids correlated with fetuin A in plasma (r = 0.34, p = .033) and with hepatic fetuin A mRNA (r = 0.54, p < .001). In addition, plasma fetuin A was related to hepatic mRNA (r = 0.32, p = .036), while circulating levels were reduced by 64% with acute liver failure (p < .001), confirming the liver as main fetuin A source. CONCLUSION: Fetuin A is suggested as noninvasive biomarker of hepatic steatosis in preoperative settings.

Severe paraneoplastic hypoglycemia secondary to a gastrointestinal stromal tumour masquerading as a stroke.

UNLABELLED: We report the case of a 70-year-old previously healthy female who presented acutely to the Accident and Emergency department with left-sided vasomotor symptoms including reduced muscle tone, weakness upon walking and slurred speech. Physical examination confirmed hemiparesis with VIIth nerve palsy and profound hepatomegaly. A random glucose was low at 1.7 mmol/l, which upon correction resolved her symptoms. In hindsight, the patient recalled having had similar episodes periodically over the past 3 months to which she did not give much attention. While hospitalized, she continued having episodes of symptomatic hypoglycaemia during most nights, requiring treatment with i.v. dextrose and/or glucagon. Blood tests including insulin and C-peptide were invariably suppressed, in correlation with low glucose. A Synacthen stimulation test was normal (Cort (0') 390 nmol/l, Cort (30') 773 nmol/l). A computed tomography scan showed multiple lobulated masses in the abdomen, liver and pelvis. An ultrasound guided biopsy of one of the pelvic masses was performed. Immunohistochemistry supported the diagnosis of a gastrointestinal stromal tumour (GIST) positive for CD34 and CD117. A diagnosis of a non islet cell tumour hypoglycaemia (NICTH) secondary to an IGF2 secreting GIST was confirmed with further biochemical investigations (IGF2=96.5 nmol/l; IGF2:IGF1 ratio 18.9, ULN <10). Treatment with growth hormone resolved the patient's hypoglycaemic symptoms and subsequent targeted therapy with Imatinib was successful in controlling disease progression over an 8-year observation period. LEARNING POINTS: NICTH can be a rare complication of GISTs that may manifest with severe hypoglycaemia and neuroglucopenic symptoms.NICTH can masquerade as other pathologies thus causing diagnostic confusion.Histological confirmation of GIST induced NICTH and exclusion of other conditions causing hypoglycaemia is essential.Mutational analysis of GISTs should be carried out in all cases as it guides treatment decision.Tailored management of hypoglycaemia, in this case using growth hormone and targeted cyto-reductive therapy, minimizes the risk of possible life-threatening complications.

Elevated fetal adipsin/acylation-stimulating protein (ASP) in obese pregnancy: novel placental secretion via Hofbauer cells.

CONTEXT AND OBJECTIVE: Obesity in pregnancy is associated with increased risks of obesity in the offspring. We investigated the relationship between obesity in pregnancy and circulating maternal and fetal levels of adipose tissue-derived factors adipsin and acylation stimulating protein (ASP) in lean and obese mothers. DESIGN: Paired peripheral and cord blood samples were taken. Paired fat and placenta tissue were taken for explant culture. Media were assayed for secreted adipsin and ASP. Clinical parameters assayed included fasting insulin, glucose, and adipsin. SETTING: The study was conducted at a university hospital maternity unit. PATIENTS: Patients included 35 lean [body mass index (BMI) 19-25 kg/m(2), mean age 32 years and 39 obese (BMI) > 30 kg/m(2), mean age 32.49 years] pregnant Caucasian women, delivered by cesarean section at term. MAIN OUTCOME MEASURE: Identification of placental macrophages [Hofbauer cells (HBCs)], as a source of adipsin and ASP was determined. RESULTS: HBCs secreted both adipsin and ASP. Cord levels of adipsin (1663.78 ± 52.76 pg/mL) and ASP (354.48 ± 17.17 ng/mL) were significantly elevated in the offspring of obese mothers compared with their lean controls [1354.66 ± 33.87 pg/mL and 302.63 ± 14.98 ng/mL, respectively (P < .05 for both)]. Placentae from obese mothers released significantly more adipsin and ASP than placentae from lean mothers [546.0 ± 44 pg/mL · g vs 284.56 ± 43 pg/mL · g and 5485.75 ± 163.32 ng/mL · g vs 2399.16 ± 181.83 ng/mL · g, respectively (P < .05 for both)]. Circulating fetal adipsin and ASP positively correlated with maternal BMI (r = 0.611, P < .0001, and r = 0.391, P < .05, respectively). Fetal adipsin correlated positively with maternal (r = 0.482, P < .01) and fetal homeostasis model assessment of insulin resistance (r = 0.465, P < .01). CONCLUSIONS: We demonstrate novel secretion of adipsin and ASP by placental HBCs.

Elevated hepatic chemerin mRNA expression in human non-alcoholic fatty liver disease.

OBJECTIVE: Adipose tissue-derived factors link non-alcoholic fatty liver disease (NAFLD) with obesity, which has also been reported for circulating chemerin. On the other hand, hepatic chemerin and chemokine-like receptor 1 (CMKLR1) mRNA expression has not yet been studied in an extensively characterized patient collective. DESIGN: This study was cross-sectional and experimental in design. METHODS: Liver tissue samples were harvested from 47 subjects and histologically examined according to the NAFLD activity score (NAS). The concentrations of chemerin and CMKLR1 were measured using semi-quantitative real-time PCR, and the concentration of serum chemerin was measured using ELISA. To evaluate potential effects of chemerin and CMKLR1, cultured primary human hepatocytes (PHHs) were exposed to selected metabolites known to play a role in NAFLD (insulin, glucagon, palmitoic acid, and interleukin-6 (IL6)). RESULTS: Chemerin and CMKLR1 mRNA levels were elevated in the human liver. Their expression was correlated with the NAS (R(2)=0.543; P<0.001 and R(2)=0.355; P=0.014 respectively) and was significantly elevated in patients with definite non-alcoholic steatohepatitis (NASH) (P<0.05 respectively). Linear regression analysis confirmed an independent association of liver fibrosis, steatosis, inflammation, and hepatocyte ballooning with hepatic chemerin mRNA expression (P<0.05 respectively). The expression of hepatic chemerin and CMKLR1 was correlated with the measures of obesity (P<0.05). The incubation of PHHs with IL6 significantly increased the expression of CMKLR1 mRNA (P=0.027), while that of chemerin remained unaffected (P>0.05). None of the other metabolites showed an influence (P>0.05). CONCLUSION: This is the first study to show that chemerin mRNA expression is significantly elevated in the liver of NASH patients and that CMKLR1 expression is upregulated in liver inflammation, whereby IL6 could play a causal role.

The impact of insulin-independent, glucagon-induced suppression of total ghrelin on satiety in obesity and type 1 diabetes mellitus.

AIMS/HYPOTHESIS: The mechanisms underlying glucagon-induced satiety are incompletely understood. The glucagon-induced reduction in total ghrelin exerted at the hypothalamo-pituitary level might be responsible for this effect. Here we investigated glucagon-suppressive effects on circulating total and acyl-ghrelin, both in obesity and in type 1 diabetes mellitus (T1DM), with respect to the role of glucagon in appetite control. We further aimed to identify a possible mechanistic impact of changes in endogenous insulin. METHODS: In our prospective, double-blinded, placebo-controlled study, we investigated the endocrine and metabolic responses to intramuscular glucagon administration in 13 patients with T1DM (6 males, 7 females; body mass index [BMI] 24.8 ± 0.95 kg/m(2)), 11 obese participants (OP; 5 males, 6 females; BMI 34.4 ± 1.7 kg/m(2)), and 13 healthy lean participants (LP; 6 males, 7 females; BMI 21.7 ± 0.6 kg/m(2)). RESULTS: As compared with placebo, glucagon significantly increased satiety index in T1DM and in LP (P < .001) but failed to induce satiety in OP (P = .152). Total ghrelin significantly decreased after glucagon administration in all study groups (P < .01). Similarly, acyl-ghrelin significantly decreased in LP (P < .01). However, acyl-ghrelin concentrations showed no change in OP (P = .248) and even increased substantially in T1DM (P < .01). Changes in acyl-ghrelin correlated positively with changes in nonesterified fatty acid concentrations in all groups (r = 0.31-0.43; P < .01). CONCLUSIONS/INTERPRETATION: Glucagon-induced satiety was preserved in T1DM but not in obesity. This effect was unrelated to changes in total or acylated ghrelin and was independent of endogenous insulin release. In contrast to the insulin-independent glucagon-induced suppression of total ghrelin, glucagon- and/or insulin-induced modification of lipolysis may determine changes in acylated ghrelin.

Levothyroxine medication is associated with adiposity independent of TSH.

AIM: In euthyroidism, higher TSH levels are weakly associated with increased BMI. Furthermore, a considerable number of patients complain of weight gain during thyroid hormone replacement after thyroidectomy. We therefore investigated the association between levothyroxine medication and BMI in a large cross-sectional study group. METHODS: We included euthyroid participants from the MeSyBePo study group (TSH between 0.3 and 4.5 µU/ml) that did not take thyreostatic drugs. Linear regression analyses were performed to address the association between levothyroxine medication and obesity. Additionally, pairs matched by sex, age and TSH but discordant in levothyroxine medication were compared. RESULTS: 1663 subjects (569 males) were eligible for inclusion. 151 participants were taking levothyroxine. Adjusted for sex and age both TSH (standardised beta 0.1, p<0.001) and levothyroxine medication (standardised beta 0.05, p=0.03) were significantly associated with BMI. There was no significant interaction between TSH and levothyroxine medication with respect to BMI. Further adjustment for smoking and the restriction to those subjects with normal glucose metabolism (947 participants (314 males, 82 on levothyroxine medication) did not alter the result. In matched pair analysis (133 pairs), BMI was significantly increased in subjects taking levothyroxine compared to controls. CONCLUSION: Independently from TSH, levothyroxine medication was associated with a higher BMI. The mechanisms, however, responsible for this association need to be elucidated.

Neuroendocrine and endocrine dysfunction in the hyperinsulinemic PCOS patient: the role of metformin.

Metformin is a widely used and extensively studied insulin sensitising drug for the treatment of women with polycystic ovary syndrome (PCOS), with various actions in tissues responding to insulin that include the liver, skeletal muscle, adipose tissue, the endothelium of blood vessels, and the ovaries. Treatment of PCOS women with metformin has been shown to reduce fasting glucose levels, blood pressure, and serum androgens; further effects of metformin in women with PCOS may include direct effects on the central nervous system; and indirect effects via the modification of gut hormone and adipokine synthesis and/or secretion. A number of "novel" adipokines and metabolic factors have been recently identified which may play a role both in the pathogenesis and the treatment of women with PCOS. We here discuss recent advances in the area, with a focus on neuroendocrine and endocrine dysfunctions in women with PCOS and the potential role of metformin in this context.

Annual change in insulin sensitivity.

The incidence of both type 2 diabetes and cardiac events is reported to be higher during winter, indicating a putative annual periodic change in insulin sensitivity (IS). Annual differences in IS - quantified as HOMA-%S and Matsuda-Sensitivity Index - were analyzed using a cosine wave-fitting algorithm in a cross-sectional study group including 2 385 participants. Additionally, semi-annual differences in IS were compared. We found periodicity for HOMA-%S and Matsuda-Sensitivity Index (p=0.02 or 0.006), which was strengthened after restriction to participants without diabetes (p=0.009 or 0.004). The rhythm amplitude of 0.08 indicated moderate changes in IS throughout the year. IS was significantly higher when participants were enrolled during the second vs. the first half of the year (HOMA-%S 112.0±3.0% vs. 97.4±2.4%, p<0.001). The impact of the half-year on IS, which remained significant after adjustment for confounders, was again moderate and explained only 0.5% of the variation. IS showed a significant moderate annual periodicity, which may affect the interpretation of studies reporting small changes in IS.

T3/rT3-ratio is associated with insulin resistance independent of TSH.

Thyroid dysfunction has been shown to be associated with insulin resistance (IR). This may involve peripheral thyroid hormone metabolism, which is assumed to be reflected by the ratio triiodothyronine/reverse triiodothyronine (T3/rT3-ratio). To explore a potential association between the T3/rT3-ratio and IR we investigated pairs which differed in IR, but were matched by sex, age, body mass index (BMI), and thyroid stimulating hormone (TSH). For this purpose, matched pair analyses were embedded into a cross sectional study group. 22 pairs were matched from either the first or the third tertile of HOMA%S of a cohort of 353 euthyroid subjects with normal glucose metabolism who did not take any medication. The T3/rT3-ratio was compared in the matched pairs. The T3/rT3-ratio was significantly increased in the insulin resistant subjects compared to their insulin sensitive partners (8.78 ± 0.47 vs. 7.33 ± 0.33, p=0.019). Furthermore the T3/rT3-ratio was lower in men compared to women (p for the within-subject effect=0.046) both in the insulin sensitive and the insulin resistant subjects. Here we show that the T3/rT3-ratio, which is supposed to reflect the tissue thyroid hormone metabolism, is significantly increased in insulin resistant subjects. This further supports a link between thyroid function and IR.

Improved insulin sensitivity, preserved beta cell function and improved whole-body glucose metabolism after low-dose growth hormone replacement therapy in adults with severe growth hormone deficiency: a pilot study.

AIMS/HYPOTHESIS: Growth hormone-deficient patients show deterioration of insulin sensitivity and beta cell function. High-dose growth hormone treatment often induces further impairment of insulin sensitivity, leading to an increase in insulin and glucose levels or even, in cases of preexisting beta cell defect, to overt diabetes. However, low-dose treatment may improve insulin sensitivity, although data in humans with detailed metabolic phenotyping are as yet not available. We postulated that long-term low-dose growth hormone replacement, restoring IGF-1 to the low-normal range, might beneficially affect glucose metabolism. METHODS: We studied prospectively the metabolic responses to 24 and 48 weeks of growth hormone treatment in a small group of six adults with severe growth hormone deficiency (four men, two women; age 40-59 years; BMI 30.2 +/- 1 kg/m(2); mean growth hormone dose 0.3 +/- 0.04 mg/day). All participants underwent an oral glucose tolerance test, euglycaemic-hyperinsulinaemic clamp and hyperglycaemic-hyperinsulinaemic clamp plus i.v. L: -arginine on three occasions. Insulin sensitivity was measured by calculating the M value during the steady state of the euglycaemic-hyperinsulinaemic clamp. Insulin secretion and clearance were estimated from AUC(C-peptide), AUC(insulin) and their ratio at each phase of the hyperglycaemic-hyperinsulinaemic clamp. RESULTS: Growth hormone significantly improved insulin sensitivity (M value 13.8 +/- 2.6 [baseline] vs 19.6 +/- 2.6 [24 weeks] and 23.7 +/- 1.9 [48 weeks] micromol kg(-1) min(-1); p < 0.01). Although the insulin response to glucose and arginine decreased slightly, the disposition index, integrating insulin sensitivity and secretion, significantly increased (p < 0.01), indicating an improvement in whole-body glucose metabolism. Insulin clearance was not affected during treatment (p > 0.05). CONCLUSIONS/INTERPRETATION: Our data indicate that long-term low-dose growth hormone treatment may improve insulin sensitivity and whole-body glucose metabolism in adults with severe growth hormone-deficiency.

Impairment of fat oxidation under high- vs. low-glycemic index diet occurs before the development of an obese phenotype.

Exposure to high vs. low glycemic index (GI) diets increases fat mass and insulin resistance in obesity-prone C57BL/6J mice. However, the longer-term effects and potentially involved mechanisms are largely unknown. We exposed four groups of male C57BL/6J mice (n = 10 per group) to long-term (20 wk) or short-term (6 wk) isoenergetic and macronutrient matched diets only differing in starch type and as such GI. Body composition, liver fat, molecular factors of lipid metabolism, and markers of insulin sensitivity and metabolic flexibility were investigated in all four groups of mice. Mice fed the high GI diet showed a rapid-onset (from week 5) marked increase in body fat mass and liver fat, a gene expression profile in liver consistent with elevated lipogenesis, and, after long-term exposure, significantly reduced glucose clearance following a glucose load. The long-term high-GI diet also led to a delayed switch to both carbohydrate and fat oxidation in the postprandial state, indicating reduced metabolic flexibility. In contrast, no difference in carbohydrate oxidation was observed after short-term high- vs. low-GI exposure. However, fatty acid oxidation was significantly blunted as early as 3 wk after beginning of the high-GI intervention, at a time where most measured phenotypic markers including body fat mass were comparable between groups. Thus long-term high-GI feeding resulted in an obese, insulin-resistant, and metabolically inflexible phenotype in obesity-prone C57BL/6J mice. Early onset and significantly impaired fatty acid oxidation preceded these changes, thereby indicating a potentially causal involvement.

Metabolic effects of diets differing in glycaemic index depend on age and endogenous glucose-dependent insulinotrophic polypeptide in mice.

AIMS/HYPOTHESIS: High- vs low-glycaemic index (GI) diets unfavourably affect body fat mass and metabolic markers in rodents. Different effects of these diets could be age-dependent, as well as mediated, in part, by carbohydrate-induced stimulation of glucose-dependent insulinotrophic polypeptide (GIP) signalling. METHODS: Young-adult (16 weeks) and aged (44 weeks) male wild-type (C57BL/6J) and GIP-receptor knockout (Gipr ( -/- )) mice were exposed to otherwise identical high-carbohydrate diets differing only in GI (20-26 weeks of intervention, n = 8-10 per group). Diet-induced changes in body fat distribution, liver fat, locomotor activity, markers of insulin sensitivity and substrate oxidation were investigated, as well as changes in the gene expression of anorexigenic and orexigenic hypothalamic factors related to food intake. RESULTS: Body weight significantly increased in young-adult high- vs low-GI fed mice (two-way ANOVA, p < 0.001), regardless of the Gipr genotype. The high-GI diet in young-adult mice also led to significantly increased fat mass and changes in metabolic markers that indicate reduced insulin sensitivity. Even though body fat mass also slightly increased in high- vs low-GI fed aged wild-type mice (p < 0.05), there were no significant changes in body weight and estimated insulin sensitivity in these animals. However, aged Gipr ( -/- ) vs wild-type mice on high-GI diet showed significantly lower cumulative net energy intake, increased locomotor activity and improved markers of insulin sensitivity. CONCLUSIONS/INTERPRETATION: The metabolic benefits of a low-GI diet appear to be more pronounced in younger animals, regardless of the Gipr genotype. Inactivation of GIP signalling in aged animals on a high-GI diet, however, could be beneficial.

Intravenous lipid and heparin infusion-induced elevation in free fatty acids and triglycerides modifies circulating androgen levels in women: a randomized, controlled trial.

BACKGROUND: The polycystic ovarian syndrome (PCOS) is characterized by hyperandrogenism and associated with obesity and impaired glucose metabolism. Despite the high prevalence of PCOS and the considerable clinical impact, the precise interplay between metabolism and hyperandrogenemia is not entirely clear. OBJECTIVE: The objective of the study was to analyze the effects of iv lipid and heparin infusion on circulating androgen levels in healthy women. DESIGN: This was a randomized, controlled, crossover trial. SETTING: The study was conducted at an endocrinology center. PATIENTS: Patients included 12 healthy young women during the early follicular phase of two subsequent cycles. INTERVENTION: After an overnight fast, a 20% lipid/heparin or a saline/heparin infusion was administered in random order for 330 min. MAIN OUTCOME MEASURES: A detailed characterization of androgen metabolism was performed. RESULTS: Elevations in free fatty acids and triglycerides, induced by lipid/heparin infusion, elevates the levels of androstenedione, dehydroepiandrosterone (DHEA), dehydroepiandrosterone sulfate (DHEAS), testosterone, 5alpha-dihydrotestosterone, estrone, and 17beta-estradiol. Urinary excretion of DHEA, DHEAS, 5-androstene-3beta,17beta-diol, and the sum of urinary excreted DHEA and its 16-hydroxylated downstream metabolites, 16alpha-hydroxy-DHEA and 5-androstene-3beta,16alpha,17beta-triol, were reduced. CONCLUSION: The mechanism of iv lipid and heparin infusion-induced elevation of circulating androgens described here might contribute to the development of hyperandrogenism in women with PCOS and suggests that lowering of hyperlipidemia might be a potential therapeutic target in patients with PCOS to treat hyperandrogenemia.

Euglycemic hyperinsulinemia differentially modulates circulating total and acylated-ghrelin in humans.

Ghrelin is a powerful orexigenic gut hormone. Circulating concentrations of total ghrelin are downregulated by food intake in both acute and chronic hyperinsulinemic states. However, in blood des-acylated (des-acyl) ghrelin is the predominant form that has no orexigenic effects in humans. Circulating acyl-ghrelin has been shown to be suppressed post-prandially and by pharmacological hyperinsulinemia. However, up to now responses of circulating acyl-ghrelin to moderate hyperinsulinemic and hyperinsulinemic-hyperlipidemic clamp conditions have not been reported. Fourteen healthy subjects were investigated using two-stepped euglycemic-hyperinsulinemic clamps (40 mU insulin/ m2/min; mean 148+/-7 min till steady state, followed by 300 min lipid/heparin infusion). Responses of total ghrelin and acyl-ghrelin were measured at timed intervals throughout the clamps. Des-acyl-ghrelin concentrations were calculated by subtraction. Total ghrelin significantly decreased vs baseline concentrations (819+/-92 vs 564+/-58 pg/ml, p<0.001), thereby confirming previous observations. Des-acyl ghrelin closely followed total ghrelin concentrations and significantly decreased vs baseline (772+/-92 vs 517+/-56 pg/ml, p<0.001). In contrast, neither euglycemichyperinsulinemia nor euglycemic-hyperinsulinemic- hyperlipidemia suppressed acyl-ghrelin below baseline concentrations throughout the clamps (46+/-3 vs 47+/-8 pg/ml, p=0.90). In conclusion, moderate hyperinsulinemic and hyperinsulinemic- hyperlipidemic clamp conditions differentially modulated circulating total ghrelin and acylghrelin in humans. Factors other than changes in insulin and lipid concentrations are likely to contribute to the previously reported post-prandial reduction of circulating acyl-ghrelin.

Effects of euglycemic hyperinsulinemia and lipid infusion on circulating cholecystokinin.

AIMS: Functions of the gut hormone cholecystokinin (CCK) include an important role in the regulation of gastric emptying, postprandial glucose homeostasis, and postmeal satiety. Postprandial CCK responses are significantly blunted in type 2 diabetic patients by unknown mechanisms. We hypothesized that hyperinsulinemia and lipid infusion influence circulating levels of biologically active CCK. METHODS: Eleven healthy subjects were studied in a cross-over design after 10-h overnight fasts, using euglycemic-hyperinsulinemic clamps for 443 min, with an additional infusion of lipid-heparin (1.25 ml.min(-1)) or saline (1.25 ml.min(-1)) for the last 300 min after constant plasma glucose levels were achieved. RESULTS: Euglycemic-hyperinsulinemia resulted in a sustained, up to 5-fold increase of plasma CCK (P < 0.001). When adding lipid infusion instead of saline, CCK concentrations rapidly declined and returned to baseline levels (CCK(300 min) 1.1 +/- 0.2 vs. 3.3 +/- 0.3 pmol/liter, P < 0.001). Partial intraclass correlation showed an independent correlation of plasma CCK with free fatty acids (r(ic) = -0.377, P < 0.001) but not with serum insulin (r(ic) = 0.077, P = 0.32). Whole-body insulin sensitivity decreased in lipid-exposed subjects (M value 7.1 +/- 0.7 vs. 5.6 +/- 0.9 mg.kg.min(-1), P = 0.017) but was not independently correlated with CCK (r(ic) = 0.040, P = 0.61). CONCLUSIONS: We report novel findings showing that circulating CCK markedly increased in the euglycemic-hyperinsulinemic state, possibly as a result of near-complete suppression of circulating free fatty acids. Moreover, raising blood lipids even moderately by lipid infusion rapidly and significantly interfered with this effect, suggesting that a negative feedback mechanism of blood lipids on circulating CCK might exist.

Arabinoxylan consumption decreases postprandial serum glucose, serum insulin and plasma total ghrelin response in subjects with impaired glucose tolerance.

OBJECTIVE: Arabinoxylan (AX) consumption is associated with metabolic improvement during diabetes and with modulation of ghrelin, an orexigenic gut hormone. The effect of AX consumption on ghrelin secretion in disturbed metabolic states is unknown. Therefore, we investigated the postprandial responses to AX consumption of serum glucose, insulin and triglycerides and plasma total and acylated ghrelin in subjects with impaired glucose tolerance (IGT). DESIGN: Randomized, single-blind, controlled, crossover intervention trial. SUBJECTS: Seven female and four male adults with IGT, aged 55.5 years, and body mass index (BMI) 30.1 kg/m(2). INTERVENTION: Subjects received either placebo or 15 g AX supplement for 6 weeks with a 6-week washout period in-between. MAIN OUTCOME MEASUREMENTS: Postprandial responses of serum glucose, insulin and triglycerides, and plasma total and acylated ghrelin after a liquid meal challenge test (LMCT) measured at the beginning and at the end of the dietary intervention at -20, -5, 0, 15, 30, 45, 60, 90, 120, 150, 180, 210 and 240 min. RESULTS: After LMCT, AX consumption resulted in lower postprandial responses in serum glucose, insulin and triglycerides (P<0.05). Compared to placebo, total plasma ghrelin was also reduced by 42+/-8 pg/ml (P<0.001) after AX consumption with no difference in plasma acylated ghrelin. CONCLUSION: AX consumption improved postprandial metabolic responses after an LMCT in subjects with IGT and reduced total ghrelin response. However, acylated ghrelin responses were unchanged, suggesting that the acylated ghrelin-mediated orexigenic regulation is not improved as only total plasma ghrelin decreased.

Effect of human body weight changes on circulating levels of peptide YY and peptide YY3-36.

BACKGROUND: Recent findings suggest that low plasma peptide YY (PYY) levels may contribute to diet-induced human obesity and justify PYY replacement therapy. Although the pharmacological value of PYY is controversial, further study of the secretion of the precursor PYY(1-36) and the pharmacologically active PYY(3-36) is indicated to determine the potential role in energy balance regulation. AIM: Our objective was to determine the effects of acute and chronic changes in human body weight on circulating levels of the putative satiety hormone peptide YY. DESIGN: Total plasma PYY levels (PYY(1-36) + PYY(3-36)) were measured in 66 lean, 18 anorectic, 63 obese, and 16 morbidly obese humans. In addition, total PYY was measured in 17 of the obese patients after weight loss and in the 18 anorectic patients after weight gain. Fasting PYY(3-36) levels were measured in 17 lean and 15 obese individuals. RESULTS: Fasting total plasma PYY levels were highest in patients with anorexia nervosa (80.9 +/- 12.9 pg/ml, P < 0.05) compared with lean (52.4 +/- 4.6 pg/ml), obese (43.9 +/- 3.8 pg/ml), or morbidly obese (45.6 +/- 11.2 pg/ml) subjects. In obese patients, weight loss of 5.4% was associated with a 30% decrease in fasting total PYY plasma levels. In anorectic patients, weight gain had no effect on fasting PYY. PYY(3-36) levels did not differ between lean (96.2 +/- 8.6 pg/ml) and obese (91.5 +/- 6.9 pg/ml) subjects. CONCLUSION: Our findings do not support a role for abnormal circulating PYY in human obesity. We conclude that circulating PYY levels in humans are significantly elevated in anorexia nervosa and, given the controversially discussed anorectic effect of PYY, could theoretically contribute to that syndrome.

Serum resistin increases in a postprandial state during liquid meal challenge test in healthy human subjects.

The role of resistin in humans is controversial although resistin has been linked to atherosclerotic and inflammatory processes. In rodents, resistin expression is suppressed after food restriction while central administration of resistin promotes short-term satiety. However, the nature of postprandial responses in circulating resistin in humans is unknown. Therefore, we investigated postprandial resistin concentrations in a pilot study in 19 healthy subjects and 19 controls matched for age and body mass index (BMI). Serum resistin, insulin and non-esterified fatty acids (NEFA) concentrations as well as plasma glucose and triglycerides were repeatedly assessed before and after ingestion of an isocaloric standardized liquid meal during a 300 min period.After consumption of liquid meal, serum resistin levels increased compared to fasting control (p=0.037). Postprandial plasma glucose and serum insulin increased (p<0.001) with lower glucose responses in females (p=0.001) and lower insulin responses in males (p=0.012). Plasma triglycerides increased and serum NEFA decreased with similar gender responses (p=0.025 and p<0.001, respectively). Serum resistin was not correlated to glucose, insulin, triglyceride, and NEFA responses to liquid meal challenge tests. The present data suggest that serum resistin increases postprandially in healthy humans. Additional studies are needed to elucidate normal 24-h daytime profiles in humans and differential response of serum resistin to macronutrient composition of meals.