Suppression of Acylated Ghrelin during Oral Glucose Tolerance Test Is Correlated with Whole-Body Insulin Sensitivity in Children with Prader-Willi Syndrome

Paik, Kyung Hoon; Choe, Yon Ho; Park, Won Hah; Oh, Yoo Joung; Kim, An Hee; Chu, Su Hyun; Kim, Seon Woo; Kwon, Eunjin; Han, Sun Ju; Shon, Woo Yun; Jin, Dong‐Kyu

doi:10.1210/jc.2005-2168

Cited by 48 publications

(41 citation statements)

References 35 publications

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“…Despite overall higher levels of ghrelin in PWS, these subjects still exhibited normal postprandial suppression of ghrelin in our study, consistent with results reported in 3 studies of children with PWS (Haqq et al, 2003, Paik et al, 2006and Paik et al, 2007b and another of adults (Gimenez-Palop et al, 2007). Future trials are needed to elucidate the role of ghrelin in PWS using specific ghrelin antagonists, currently in development.…”

Section: Discussionsupporting

confidence: 90%

In adults with Prader–Willi syndrome, elevated ghrelin levels are more consistent with hyperphagia than high PYY and GLP-1 levels

et al. 2011

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ObjectivePrader-Willi syndrome (PWS) is a leading genetic cause of obesity, characterized by hyperphagia, endocrine and developmental disorders. It is suggested that the intense hyperphagia could stem, in part, from impaired gut hormone signaling. Previous studies produced conflicting results, being confounded by differences in body composition between PWS and control subjects. Design Fasting and postprandial gut hormone responses were investigated in a cross-sectional cohort study including 10 adult PWS, 12 obese subjects matched for percentage body fat and central abdominal fat, and 10 healthy normal weight subjects. Methods PYY [total], PYY , GLP-1[active] and ghrelin [total] were measured by ELISA or radioimmunoassay. Body composition was assessed by dual energy X-ray absorptiometry. Visual analog scales were used to assess hunger and satiety. Results In contrast to lean subjects (p < 0.05), PWS and obese subjects were similarly insulin resistant and had similar insulin levels. Ghrelin[total] levels were significantly higher in PWS compared to obese subjects before and during the meal (p < 0.05). PYY meal responses were higher in PWS than in lean subjects (p = 0.01), but not significantly different to obese (p = 0.08), with an additional non-significant trend in PYY[total] levels. There were no significant differences in self-reported satiety between groups, however PWS subjects reported more hunger throughout (p = 0.003), and exhibited a markedly reduced mealinduced suppression of hunger (p = 0.01) compared to lean or obese subjects. Conclusions Compared to adiposity-matched control subjects, hyperphagia in PWS is not related to a lower postprandial GLP-1 or PYY response. Elevated ghrelin levels in PWS are consistent with increased hunger and are unrelated to insulin levels.

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Section: Discussionsupporting

confidence: 90%

In adults with Prader–Willi syndrome, elevated ghrelin levels are more consistent with hyperphagia than high PYY and GLP-1 levels

et al. 2011

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“…26,27,32,34,36 --38,40,43 --48 Levels of ghrelin do fall after food intake in children and adults with PWS but remain elevated compared with the controls relative to their obesity. 37,38,40,43,44 In our current study, we were unable to demonstrate any elevation of plasma ghrelin levels in PWS children under 5 years, unadjusted or when correcting for age, BMI, fasting insulin or insulin resistance. This finding is in agreement with previous studies of PWS children aged under 3 or 5 years, 39,42,46 although it should be noted that one of these studies did not find hyperghrelinaemia in PWS children over 3 years and adults either.…”

Section: Ghrelincontrasting

confidence: 80%

“…39,42,46 Furthermore, hyperghrelinaemia in older children and PWS adults may be partially, though not solely, explained by preserved insulin sensitivity and relative hypoinsulinaemia, as ghrelin levels are negatively correlated with insulin. 29,34,38,40,46,47 Ghrelin levels also rise with starvation and weight loss. 18,20 Thus, differences between studies might also depend on differences in the dynamic nutritional state, body composition and insulin status.…”

Section: Ghrelinmentioning

confidence: 99%

“…47 Indeed, body composition parameters varied widely between these studies, with range of weight for length Z scores À0.69 to þ 1.67, 46 BMI SDS À1.86 to þ 5.79 (current study) and BMI Z score À4.0 to þ 2.0. 47 Furthermore, these studies have only measured total ghrelin and did not distinguish between desacyl and active acyl ghrelin, although elevations in the active form in PWS children over 6 years 40 and adults 38 are reported. PYY Fasting PYY levels in PWS did decline with age (more steeply than in controls) and eating code in our study.…”

Section: Ghrelinmentioning

confidence: 99%

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Appetite hormones and the transition to hyperphagia in children with Prader-Willi syndrome

et al. 2012

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OBJECTIVE: Prader --Willi syndrome (PWS) is a genetic neurodevelopmental disorder with several nutritional phases during childhood proceeding from poor feeding, through normal eating without and with obesity, to hyperphagia and life-threatening obesity, with variable ages of onset. We investigated whether differences in appetite hormones may explain the development of abnormal eating behaviour in young children with PWS. SUBJECTS: In this cross-sectional study, children with PWS (n ¼ 42) and controls (n ¼ 9) aged 7 months --5 years were recruited. Mothers were interviewed regarding eating behaviour, and body mass index (BMI) was calculated. Fasting plasma samples were assayed for insulin, leptin, glucose, peptide YY (PYY), ghrelin and pancreatic polypeptide (PP). RESULTS: There was no significant relationship between eating behaviour in PWS subjects and the levels of any hormones or insulin resistance, independent of age. Fasting plasma leptin levels were significantly higher (mean±s.d.: 22.6±12.5 vs 1.97 ± 0.79 ng ml À1 , P ¼ 0.005), and PP levels were significantly lower (22.6 ± 12.5 vs 69.8 ± 43.8 pmol l À1 , Po0.001) in the PWS group compared with the controls, and this was independent of age, BMI, insulin resistance or IGF-1 levels. However, there was no significant difference in plasma insulin, insulin resistance or ghrelin levels between groups, though PYY declined more rapidly with age but not BMI in PWS subjects. CONCLUSION: Even under the age of 5 years, PWS is associated with low levels of anorexigenic PP, as in older children and adults. Hyperghrelinaemia or hypoinsulinaemia was not seen in these young children with PWS. Change in these appetite hormones was not associated with the timing of the transition to the characteristic hyperphagic phase. However, abnormal and/or delayed development or sensitivity of the effector pathways of these appetitive hormones (for example, parasympathetic and central nervous system) may interact with low PP levels, and later hyperghrelinaemia or hypoinsulinaemia, to contribute to hyperphagia in PWS.

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“…Moreover, the correlation between the effects of DAG infusion on postprandial glycemia and baseline AG levels before the start of the meal in the SBM protocol warrants further study, as it suggests the clinical benefits of DAG administration in subjects with relatively high levels of AG. Appropriate subjects to study might be those with Prader-Willi syndrome (PWS), who not only are hyperphagic and morbidly obese but have elevated ghrelin levels (18,19). This shows that there may be a suppressive (or upregulating) controlling mechanism of ghrelin secretion in PWS children.…”

Section: European Journal Of Endocrinologymentioning

confidence: 99%

Does des-acyl ghrelin improve glycemic control in obese diabetic subjects by decreasing acylated ghrelin levels?

Özcan¹,

Neggers²,

Miller³

et al. 2014

European Journal of Endocrinology

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Objective: The objective of this study was to assess the effects of a continuous overnight infusion of des-acyl ghrelin (DAG) on acylated ghrelin (AG) levels and glucose and insulin responses to a standard breakfast meal (SBM) in eight overweight patients with type 2 diabetes. Furthermore, in the same patients and two additional subjects, the effects of DAG infusion on AG concentrations and insulin sensitivity during a hyperinsulinemic-euglycemic clamp (HEC) were assessed. Research design and methods: A double-blind, placebo-controlled cross-over study design was implemented, using overnight continuous infusions of 3 and 10 mg DAG/kg per h and placebo to study the effects on a SBM. During a HEC, we studied the insulin sensitivity. Results: We observed that, compared with placebo, overnight DAG administration significantly decreased postprandial glucose levels, both during continuous glucose monitoring and at peak serum glucose levels. The degree of improvement in glycemia was correlated with baseline plasma AG concentrations. Concurrently, DAG infusion significantly decreased fasting and postprandial AG levels. During the HEC, 2.5 h of DAG infusion markedly decreased AG levels, and the M-index, a measure of insulin sensitivity, was significantly improved in the six subjects in whom we were able to attain steady-state euglycemia. DAG administration was not accompanied by many side effects when compared with placebo. Conclusions: DAG administration improves glycemic control in obese subjects with type 2 diabetes through the suppression of AG levels. DAG is a good candidate for the development of compounds in the treatment of metabolic disorders or other conditions with a disturbed AG:DAG ratio, such as type 2 diabetes mellitus or Prader-Willi syndrome.

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Suppression of Acylated Ghrelin during Oral Glucose Tolerance Test Is Correlated with Whole-Body Insulin Sensitivity in Children with Prader-Willi Syndrome

Abstract: Our results suggest that AG is sensitively suppressed by insulin and that this suppression correlated with insulin sensitivity in PWS children.

Cited by 48 publications

References 35 publications

In adults with Prader–Willi syndrome, elevated ghrelin levels are more consistent with hyperphagia than high PYY and GLP-1 levels

In adults with Prader–Willi syndrome, elevated ghrelin levels are more consistent with hyperphagia than high PYY and GLP-1 levels

Appetite hormones and the transition to hyperphagia in children with Prader-Willi syndrome

Does des-acyl ghrelin improve glycemic control in obese diabetic subjects by decreasing acylated ghrelin levels?

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