Hormonal and Metabolic Effects of Carbohydrate Restriction in Children With Prader-Willi Syndrome

Krystal A. Irizarry; Diana R. Mager; Lucila Triador; Michael J. Muehlbauer; Andrea M. Haqq; Michael Freemark

Disclosures

Clin Endocrinol. 2019;90(4):553-561. 

In This Article

Abstract and Introduction

Abstract

Objective: Macronutrient regulation of hyperphagia and adiposity in Prader-Willi syndrome (PWS) is poorly understood. We compared fasting and postprandial concentrations of hormones and metabolites in eight PWS children (age 9–18 years) fed, in random order, low carbohydrate, high-fat (LC, 15% carb; 65% fat; 20% protein) and low-fat, high carbohydrate (LF, 65% carb, 15% fat, 20% protein) diets matched for calories and protein.

Methods: Participants were randomized to consume either the LC or LF diet during a first hospital admission and the second diet during a subsequent admission. Blood samples were obtained after overnight fasting and 1 hour after a mixed meal.

Results: Relative to subjects consuming the LF diet, subjects consuming the LC diet had: lower postprandial insulin concentrations (P = 0.02); higher fasting GLP-1 AND GIP concentrations and increased postprandial GLP-1 (P < 0.02); reduced ratio of fasting ghrelin to GLP-1 (P = 0.0078); increased FFA and fatty acid oxidation, as assessed by concentrations of even-chain acylcarnitines (P < 0.001); lower fasting TG and TG/HDL ratio (P < 0.01); and higher concentrations of branch chain amino acids (P < 0.01). There were no changes in glucose, PYY, or adiponectin. CRP, AST and ALT were all higher (P < 0.01) on the LC diet.

Conclusions: Increases in GLP-1 with low carbohydrate feeding and reductions in the ratio of ghrelin to GLP-1 might limit food intake and improve glycaemic control in PWS. Other potential benefits of carbohydrate restriction may include fat mobilization and oxidation and reductions in the TG/HDL ratio, a marker of insulin resistance. However, increases in CRP, AST and ALT necessitate longer-term studies of low carbohydrate efficacy and safety.

Introduction

Prader-Willi syndrome (PWS) is the most common genetic obesity disorder, resulting from absence of expression of paternally derived genes on chromosome 15q11.2-q13.[1,2] Lack of satiety contributes to hyperphagia, which promotes increases in body fat mass.[1–3] In combination with reductions in lean body mass,[2,3] adiposity limits physical activity and exercise tolerance[4] and predisposes to chronic comorbidities including glucose intolerance, hypertension, hyperlipidaemia and sleep apnoea.[2]

Attempts to control weight and prevent metabolic decompensation in PWS through dietary interventions have had variable and limited success. Energy restriction can decrease the rate of weight gain in selected patients[5] but if severe may attenuate linear growth and reduce lean body mass.[6] One uncontrolled study[7] found that PWS children consuming chronically a diet lower in carbohydrate (45% of calories) and higher in fat and protein (30% and 25% of calories, respectively) had lower body mass index (BMI) z-scores and lower body fat content than age-matched PWS children consuming a diet high in carbohydrate (~50%-70% of daily calories) and low in fat and protein (10%-23% and 10%-15% of calories, respectively). These observations suggest that carbohydrate restriction might limit adiposity and weight gain in PWS. To that end, some parents have placed their PWS children on low carbohydrate diets in an attempt to limit fat deposition and reduce long-term metabolic risk. Yet there are no controlled studies comparing the effects of low carbohydrate and low-fat diets on appetite-regulating hormones, insulin sensitivity, or glucose tolerance in PWS.

To assess the roles of dietary carbohydrate and fat in the control of appetite and metabolic function, we compared fasting and postprandial concentrations of various hormones and metabolites in eight PWS children fed, sequentially and in randomized order, low carbohydrate, high-fat (LC, 15% carb; 65% fat; 20% protein) and low-fat, high carbohydrate diets (LF, 65% carb; 15% fat; 20% protein) diets matched for calories and protein content. We hypothesized that carbohydrate restriction would reduce the concentrations of the orexigenic hormone ghrelin, increase the concentrations of anorexigenic hormones including Glucagon-like Peptide 1 (GLP-1) and peptide YY (PYY), and increase insulin sensitivity as measured by fasting insulin and glucose concentrations, total and high-molecular weight adiponectin, and the ratio of triglycerides (TG) to high-density lipoprotein (HDL).

Comments

3090D553-9492-4563-8681-AD288FA52ACE

processing....