Nutritional Regulators

The normal Ghrelin concentration in plasma is 100-150 fmol/ml of total Ghrelin (acyl-modified + des-acyl) and 10-20 fmol/ml of n-octanoyl Ghrelin. Nutritional and hormonal factors can regulate Ghrelin production and release from the stomach. Ghrelin is released in a dose dependent fashion by the calorie content of the meal with no relation to gastric distension. Regul Pept. 2003 Nov 15;116(1-3):101-7. But release requires post gastric feedback (as evidenced by pyloric cuff studies which altered gastric emptying). 

Glucose

Glucose is thought to be the other possible regulator of circulating Ghrelin. IV glucose with humalog SC (n=10) was found not to suppress Ghrelin levels as compared with oral glucose (n=7) in humans. But another study in humans comparing Oral glucose with intravenous glucose administration (n=10; cross over) found equal suppression in both groups irrespective of level of glycaemia. But in this latter study, does the equal suppression suggest a ceiling effect of hyperglycaemia or maximal insulin stimulation? Insulin levels are higher after oral glucose for similar blood glucose levels due to GLP 1, but GLP 1 has been found not to be a regulator of Ghrelin levels. No insulin levels were available in this study; hence the relationship of Ghrelin response to varying insulin levels would be enlightening. Hypoglycaemia during Insulin tolerance testing (ITT) has failed to show a rise in Ghrelin or rather, ITT suppressed Ghrelin levels as expected due to the higher insulin levels, while OGTT  had a similar effect due to endogenous insulin stimulation. Clin Endocrinol (Oxf). 2004 Oct;61(4):503-9. Interestingly, Glucagon which has the potential to increase insulin levels did not produce suppression of Ghrelin release in that study. Does this suggest that insulin and glucose do not directly suppress Ghrelin and there are other concomitant factors involved?

Ghrelin responses to a high-carbohydrate meal (1217 kcal with 77% carbohydrates, 10% protein, and 13% lipids) and to an iso-caloric high-fat meal (15% carbohydrates, 10% proteins, and 75% lipids) was evaluated  in 14 non-obese healthy women. J Clin Endocrinol Metab. 2003 Nov;88(11):5510-4  Circulating Ghrelin fell abruptly after both meals, but, after the carbohydrate meal the maximal decrease was significantly greater (P = 0.02). Plasma insulin and glucose levels rose after both meals, although significantly higher following the carbohydrate meal. No significant change was observed in circulating Leptin after either meal. The carbohydrate meal had a significantly greater suppressant effect on hunger.

Interestingly, another study evaluated the effect of sham feeding on Ghrelin levels in healthy volunteers. J Clin Endocrinol Metab. 2004 Oct;89(10):5101-4. Ghrelin levels rose pre-meals in sham fed and actually-fed subjects to equal levels, and decreased in response to both sham feeding and actual feeding to levels that were not significantly different suggesting the major role of the cephalic phase (vagally mediated) in Ghrelin suppression with meals. Importantly glucose and insulin levels were not altered by the sham feeding, despite which Ghrelin suppression happened. Pancreatic polypeptide rise was documented in the study showing the vagal component to the sham feeding.  This contradicts a previous study in 10 human volunteers which revealed no effect on Ghrelin with sham feeding! Regul Pept. 2003 Nov 15;116(1-3):101-7.

Fat and Free fatty acids

A 3 week study has shown decreased Ghrelin levels in humans on increasing dietary fat.   Plasma Ghrelin response following a 3 week period of acute overfeeding with excess fat (88 g fat, 15 g Protein, 8 g carbohydrate) was studied in 6 normal weight men.(21-34 y; BMI 21-24 kg/m2).  Oral fat tolerance testing revealed that the postprandial Ghrelin response  was significantly reduced following 2 weeks of dietary supplementation. Plasma  leptin concentrations were also significantly elevated. Int J Obes Relat Metab Disord. 2004 Apr 13

At the same time, free fatty acids have been shown not to suppress Ghrelin. FFA infusion reduces the ability of Ghrelin to induce GH secretion from the pituitary Clin Endocrinol (Oxf) 57:265–271

Proteins and Amino Acids:

Protein ingestion may increase Ghrelin levels acutely while glucose and fat suppresses it. Regul Pept. 2003 Nov 15;116(1-3):101-7     Ghrelin suppression by fat feed was much slower than with glucose (180 min vs. 60 min). There was no significant change of Ghrelin levels after modified sham feeding or gastric distension.

Healthy male, fasted volunteers (aged 18-40 yrs, BMI 18.0-24.5 kg/m²) ingested a standardized physiological dose of essential amino acids (AA).  At 20 minutes, insulin reached peak concentrations that were up to 500% higher than basal values.  AA ingestion led to an increase in GH secretion (P<0.0001) while there was no change in the iso-caloric control group.  Changes in Leptin levels remained insignificant  whereas Ghrelin showed a continuous rise towards the end of the study period (P<0.001) in the AA group,  and no effect at all in the iso-caloric control group. J Endocrinol. 2003 Nov;179(2):237-44)

A study in 13 men and 11 women using different nutrients( oral glucose load, oral lipid load, and oral protein load) revealed that  glucose loading and fat loading reduced Ghrelin levels, while protein did not alter Ghrelin levels. The reduction of Ghrelin with glucose was more marked in men. After an initial decline Ghrelin levels started to rise back to baseline earlier in obese than in lean subjects. Clin Endocrinol (Oxf). 2004 Mar;60(3):382-8.

Another study looked at the effect of various nutrients administered by intravenous and intragastric routes.  Intragastric administration of protein, dextrose, or fat decreased plasma Ghrelin levels significantly and equally. Fat and dextrose given intravenously also reduced Ghrelin secretion. Thus all nutrient types given orally are capable of inhibiting Ghrelin secretion. Regul Pept. 2004 Jan 15;117(1):33-6

Calorie load: 10 healthy people were given a similar volume of varying calorie loads as liquid meals (7.5%, 16%, or 33% of total daily energy expenditure). The mean  intervals between ingestion of the 7.5%, 16%, and 33% preloads and the subsequent voluntary meal requests were 247,  286, and 321 min, respectively (P = 0.015). The nadir plasma Ghrelin levels were 80.2 %, 72.7 %, and 60.8 % of baseline for the respective loads suggesting greater Ghrelin suppression by greater caloric loads. Although the degree of postprandial Ghrelin suppression was proportional to ingested caloric load, no statistically significant relationship was evident between the recovery of plasma Ghrelin and the patients' demand for the next meal. J Clin Endocrinol Metab. 2004 Mar;89(3):1319-24

Hormonal Regulators

Insulin

Insulin is thought to be a major regulator of circulating Ghrelin. Reciprocal changes of the two have been fairly consistently demonstrated in humans although rat studies have shown contradictions. But type1 diabetics given meals and type 2 diabetic patients given low dose glucose IV suppressed their Ghrelin despite no detectable insulin levels or insulin rise respectively! Insulin decreased Ghrelin levels in normal humans but to a lesser extent only in type 2 diabetics. Eur J Endocrinol. 2003 Nov;149(5):403-6. . Insulin infusion (euglycemic hyperinsulinaemic clamp) in 35 patients with uncomplicated obesity suppressed Ghrelin levels, with suppression being directly proportional to the insulin sensitivity. Regul Pept. 2004 Nov 15;122(3):179-83

 The effect of gastrointestinal hormones and insulin on Ghrelin secretion in isolated rat stomach has been assessed during vagal prestimulation. This model offers the advantage of avoiding systemic interactions. GLP-1 decreased Ghrelin secretion significantly.  Insulin,  gastrin  and somatostatin also significantly inhibited Ghrelin secretion. In contrast, GIP  augmented both pre-stimulated and basal Ghrelin secretion. Regul Pept. 2004 Jun 15;119(1-2):93-8.
 

A further study was undertaken to investigate whether insulin was the predominant regulator of Ghrelin.  Obese subjects with and without insulin resistance and similar glycaemic levels (steady-state glucose levels) were assessed for Ghrelin levels in the fasting state. Fasting insulin concentrations were clearly higher in the insulin resistant subjects who had lower Ghrelin levels compared to insulin sensitive obese patients. The study shows that Ghrelin concentration is inversely related to insulin resistance and hyperinsulinism rather than glucose levels. J Clin Endocrinol Metab. 2004 Apr;89(4):1630-5. Another study in obese subjects using DEXA scanning for body composition and the euglycemic hyperinsulinaemic clamp demonstrated that Ghrelin level changes were predominantly determined by fat mass rather than metabolic syndrome features (hypertension and HDL levels). Metabolism. 2003 Nov;52(11):1460-3.

Intravenous glucose administration in 7 healthy control subjects and 8 T2DM subjects compared Ghrelin responses in the first 10 minutes, taking advantage of the fact that type 2 diabetics are unable to mount a significant first phase response of insulin secretion. In the first ten minutes of this study, no insulin response occurred in the type 2 diabetics. This group attained higher glucose levels with equal Ghrelin decreases as the normal controls with higher insulin response. Eur J Endocrinol. 2003 Nov;149(5):403-6  This could suggest a regulation of Ghrelin independent of insulin and probably more dependent on glucose, at least in the early phases of meal ingestion.

At 2 and 12 months post Biliopancreatic diversion (BPD) surgery for obesity, body weight and BMI dropped sharply, with a reduction in insulin resistance (HOMA IR), as well as serum Leptin concentration. But serum Ghrelin levels increased significantly at 12 months, when food intake had returned to preoperative levels. The negative relationship observed between post-BPD changes in HOMA IR values and changes in serum Ghrelin concentration is suggested as supporting the assumption of the role of insulin in the modulation of Ghrelin production. Obes Res. 2004 Apr;12(4):684-7

PYY an intestinal hormone which suppresses appetite, has been shown to suppress Ghrelin levels with satiety induction. N Engl J Med. 2003 Sep 4;349(10):941-8.

Leptin has variable effects on Ghrelin levels and does not seem to be a regulator of Ghrelin. Leptin deficient states (humans or rodents with absent Leptin signaling due to inactivating mutations in ligand or its receptor) show low Ghrelin levels with obesity (similar to obese individuals with intact Leptin signalling). Conversely, increased circulating Leptin (achieved either transgenically or by peripheral injections) produces animals that are lean and shows increased Ghrelin expression. These 2 examples show that Ghrelin tracks alteration in body weight rather than Leptin.

A study of 120 healthy men and women revealed that Ghrelin levels were inversely related to Leptin and Central adiposity and not related to total energy intake.  A three-day Fast abolished the meal related Ghrelin secretion patterns with low Leptin levels and no significant change in fat mass. Recombinant Leptin administration did not regulate Ghrelin levels in the short-term (several hours to a few days ). Overall it may well be that Leptin and Ghrelin function independently of each other in healthy humans. J Clin Endocrinol Metab. 2004 Jan;89(1):335-43

A study assessing the response of fasting and postprandial total Ghrelin to short-term energy restriction found that with short-term energy restriction without change in fat mass, fasting and postprandial total Ghrelin levels do not change despite a significant reduction in Leptin levels J Clin Endocrinol Metab. 2004 Apr;89(4):1727-32.

Omeprazole treatment for 10 weeks in rats did not change Ghrelin levels, nor did a 2 day infusion of gastrin. These make Gastrin an unlikely candidate in Ghrelin secretion regulation. Regul Pept. 2001 Jun 15;99(2-3):141-50

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    This page was last updated on: 07/03/2007

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