Niamh M. Martin

Ghrelin enhances gastric emptying in diabetic gastroparesis: a double blind, placebo controlled, crossover study

Background: Diabetic gastroparesis is a disabling condition with no consistently effective treatment. In animals, ghrelin increases gastric emptying and reverses postoperative ileus. We present the results of a double blind, placebo controlled, crossover study of ghrelin in gastric emptying in patients with diabetic gastroparesis. Methods: Ten insulin requiring diabetic patients (five men, six type I) referred with symptoms indicative of gastroparesis received a two hour infusion of either ghrelin (5 pmol/kg/min) or saline on two occasions. Blood glucose was controlled by euglycaemic clamp. Gastric emptying rate (GER) was calculated by real time ultrasound following a test meal. Blood was sampled for ghrelin, growth hormone (GH), and pancreatic polypeptide (PP) levels. Cardiovagal neuropathy was assessed using the Mayo Clinic composite autonomic severity score (range 0 (normal)–3). Results: Baseline ghrelin levels were mean 445 (SEM 36) pmol/l. Ghrelin infusion achieved a peak plasma level of 2786 (188) pmol/l at 90 minutes, corresponding to a peak GH of 70.9 (19.8) pmol/l. Ghrelin increased gastric emptying in seven of 10 patients (30 (6)% to 43 (5)%; p = 0.04). Impaired cardiovagal tone correlated inversely with peak postprandial PP values (p<0.05) but did not correlate with GER. Conclusions: Ghrelin increases gastric emptying in patients with diabetic gastroparesis. This is independent of vagal tone. We propose that analogues of ghrelin may represent a new class of prokinetic agents.

Hypothalamic regulation of food intake and clinical therapeutic applications

Current estimates suggest that over 1 billion people are overweight and over 300 million people are obese. Weight gain is due to an imbalance between energy expenditure and dietary intake. This review discusses the hypothalamic control of appetite and highlights key developments in research that have furthered our understanding of the complex pathways involved. Nuclei within the hypothalamus integrate peripheral signals such as adiposity and caloric intake to regulate important pathways within the central nervous system controlling food intake and energy expenditure. Firmly established pathways involve the orexigenic NPY/AgRP and the anorexigenic POMC/CART neurons in the arcuate nucleus (ARC) of the hypothalamus. These project from the ARC to other important hypothalamic nuclei, including the paraventricular, dorsomedial, ventromedial and lateral hypothalamic nuclei. In addition there are many projections to and from the brainstem, cortical areas and reward pathways, which modulate food intake.

PYY3-36 and oxyntomodulin can be additive in their effect on food intake in overweight and obese humans.

OBJECTIVE Peptide YY3–36 (PYY3–36), a Y2 receptor agonist, and oxyntomodulin, a glucagon-like peptide 1 (GLP-1) receptor agonist, are cosecreted by intestinal L-cells after each meal. Separately each hormone acts as an endogenous satiety signal and reduces appetite in humans when infused intravenously. The aim of the current study was to investigate whether the anorectic effects of PYY3–36 and oxyntomodulin can be additive. RESEARCH DESIGN AND METHODS Twelve overweight or obese human volunteers underwent a randomized, double-blinded, placebo-controlled study. An ad libitum test meal was used to measure energy intake during intravenous infusions of either PYY3–36 or oxyntomodulin or combined PYY3–36/oxyntomodulin. RESULTS Energy intake during coadministration of PYY3–36 and oxyntomodulin was reduced by 42.7% in comparison with the saline control and was significantly lower than that during infusions of either hormone alone. CONCLUSIONS The anorectic effects of PYY3–36 and oxyntomodulin can be additive in overweight and obese humans. Coadministration of Y2 receptor agonists and GLP-1 receptor agonists may be a useful treatment strategy for obesity.

Effective Combination Treatment with Cabergoline and Low-Dose Pegvisomant in Active Acromegaly: A Prospective Clinical Trial

CONTEXT With adequate dose titration, pegvisomant normalizes IGF-I in up to 97% of patients with acromegaly. Pegvisomant is indicated for treatment-resistant disease but is expensive, particularly at a high dose. It has been used successfully in combination with somatostatin analogs. However, there are no therapeutic reports of pegvisomant in combination with dopamine agonists. Cabergoline is orally active, well-tolerated, and relatively inexpensive, and as monotherapy for acromegaly it is reported to normalize IGF-I in up to 30% of patients. OBJECTIVE The aim of the study was to investigate the efficacy of cabergoline monotherapy and pegvisomant in combination with cabergoline to control serum IGF-I in patients with active acromegaly. Twenty-four patients were recruited into a United Kingdom, multicenter, open-label, prospective clinical trial. MAIN OUTCOME MEASURE We measured the change in serum IGF-I. RESULTS After 18 wk of dose titration to a maximum dose of 0.5 mg once daily, cabergoline monotherapy did not significantly reduce IGF-I (454 ± 219 baseline vs. 389 ± 192 ng/ml cabergoline), although two patients did normalize IGF-I. The addition of 10 mg pegvisomant daily for 12 wk significantly reduced IGF-I (389 ± 192 ng/ml cabergoline vs. 229 ± 101 ng/ml combination), and 68% achieved a normal IGF-I. Twelve weeks after cabergoline withdrawal, while continuing to receive pegvisomant 10 mg, only 26% of patients maintained an IGF-I within the reference range (229 ± 101 ng/ml combination vs. 305 ± 177 ng/ml pegvisomant). There were no significant changes in liver transaminases or glucose metabolism throughout the study. CONCLUSION These data suggest that combination treatment with cabergoline and pegvisomant is more effective at reducing IGF-I levels than either cabergoline or pegvisomant monotherapy.

Hepcidin levels in diabetes mellitus and polycystic ovary syndrome

Increased body iron is associated with insulin resistance. Hepcidin is the key hormone that negatively regulates iron homeostasis. We hypothesized that individuals with insulin resistance have inadequate hepcidin levels for their iron load.

Overexpression of CART in the PVN increases food intake and weight gain in rats.

Objective: Cocaine‐ and amphetamine‐regulated transcript (CART) codes for a hypothalamic neuropeptide, CART (55–102), which inhibits food intake. Intracerebroventricular injection of CART (55–102) reduces appetite, but also results in motor abnormalities. More recently, studies have demonstrated that administration of CART directly into the paraventricular nucleus (PVN) increases food intake. To investigate the role of CART in the regulation of energy balance in the PVN, we used recombinant adeno‐associated virus (rAAV) to overexpress CART in the PVN.

Quantifying the Effects of Renal Impairment on Plasma Concentrations of the Neuroendocrine Neoplasia Biomarkers Chromogranin A, Chromogranin B, and Cocaine- and Amphetamine-Regulated Transcript

To the Editor: Neuroendocrine neoplasia (NEN)1 accounts for 2% of all malignancies (1). Patients with NEN often present with nonspecific symptoms and thus represent a major diagnostic challenge. There are several circulating NEN biomarkers, and chromogranin A (CgA) is regarded as the gold standard (2). Chromogranin B (CgB) has been found to be a useful diagnostic addition to CgA measurements (3). The peptide product of cocaine- and amphetamine-regulated transcript (CART) is also increased in patients with NENs, particularly in those with pancreatic NENs (4). Renal impairment or failure can increase circulating concentrations of CgA (2) and CART (4); however, CgB may be unaffected by mild renal impairment and is increased only in severe renal failure (3). The population most likely to be affected by NEN is also susceptible to renal impairment: Chronic kidney disease (CKD) occurs in approximately 10% of the population between 50 and 60 years of age, and the mean age of patients with a NEN diagnosis is 61 years (1, 5). We therefore examined the effect of varying degrees of renal impairment/failure on plasma concentrations of CgA, CgB, and CART in patients without NEN. Ethics approval for this study was obtained from the Hammersmith and Queen Charlottes and Chelsea Hospitals Research Ethics Committee (04/Q0406/80). After informed written consent was obtained, 5 mL of blood was collected from 40 healthy volunteers. In addition, samples from 107 patients with different stages of renal impairment were obtained and irreversibly anonymized as per Royal College of Pathology, UK, guidelines (D035, September 2007). All blood samples were collected into EDTA-containing tubes and centrifuged at 10 000 g for …

Assessment of cardiac valve dysfunction in patients receiving cabergoline treatment for hyperprolactinaemia

Objective  Cabergoline is a highly effective medical treatment for patients with hyperprolactinaemia. There is an increased risk of valvular heart disease in patients receiving cabergoline for Parkinson’s disease. This study examined whether cabergoline treatment of hyperprolactinaemia is associated with a greater prevalence of valvulopathy.

Interactions between the melanocortin system and the hypothalamo-pituitary-thyroid axis.

Recent studies of transgenic mice and humans have provided compelling evidence for the importance of the hypothalamic melanocortin system in the regulation of energy balance. Energy homeostasis is a balance between food intake (energy input) and energy expenditure. The melanocortin system regulates feeding via effects of the endogenous agonist, alpha-melanocyte stimulating hormone (alpha-MSH) and the endogenous antagonist agouti-related protein (AGRP) on melanocortin 3 and 4 receptors (MC3-Rs and MC4-Rs). It has been demonstrated that the melanocortin system interacts with the hypothalamo-pituitary-thyroid (HPT) axis. Thyroid hormones influence metabolism and hence energy expenditure. Therefore, an interaction between the HPT axis and the melanocortin system would allow control of both sides of the energy balance equation, by the regulation of both energy input and energy expenditure. Here we will discuss the evidence demonstrating interactions between the melanocortin system and the HPT axis.

Plasma gastrin measurement cannot be used to diagnose a gastrinoma in patients on either proton pump inhibitors or histamine type-2 receptor antagonists

Background: Patients with a gastrinoma are treated with proton pump inhibitors (PPI) and histamine type-2 receptor antagonists (H2). In order to diagnose a gastrinoma these drugs must be discontinued, but this increases the risk of gastrointestinal perforation. We aimed to determine if a gastrinoma could be diagnosed without cessation of PPI/H2 therapy. Methods: In all, 90 patients (controls and patients diagnosed with a gastrinoma both on and off PPI/H2 therapy) were recruited, and plasma gastrin measured. Results: Patients with a gastrinoma on PPI/H2 medication had a significantly higher fasting plasma gastrin concentration than control patients on PPI/H2 medication (298±33 versus 204±30 pmol/L, P = 0.01). However, there was substantial overlap between gastrin levels in these two groups. Conclusion: This study confirms that a gastrinoma cannot be diagnosed on the basis of a fasting plasma gastrin assay while patients remain on PPI/H2 therapy.