Bone turnover response is linked to both acute and established metabolic changes in ultra-marathon runners.

Bone and energy metabolisms regulation depends on a two-way street aimed at regulating energy utilization. Mountain ultra-marathons are highly demanding aerobic performances that deeply affect the whole body homeostasis. In this study we aimed to investigate and characterize the metabolic profile (in terms of hormones involved in energy metabolism), the inflammatory adipokines, and the bone turnover; in particular the osteocalcin-mediated response has been compared in experienced mountain ultra-marathons runners versus control subjects. Serum concentrations of specific markers of bone turnover (pro-collagen type I N-terminal propeptide, carboxylated/undercarboxylated osteocalcin), measured by enzyme-linked immunosorbent assay, and metabolic hormones (C-peptide, insulin, glucagon, glucagon-like peptide, gastric-inhibitory peptide, ghrelin, leptin, resistin, and visfatin), measured by fluorescent-based multiplex assay, were compared before and after a 65 km mountain ultra-marathons in 17 trained runners and 12 age-matched controls characterized by a low physical activity profile. After the mountain ultra-marathons, runners experienced a reduction in pro-collagen type I N-terminal propeptide, though it remained higher than in controls; while carboxylated osteocalcin remained unchanged. Among the metabolic hormones, only glucagon and leptin were different between runners and controls at rest. C-peptide and leptin decreased after the mountain ultra-marathons in runners; while glucagon, glucagon-like peptide 1, resistin, and visfatin were all increased. Uncarboxylated osteocalcin (and uncarboxylated/carboxylated osteocalcin ratio) was decreased and this highly correlated with insulin and C-peptide levels. In conditions of high energy expenditure, homeostasis is maintained at expenses of bone metabolism. Changes in the uncarboxylated osteocalcin clearly mark the global energy needs of the body.

Putting the pieces together: necrolytic migratory erythema and the glucagonoma syndrome.

Glucagonomas are slow-growing, rare pancreatic neuroendocrine tumors. They may present with paraneoplastic phenomena known together as the "glucagonoma syndrome." A hallmark sign of this syndrome is a rash known as necrolytic migratory erythema (NME). In this paper, the authors describe a patient with NME and other features of the glucagonoma syndrome. The diagnosis of this rare tumor requires an elevated serum glucagon level and imaging confirming a pancreatic tumor. Surgical and medical treatment options are reviewed. When detected early, a glucagonoma is surgically curable. It is therefore imperative that clinicians recognize the glucagonoma syndrome in order to make an accurate diagnosis and refer for treatment.

Arterial stimulation and venous sampling for glucagonomas of the pancreas.

BACKGROUND/AIMS: Arterial stimulation and venous sampling (ASVS) is a catheter-based diagnostic technique used to identify the localization of an insulinoma or gastrinoma. The aim of this study was to clarify the clinical significance of ASVS for glucagonomas. METHODOLOGY: Eight patients with pancreatic hypervascular tumors and elevated serum glucagon levels in the peripheral blood were enrolled. Pancreatic angiography was performed and a bolus dose of calcium was injected into a suitable artery. Hepatic venous blood samples were then obtained to measure concentrations of glucagon and insulin. All patients underwent surgical resection, and the resected specimens were investigated immunohistochemically. RESULTS: Compared to insulin, the glucagon levels stabilized after calcium stimulation in four patients, with a 1.2-fold increase or decrease. In the remaining four patients, there was a 1.6- to 5.8-fold increase in glucagon levels. The peak value of glucagon was observed at 90s or 120s which was slower than the insulin peak observed in patients with insulinoma. The patients with elevated glucagon levels during ASVS exhibited positive immunostaining of glucagon in resected specimens. CONCLUSIONS: Increase in glucagon after calcium stimulation was observed in patients with glucagonomas. ASVS for glucagonomas may be useful in determining the most suitable surgical procedure.

Glucagonoma diagnosed by arterial stimulation and venous sampling (ASVS).

To identify the location of pancreatic endocrine tumors, arterial stimulation and venous sampling (ASVS) is known to be useful for insulinoma and gastrinoma, but its usefulness for glucagonoma has not been verified to date. Here we report a case of glucagonoma that was diagnosed by ASVS with calcium loading, in which an approximately 6-fold increase of glucagon was observed in the splenic artery territory. MEN1 gene analysis verified the presence of a mutation and the glucagonoma was confirmed after operation. In conclusion, ASVS could be useful for the diagnosis of glucagonoma.

Plasma glucagon levels suppressed by a glucose load in a man with incidental pancreatic glucagonoma.

OBJECTIVE: To describe a patient with a histologically proven pancreatic glucagonoma, noted incidentally during a follow-up visit for high aminotransferase levels, and to evaluate its autonomy with a standard 75-g oral glucose tolerance test. METHODS: We present the results of a 2-hour oral glucose tolerance test, with plasma glucagon and blood glucose levels measured every 30 minutes after an oral glucose load. In addition, we provide a brief review of the literature on the diagnosis and management of glucagonomas and the importance of long-term surveillance. RESULTS: In our patient, who had a 1-year history of impaired fasting glucose, plasma glucagon levels were persistently suppressed to within the normal range after oral glucose challenge. Octreotide scintigraphy revealed abnormal uptake in the pancreatic tail, and a 2.8-cm mass was removed at laparoscopic distal pancreatectomy. Immunohistochemical staining of the tumor tissue showed intense reactivity for glucagon. Plasma glucagon levels were reduced to <50 pg/mL postoperatively, and scintigraphic study at 4-month follow-up showed no residual uptake at the previous tumor site or elsewhere. CONCLUSION: Glucagon-secreting pancreatic tumors are extremely rare. A substantially elevated plasma level of glucagon is usually seen in patients with metastatic tumors. In the early stage of a glucagonoma, however, the plasma glucagon level may be only modestly elevated and may still be susceptible to normal negative feedback inhibition. We demonstrated plasma glucagon complete suppressibility after oral glucose challenge in a patient with a glucagonoma, the first such report in the literature.

Necrolytic migratory erythema: a cutaneous clue to glucagonoma syndrome.

Necrolytic migratory erythema (NME) is a cutaneous manifestation of the glucagonoma syndrome. We present a case with a pancreatic glucagon-secreting tumour, skin eruption and a good response to treatment.

Circulating ghrelin levels in patients with pancreatic and gastrointestinal neuroendocrine tumors: identification of one pancreatic ghrelinoma.

Ghrelin is a novel gastrointestinal hormone involved in several metabolic functions. Although the expression of ghrelin has been demonstrated in most gastrointestinal carcinoids and pancreatic tumors, the circulating levels of this peptide have been marginally assessed in patients with these disorders. We measured plasma ghrelin levels in 16 patients with gastrointestinal carcinoid (10 with midgut and 6 with gastric carcinoid), 24 patients with pancreatic tumor (8 with gastrinoma, 2 with insulinoma, 2 with vipoma, 1 with glucagonoma, and 11 with nonfunctioning tumor), and 35 healthy controls. Plasma ghrelin levels recorded in patients with gastroenteropancreatic tumors were similar to controls (mean +/- SE, 182.7 +/- 66.5 pM in patients vs. 329 +/- 32 pM in controls, P = not significant), and no significant difference between gastrointestinal and pancreatic, functioning and nonfunctioning, and metastatic and nonmetastatic tumors was observed. One patient with metastatic nonfunctioning pancreatic tumor had circulating ghrelin levels of 12,000 pM that were slightly reduced during chemotherapy and interferon therapy. Immunohistochemistry performed on peritoneal lesions showed an intense, focal cytoplasmic positivity for ghrelin. Despite the 50-fold increase in ghrelin concentrations, the patient had normal serum GH and IGF-I levels. In conclusion, the study showed that carcinoids and pancreatic tumors rarely cause ghrelin hypersecretion. However, in this series, 1 pancreatic ghrelinoma not associated with clinical features of acromegaly was identified.

[Necrolytic migratory erythema revealing glucagonoma without diabetes]. / Erythème nécrolytique migrateur révélateur d'un glucagonome sans diabète.

We report a case of glucagonoma syndrome, revealed by a necrolytic migratory erythema that had developed for four Years, associated with anorexia, severe weight loss, anemia, hypoprotidemia, and hypoaminoacidemia. The fasting blood glucose level tended paradoxically to be low (0.6 g/l). Elevated plasma glucagon levels confirmed our diagnosis. The absence of diabetes was explained by an independent insulin secretion derived from this composite pancreatic tumor, authenticated by the histological analysis and the proinsulin level. This level was similar to those typically observed in insulinomas. Six Months after a complete surgical exeresis, symptoms disappeared and biological results returned to normal values.

Peripheral amino acid and fatty acid infusion for the treatment of necrolytic migratory erythema in the glucagonoma syndrome.

Necrolytic migratory erythema (NME), the characteristic rash associated with the glucagonoma syndrome, is a cause of substantial morbidity among patients with this rare malignancy. Treatment options are suboptimal, and often useful for only short or moderate durations. We report the effective, long-term (> 1 year) use of intermittent infusions of amino acids (AA) and fatty acids (FA) administered via peripheral intravenous access for the treatment of NME in the glucagonoma syndrome. Despite resolution of the NME, serum amino acid (initially subnormal) and fatty acid (initially normal) levels remained unchanged. Tumour growth and other symptoms related to the glucagonoma syndrome appear unaffected by such infusions.

Eritema migratorio necrolítico como manifestación inicial de glucagonoma normoglucémico / Necrolytic migratory erythema assocaited normoglycemic glucagonoma

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The hypothalamic satiety peptide CART is expressed in anorectic and non-anorectic pancreatic islet tumors and in the normal islet of Langerhans.

The hypothalamic satiety peptide CART (cocaine and amphetamine regulated transcript) is expressed at high levels in anorectic rat glucagonomas but not in hypoglycemic insulinomas. However, a non-anorectic metastasis derived from the glucagonoma retained high CART expression levels and produced circulating CART levels comparable to that of the anorectic tumors. Moreover, distinct glucagonoma lines derived by stable HES-1 transfection of the insulinoma caused severe anorexia but retained low circulating levels of CART comparable to that of insulinoma bearing or control rats. Islet tumor associated anorexia and circulating CART levels are thus not correlated, and in line with this peripheral administration of CART (5-50 mg/kg) produced no effect on feeding behavior. In the rat two alternatively spliced forms of CART mRNA exist and quantitative PCR revealed expression of both forms in the hypothalamus, in the different islet tumors, and in the islets of Langerhans. Immunocytochemistry as well as in situ hybridization localized CART expression to the somatostatin producing islet D cell. A potential endocrine/paracrine role of islet CART remains to be clarified.

Protein metabolism in glucagonoma.

Although protein wasting and reduced amino acid concentrations are common findings in glucagonoma patients, the mechanisms underlying these alterations are unclear. Therefore, we studied basal postabsorptive leucine, phenylalanine and tyrosine turnover following L-[D3]-Leucine, L-[D5]-Phenylalanine and L-[D2]-Tyrosine i.v. infusions in one male and one female patient with glucagonoma, compared with healthy control volunteers. Plasma amino acid concentrations were reduced (-40 to 80%, delta >2 SD vs. control subjects) in both patients. Plasma leucine, phenylalanine and tyrosine rates of appearance in patients with glucagonoma were similar to values in the control subjects, except leucine rate of appearence in the female patient with glucagonoma (+ approximately 30%, delta >2 SD). In contrast, the intracellular leucine rate of appearence, reflecting protein degradation, was considerably increased in both patients (+60-80%, delta >2 SD). Phenylalanine hydroxylation was moderately higher only in the male patient with glucagonoma (+ approximately 30%, delta >2 SD). Leucine, phenylalanine and tyrosine clearances (+100-300%), as well as phenylalanine hydroxylative clearance (+75-100%) were also increased in the patients. In conclusion, whole-body protein breakdown is enhanced in patients with glucagonoma compared with healthy control subjects. Phenylalanine hydroxylative clearance is also higher. Reduced plasma amino acid concentrations are probably due, at least in part, to their increased clearance. These alterations could contribute to the determination of the catabolic state of the glucagonoma syndrome.

Uptake of mangafodipir trisodium in liver metastases from endocrine tumors.

The purpose of the study was to investigate retrospectively whether mangafodipir trisodium (MnDPDP) can enhance the liver metastases from endocrine tumors. Thirteen patients with endocrine tumors and liver metastases underwent T1-weighted spin-echo (SE) and turbo gradient-echo (GRE) MRI conducted before and 20 to 60 minutes after i.v. infusion of MnDPDP. Additional 24-hour-delay scans were performed in 8 of 13 patients. MR signal intensity (SI) was measured in liver parenchyma and metastases, which was then related to that of paraspinal muscle. A total of 30 lesions on precontrast and postcontrast images and 18 lesions on 24-hour-delay images were measured. An enhancement by 49% in SE and 40% in GRE images (P = .0001) was observed in tumor tissues after MnDPDP infusion. In 24-hour-delay images, the SI of the lesions remained relatively high, but in liver parenchyma, it decreased significantly, and the tumor-liver tissue contrast was reduced.

In vivo and in vitro effects of somatostatin and insulin on glucagon release in a human glucagonoma.

Inhibition of pancreatic glucagon secretion has been reported to be mediated by glucose, insulin and somatostatin. As no human pancreatic alpha-cell lines are available to study in vitro the relative importance of insulin and glucose in the control of pancreatic glucagon release, we investigated a patient presenting with a malignant glucagonoma who underwent surgical resection of the tumour. Functional somatostatin receptors were present as octreotide administration decreased basal glucagon and insulin secretion by 52 and 74%, respectively. The removed tumour was immunohistochemically positive for glucagon, chromogranin A and pancreatic polypeptide but negative for insulin, gastrin and somatostatin. The glucagonoma cells were also isolated and cultured in vitro. Incubation experiments revealed that change from high (10 mM) to low (1 mM) glucose concentration was unable to stimulate glucagon secretion. A dose-dependent inhibition of glucagon release by insulin was however, observed at low glucose concentration. These findings demonstrate that insulin could inhibit glucagon secretion in vitro in the absence of elevated glucose concentrations. These data suggest, as observed in vivo and in vitro in several animal studies, that glucopenia-induced glucagon secretion in humans is not mediated by a direct effect of low glucose on alpha-cells but possibly by a reduction of insulin-mediated alpha-cell suppression and/or an indirect neuronal stimulation of glucagon release.