Is insulin a satiety signal? Insulin treatment antagonises starvation-induced increases in neuropeptide Y concentrations in the arcuate nucleus of the rat

Neuropeptide Y (NPY), the most powerful appetite stimulant known, is synthesised in hypothalamic arcuate nucleus (ARC). NPY levels rise in the ARC and in appetite-regulating hypothalamic nuclei in food-deprived rats, and may drive compensatory hyperphagia in starvation. Circulating insulin levels fall in starvation and insulin deficiency has been postulated to stimulate hypothalamic NPY; this supports the suggestion that insulin acts on the brain to inhibit feeding. We tested this hypothesis by determining whether the increase in NPY in the ARC of starved rats was suppressed by insulin treatment. Adult male Wistar rats were studied. Controls (n=8) were freely-fed and two other groups were food-deprived for 72 hours, both losing 20% of initial weight (p<O.OOI vs controls). One food·deprived group n=10) received insulin (5 U/kg/day) injected subcutaneously twice daily and both other groups recieved saline. Mean blood glucose values (measured in tail-prick samples) were 5.9± 0.1 mmoVI in controls, 4.6± 0.3 mmol/l in food-deprived (p<O.OOI. vs controls) and in insulin·treated 4.4± 0.3 mmol/I (p<O.OOI vs controls; NS vs food-deprived group). Final plasma insulin levels in insulin·treated rats were higher than in saline-treated food-deprived rats (46.6± 8.9 vs 28.9± 4.5 pmol/l; p<O.OOI) and comparable with controls (52.6± 16.2 pmol/l; p=NS). ARC NPY concentrations rose significantly above controls in food·deprived rats (14.18± 1.79 vs 8.4± 2.16 fmol/ug protein; p<O.OOI) and were intermediate in the insulin-treated food-deprived group (11.19± 1.36 fmol/ug protein: p<O.OI vs controls and p<O.OOI vs saline-treated, food deprived). Other hypothalamic regions showed no differences between groups. Insulin therefore antagonises fasting·induced increases in NPY concentrations in the ARC. This is consistent with the hypotheses that insulin deficiency stimulates hypothalamic NPY synthesis, and that peripheral insulin acts as a satiety factor by inhibiting hypothalamic NPY

Insulinoma in Saudi Arabia: a twenty-year hospital study

The study was designed to assess retrospectively clinical pattern of insulinoma at a national referral center in the Kingdom of Saudi Arabia. All cases of insulinoma recorded at King Khalid University Hospital Riyadh between January 1987 and December 2006 were reviewed. During the 20-year period five patients were seen comprising three females (ages 38, 40, and 70 years) and two males (17 and 34 years). The duration of symptoms prior to diagnosis ranged between one and eight years. The commonest mode of presentation before diagnosis was inability to observe Ramadan fasting. Other notable symptoms included dizziness and loss of consciousness. All the five patients proceeded to operation. At surgery all were found to be benign tumors. Post-operatively, three of the patients developed pseudocyst, which resolved upon undergoing second surgery. Though clinical presentation of insulinoma in Saudi subjects is similar to those reported in the literature, our study revealed prominent symptoms occurring during yearly ramadan religious fast could be a useful information in history taking. Further studies on a larger population are needed to further characterize our findings

Primary hyperparathyroidism in Saudi Arabia: a review of 46 cases

Records of 46 patients who were treated for primary hyperparathyroidism at King Khalid University Hospital, Riyadh Saudi Arabia from 1st July 2000 to 30th June 2006 were reviewed. Mean age at diagnosis was 44 years (range 13-70 years) and average duration of symptoms was 39 months (1 month to 11 years). There were 35 females and 11 males with a ratio of 3.2:1. Bone pains were the major symptoms at presentation in 45.7% followed by no symptom in 23.9%, renal stones in 15.2%, polyuria in 6.5%, while 4.3% each presented with depression, and constipation. Males had significantly more severe disease with higher serum calcium, higher urinary calcium excretion, and higher serum creatinine. Ninety six percent of patients had successful surgery and 4% (two patients) each had recurrence and hungry bone syndrome. It is concluded that PHPT in Saudi Arabia continues to be a symptomatic disorder with skeletal and renal manifestations occurring at a younger age and males having more severe disease. Further prospective studies are needed to verify our findings

Cutaneous manifestations of liver cirrhosis in an African (negroid) population

Sixty negroid patients with liver cirrhosis were examined for their cutaneous features at the University College Hospital, Ibadan, Nigeria. When compared with age and sex matched controls, the cirrhotic patients had significantly lower body temperature, onycholysis and hyperpigmented palmo-plantar macular areas (p < 0.05). Until now, these features have not been previously associated with liver cirrhosis. Other cutaneous signs such as sparse silky hair, female public hair pattern, digital clubbing, leuconychia, ankle oedema and corneal jaundice are found more commonly in cirrhotic patients (p < 0.05) and have been previously documented. All these features in a middle-aged man with hepatomegaly may be of added distinctive value particularly in many rural centres in tropical countries where facilities for definitive histological diagnosis are frequently lacking. The relevance of some of these cutaneous features in the light of the pattern described in Caucasians is also discussed

Ascites in Ibadan, Nigeria – usefulness of albumin gradient in its etiologic diagnosis

In a 2-year prospective study, ninety adult patients with ascites at the University College Hospital Ibadan were evaluated clinically in addition to a diagnostic work‑up protocol. Of these, 40 (44%) had liver cirrhosis, 21 (23%) had tuberculous peritonitis, 20 (22%) had malignant ascites, 5 (6%) had heart diseases and\ud 4 (5%) had nephrotic syndrome.\ud \ud Albumin gradient was compared with the usual parameters of ascitic fluid analysis in the differential diagnosis of ascites. We showed that the ascitic fluid total protein concentration, the ascitic fluid/serum total protein, the ascitic fluid lactic dehydrogenase, and the ascitic fluid/serum lactic dehydrogenase were lower in the patients with liver cirrhosis than in the patients with tuberculous peritonitis (p<0.0001) or malignant ascites (p<0.0001). In contrast, the albumin gradient (serum albumin minus ascitic fluid albumin) in the patients with liver cirrhosis was significantly higher than in the patients with tuberculous peritonitis (p<0.0001) or malignant ascites (p<0.0001). There was no difference in these biochemical parameters between the patients with tuberculous peritonitis and malignant ascites. Overall, the efficiency of the biochemical parameters in correctly diagnosing patients with ascites caused by liver cirrhosis and those due to tuberculous peritonitis or malignancies was highest for albumin gradient <1.1 g/dL (96%), followed by ascitic fluid lactic dehydrogenase level >180 IU/L (77%), ascitic fluid total protein >3.0 g/dL (73%), ascitic fluid to serum lactic dehydrogenase ratio >0.6 (70%) and ascitic fluid to serum total protein ratio >0.5 (63%)

Diabetic foot osteomyelitis: usefulness of erythrocyte sedimentation rate in its diagnosis

BACKGROUND: Recently, ESR was reported to have a useful diagnostic value in detecting diabetic osteomyelitis. The test has been performed in a limited number of patients. This laboratory parameter is simple and could be routinely performed in developing countries where diabetes and its complication are increasingly being encountered.\ud \ud OBJECTIVE: To evaluate the reliability of erythrocyte sedimentation rate (ESR) in differentiating diabetic osteomyelitis from cellulitis, and to compare its diagnostic value with other hematological indices.\ud \ud METHODS: In a one-year prospective study, forty -three adult diabetic patients with foot ulcers were assessed at King Abdulaziz University Hospital Diabetes Center Riyadh from 1st January to 31st December 2005. ESR was compared with other hematological profiles in differentiating osteomyelitis from cellulitis.\ud \ud RESULTS: ESR, white blood cell count (WBC), platelet count, and red cell distribution width (RDW) were higher in patients with osteomyelitis than in patients with cellulitis (p<0.0001 for ESR; others p<0.05). In contrast, haematocrit and haemoglobin levels were lower in patients with osteomyelitis than in patients with cellulitis (p<0.0001). Overall, the efficiency of the haematological parameters in correctly diagnosing diabetic osteomyelitis from cellulitis was highest for ESR > 70 mm/hr (92%), followed by haematocrit < 36% (89%), haemoglobin < 12 g/dl (85%), platelet count > 400x10(9) (69%), RDW > 14.5 (65%), and WBC >11x10(9) (63%).\ud \ud CONCLUSION: It is concluded that of the haematological parameters, ESR has the best diagnostic discrimination between diabetic foot osteomyelitis from cellulitis. Further studies on larger population in this environment are however indicated

Ascitic lipids and albumin gradient in the differentiation between cirrhotic and malignant ascites in Nigerian Africans

The purpose of this study was to investigate the efficacy of ascitic fluid lipid analysis, and to compare it with albumin gradient and AF total protein in discriminating between cirrhotic ascites and ascites caused by malignancies in Nigerian patients. 40 consecutive ascitic patients, (22 with cirrhotic ascites and 18 with neoplasms metastatic to the peritoneum) were studies prospectively. The roup with liver cirrhosis (LC) consisted of non-alcoholics; 60 percent were hepatitis B surface antigen positive. The patients with malignant ascites comprised four with ovarian carcinoma; three each of lymphoma, gastric and breast carcinoma; two bronchogenic carcinoma; and one each of prostatic, testicular and colon carcinoma. The results show that AF cholesterol provides excellent discrimination between the two types of ascites. Of five diagnostic parameters tested, AF cholesterol gave the best combination of results for the predictive value of a positive test and the predictive value of a negative test. Determination of AF cholesterol and albumin gradient are useful in differentiation ascites caused by malignancies from ascites due to LC. However, AF cholesterol measurement may have considerable advantages in cost effectiveness

Dexamethasone suppression tests in liver cirrhosis - abnormalities in patients with primary hepatocellular carcinoma.

[Extract] Primary hepatocellular carcinoma (PHC), an important cause of morbidity and mortality in many African and Asian countries [1-4], has protean manifestations. Aside from its classical clinical and biochemical presentation, PHC is associated with a variety of paraneoplastic phenomena, including increased erythropoietin production, hypoglycaemia, hypercholesterolaemia and hypercalcaemia [5,6]. The terminal patient with PHC in Nigeria may have a variety of fluid and electrolyte abnormalities, particularly resistant ascites and hypokalaemia

Hydroxyoctadecadienoic acids (HODEs) regulate fatty acid binding protein-4 (FABP4) secretion in human monocytes and macrophages

9-HODE is an oxidation product of linoleic acid (LA, C18:2), is pro-inflammatory, and is a ligand for GPR132 which is involved in atherogenesis. By contrast, 13-HODE is protective and acts through PPARgamma. Plasma FABP4 is increased in diabetes and coronary artery disease. 9-HODE increases FABP4 expression in macrophages. We investigated whether GPR132 is a monocyte activation marker in diabetes, and if it mediates the effect of 9-HODE on FABP4. Monocyte populations from 31 type 2 diabetic patients and controls were studied using FACS. Plasma cytokines were measured using bead arrays and ELISA. THP-1 cells were used to investigate regulation of FABP4 secretion. Diabetic subjects had increased circulating CD14+, CD14+CD36+, CD14+CD11b+, CD14+CD54+ cells (p<0.01), and also increased GPR132 mRNA expression in CD14+ monocytes (p < 0.01). Levels of GPR132 expression did not correlate with any of the above cell populations, or with increased plasma levels of FABP4, sTNF-R, osteoprotegerin, MCP-1, resistin or leptin. FABP4 mRNA expression was markedly increased in both THP-1 monocytes and macrophages (differentiated with 100nM PMA) by 9-HODE and 13-HODE (all p < 0.001). 9-HODE (p < 0.01) and 13-HODE (p < 0.05) also increased GPR132 expression. The stimulatory effect of HODEs was replicated by the PPARgamma agonist rosiglitazone (p<0.001). The PPARgamma antagonist T0070907 decreased the effect of all three ligands (p<0.001). Similar effects on FABP4 protein secretion were documented (ELISA). LA and alpha-linolenic acid (C18:3) were without effect on FABP4 mRNA or protein. GPR132 gene silencing using siRNA had no effect on increased FABP4 expression in response to 9-HODE, 13-HODE, or rosiglitazone. In conclusion, GPR132 is an independent activation marker for monocytes, but does not mediate the increase in FABP4 expression induced by 9-HODE. FABP4 secretion is regulated through PPARgamma. Study of the signaling functions of fatty acids may lead to new treatments for diabetes and atherosclerosis

Hydroxyoctadecadienoic acids (HODEs) increase apoptosis in human THP1 monocytes and macrophages

Certain fatty acids function as signaling molecules. HODEs are stable oxidation products of linoleic acid (LA; C18:2), are abundant in atherosclerotic plaque, and known to signal through GPR132 (9-HODE only) or PPARgamma (9-HODE and 13-HODE). Macrophage apoptosis is an important process, contributing to atherosclerosis progression. Both GPR132 and PPARgamma were expressed in THP1 (RT-PCR and immunohistochemistry) with expression of both increased when cells were differentiated into macrophages (PMA). In 24-hour cultures, 9-HODE but not 13-HODE or LA decreased cell number (68%, p<0.001). We aimed to determine whether this was due to apoptosis and how it was mediated. Using a caspase 3/7 assay, 9-HODE and 13-HODE (30-100mM) but not LA increased caspase activity in monocytes and macrophages, with 9-HODE being more potent (p<0.001). This was accompanied by decreased cell viability (ATP generation assay, both p<0.001). FACS was used to quantify cells that were either viable or apoptotic (7AAD and annexin V positive). There was a time-dependent (over 24 hours) increase in apoptotic cells with 9-HODE and 13-HODE (both p<0.001), with 9-HODE being more potent (p<0.001). The effect of HODEs was replicated with campothecin (10mM) but not with the PPARgamma agonist rosiglitazone (1mM). The pro-apoptotic effects of HODEs were abolished by addition of the caspase inhibitor DEVA-CHO but not affected by the PPARgamma antagonist T0070907. In a gel-based assay, DNA fragmentation was apparent with campothecin and 9-HODE but not with LA or 13-HODE. GPR132 expression was silenced using siRNA oligonucleotides. There was no evidence of decreased effect of either 9-HODE or 13-HODE with GPR132 silencing. In conclusion, HODEs, and particularly 9-HODE, are potent regulators of macrophage apoptosis. They do not appear to be signaling through GPR132 or PPARgamma, both of which have regulatory roles in atherosclerosis. Further study of their mode of action may lead to identification of novel therapeutic targets for atherosclerosis