Glucagon—New Concepts About an "Old" Hormone

Summary: Recent technical advances have led to a great increase in information regarding the role of glucagon in normal human physiology and in diabetes. In man, physiological actions appear to be limited to stimulation of hepatic glycogenolysis, gluconeogenesis, and possibly ketogenesis. Glucagon plays an important role (with insulin) to maintain basal hepatic glucose output and acts synergistically with catecholamines and Cortisol as a counter-regulatory hormone in preventing hypoglycaemia. On the other hand glucagon is relatively unimportant (in contrast to insulin) in the assimilation of a glucose or carbohydrate load. Glucagon secretion is mainly controlled by the nervous system, both sympathetic and parasympathetic. Nervous control of the pancreatic A (glucagon-releasing) cell is in turn modulated by plasma concentrations of glucose and other substrates and by hormonal influences. Circulating “glucagon” consists of several different peptides of varying molecular weight and differing biological activity. Also “glucagon” may be secreted by tissues other than the pancreas. Both the liver and kidney are important sites of metabolism of the various “glucagons”. Glucagon levels are raised in human diabetes mellitus. It appears that the hyper-glucagonaemia in human diabetes is secondary to the diabetic state, rather than a primary defect of the A cell. Glucagon may accentuate hyperglycaemia and ketogenesis but is not essential for the development of the diabetic state. A clinical syndrome of excess glucagon production from an islet cell tumour (glucagonoma) has recently been defined. Diabetes, though common, is not always present and the most prominent clinical feature is an unusual skin rash, migratory necrolytic erythema. Pharmacological doses of glucagon have a wide range of effects in humans. In addition to treating hypoglycaemia, glucagon may be used as an inotropic cardiac stimulant, or to inhibit gastrointestinal motility during endoscopy. Other suggested uses are mainly related to tests of endocrine function.     

Variants in the cholesterol ester transfer protein and lipoprotein lipase genes are predictors of plasma cholesterol response to dietary change

There are no definitive explanations as to why individuals with hypercholesterolemia, a major cardiovascular risk factor, respond differently to dietary change. Fifty five free-living individuals completed a double crossover trial with two dietary regimens, a high saturated fat diet (providing 21% energy from saturated fat and 3% energy from polyunsaturated fat) and a high polyunsaturated fat diet (providing 11% energy as saturated fat and 10% energy as polyunsaturated fat), each phase continuing for 4 weeks. Extensive genotyping and several measures of dietary compliance have provided further insights regarding the determinants of extent of cholesterol response to changes in the nature of dietary fat. Individuals with the CETP B1B1 genotype and the LPL X447+ allele showed an average 0. 44 (95% CI: 0.22, 0.66) and 0.45 (95% CI: 0.18, 0.72) mmol/l greater change in total cholesterol, respectively, than those with one or more CETP B2 allele or homozygous for the LPL S447 allele when comparing diets high and low in saturated fat. Indices of dietary compliance including changes in reported saturated and polyunsaturated fat intake and change in triglyceride linoleate were not significantly different between the CETP genotypes. Change in reported saturated (r=0.36, P=0.04) and polyunsaturated (r=0.22, P=0. 05) fat intake and change in triglyceride linoleate (reflecting polyunsaturated fat intake) (r=0.21, P=0.07), also predicted total cholesterol response to dietary fat changes. In multivariate analyses, variation in the cholesterol ester transfer protein and lipoprotein lipase genes predicted response independent of measures of dietary compliance, suggesting that these two genes are important determinants of variation in cholesterol response to dietary change in free-living individuals.     

Isocaloric substitution of plant sterol-enriched fat spread for carbohydrate-rich foods in a low-fat, fibre-rich diet decreases plasma low-density lipoprotein cholesterol and increases high-density lipoprotein concentrations

BACKGROUND AND AIM: The aim of the study was to determine the effects on plasma cholesterol of replacing a plant sterol-enriched fat spread with carbohydrate-rich foods relative to a diet high in saturated fat. METHODS AND RESULTS: Twenty-nine men and women, from the general community, with mean age (SD) 48 (14)y, body mass index 29.0 (6.2)kg/m(2), and plasma total cholesterol concentration 6.48 (0.97)mmol/L completed the randomised, crossover dietary intervention. There were three diets: New Zealand diet (NZ diet) high in total (34%kJ) and saturated (15%kJ) fat, a cholesterol-lowering fibre-rich diet reduced in total (30%kJ) and saturated fat (8%kJ) but including a plant sterol spread (PS diet), and the same cholesterol-lowering diet with the plant sterol spread isocalorically replaced with carbohydrate (CHO diet); total fat, 26%kJ; saturated fat 7%kJ. All foods were provided and each diet was followed for four weeks. Mean (SD) plasma low-density lipoprotein cholesterol concentration declined from 4.68 (0.91)mmol/L on the high saturated fat diet to 4.12 (0.83)mmol/L (P<0.001) on the carbohydrate diet and 3.76 (0.84)mmol/L (P<0.001) on the plant sterol diet. The 20% decrease on the plant sterol diet was significantly greater (P<0.001) than the 12% decrease on the carbohydrate diet. Relative to the NZ diet, mean (95% CI) plasma high-density lipoprotein cholesterol concentration changed by -0.11 (-0.16, -0.06)mmol/L on the CHO diet but was not different at the end of the PS diet, -0.03 (-0.09, 0.02). CONCLUSION: Including a plant sterol-enriched fat spread in a cholesterol-lowering diet produces a more favourable plasma lipid profile than the same diet made lower in total and saturated fat by replacing the spread with carbohydrate-rich foods.     

Signaling by N- and C-terminal sequences of parathyroid hormone-related protein in hippocampal neurons.

Parathyroid hormone-related protein (PTHrP) is synthesized in the brain, and a single type of cloned receptor for the N-terminal portion of PTHrP and PTH is present in the central nervous system. Nothing is known about the physiological actions or signaling pathways used by PTHrP in the brain. Using cultured rat hippocampal neurons, we demonstrate that N-terminal PTHrP[1-34] and PTH[1-34] signal via cAMP and cytosolic calcium transients. The cAMP response showed strong acute (< or = 6 h) homologous and heterologous desensitization after preincubation with PTHrP or PTH. In contrast, the acute calcium response did not desensitize after preincubation with PTHrP; in fact, preincubation dramatically recruited additional responsive neurons. Unexpectedly, C-terminal PTHrP[107-139], which does not bind or activate the cloned PTH/PTHrP receptor, signaled in neurons via cytosolic calcium but not cAMP. Although some neurons responded to both PTHrP[1-34] and PTHrP[107-139], others responded only to PTHrP[1-34]. We conclude that certain hippocampal neurons exhibit dual signaling in response to PTHrP[1-34] and that some neurons have a receptor for C-terminal PTHrP that signals only via cytosolic calcium.     

Variations in non-pharmacological anti-infective measures in childhood leukemia - results of an international survey

Background Standardization in clinical practice may lead to improved outcomes. Unfortunately, little is known about the variability of non-pharmacological anti-infective measures in children with cancer. DESIGN AND METHODS: A web-based survey assessed institutional recommendations regarding restrictions of social contacts, pets and food and instructions on wearing face masks in public for children with standard- risk acute lymphoblastic leuk emia and acute myeloid leukemia during intensive chemotherapy. RESULTS: A total of 336 institutions in 27 countries responded to the survey (range, 1-76 institutions per country; overall response rate 61%). Most institutions recommend that patients with acute myeloid leukemia avoid indoor public places and daycare, kindergarten and school, whereas recommendations for patients with acute lymphoblastic leukemia differ considerably by institution. In terms of restrictions related to pets, there was a wide variability between institutions for both acute lymphoblastic and acute myeloid leukemia patients. Most, but not all institutions do not allow children with either acute lymphoblastic or acute myeloid leukemia to eat raw meat, raw seafood or unpasteurized milk. Whereas most institutions do not routinely recommend that patients with acute lymphoblastic leukemia wear face masks in public, advice on this matter varies for patients with acute myeloid leukemia. Conclusions The survey demonstrates that there is a wide variation in recommendations on non-pharmacological anti-infective measures between different institutions, countries and continents. This information may be used to encourage harmonization of supportive care practices and future clinical trials.     

The diagnostic value of fine needle aspiration in parotid lumps

Introduction

Fine needle aspiration (FNA) is a safe and quick method of diagnosing superficial lumps, which aids preoperative planning. However, FNA of the parotid gland has not gained the widespread acceptance noted in other head and neck lumps. The aim of this study was to determine the ability of FNA of the parotid gland to differentiate benign and malignant disease, and to determine the impact on surgical outcome.

Methods

A retrospective analysis of 201 consecutive parotid operations with preoperative FNA in a large district hospital in the UK was performed. The diagnostic characteristics were calculated for benign and malignant disease, and the impact on surgical procedure was determined.

Results

In identifying benign disease, FNA has a sensitivity of 85% and a specificity of 76%. In detecting malignant disease, FNA has a sensitivity and specificity of 52% and 92% respectively. A false positive on FNA was associated with a higher incidence of neck dissection.

Conclusions

FNA is a useful diagnostic test. However, owing to low sensitivity, it is necessary to interpret it in the context of all other clinical information.     

Effects of losartan on whole body, skeletal muscle and vascular insulin responses in obesity/insulin resistance without hypertension

Aims: Renin‐angiotensin system antagonists have been found to improve glucose metabolism in obese hypertensive and type 2 diabetic subjects. The mechanism of these effects is not well understood. We hypothesized that the angiotensin receptor antagonist losartan would improve insulin‐mediated vasodilation, and thereby improve insulin‐stimulated glucose uptake in skeletal muscle of insulin‐resistant subjects. Methods: We studied subjects with obesity and insulin resistance but without hypertension, hypercholesterolaemia or dysglycaemia [age 39.0 ± 9.6 yr (mean ± SD), body mass index (BMI) 33.2 ± 5.9 kg/m², BP 115.8 ± 12.2/70.9 ± 7.2 mmHg, LDL 2.1 ± 0.5 mmol/l]. Subjects were randomized to 12 weeks' double‐blind treatment with losartan 100 mg once daily (n = 9) or matching placebo (n = 8). Before and after treatment, under hyperinsulinaemic euglycaemic clamp conditions we measured whole‐body insulin‐stimulated glucose disposal, insulin‐mediated vasodilation, and insulin‐stimulated leg glucose uptake by the limb balance technique. Results: Whole‐body insulin‐stimulated glucose disposal was not significantly increased by losartan. Insulin‐mediated vasodilation was augmented following both treatments [increase in leg vascular conductance: pretreatment 0.7 ± 0.3 l/min/mmHg (losartan, mean ± SEM) and 0.9 ± 0.3 (placebo), posttreatment 1.0 ± 0.4 (losartan) and 1.3 ± 0.6 (placebo)] but not different between treatment groups (p = 0.53). Insulin's action to augment nitric oxide (NO) production and to augment endothelium‐dependent vasodilation was also not improved. Leg glucose uptake was not significantly changed by treatments, and not different between groups (p = 0.11). Conclusions: These findings argue against the hypothesis that losartan might improve skeletal muscle glucose metabolism by improving insulin‐mediated vasodilation in normotensive insulin‐resistant obese subjects. The metabolic benefits of angiotensin receptor blockers may require the presence of hypertension in addition to obesity‐associated insulin resistance.     

Cases of antiretroviral-associated gynaecomastia reported to the National HIV &amp; Tuberculosis Health Care Worker Hotline in South Africa

Background

Gynaecomastia is associated with exposure to antiretroviral therapy (ART), in particular efavirenz. There is limited data on clinical characteristics of patients with ART-associated gynaecomastia in resource-limited settings and little guidance on the optimal management of this adverse drug reaction (ADR). We describe the clinical characteristics, management and outcomes of gynaecomastia cases reported to the National HIV & Tuberculosis Health Care Worker Hotline in South Africa.

Methods

We identified all gynaecomastia cases in adolescent boys and men on ART reported to the hotline between June 2013 and July 2014. We collected follow up data telephonically at monthly intervals to document clinical management and outcomes.

Results

We received 51 reports of gynaecomastia between June 2013 and July 2014; 11% of the 475 patient-specific ADR queries to the hotline. All patients were on efavirenz-based ART. Mean age was 34 years (standard deviation 12) and seven were adolescents. The median onset of gynaecomastia was 15 months after efavirenz initiation (interquartile range 6–42). Gynaecomastia was bilateral in 29 patients (57%) and unilateral in 16 (31%). Serum testosterone was quantified in 25 of 35 patients with follow up data, and was low in 2 (8%). Efavirenz was replaced with an alternative antiretroviral in 29/35 patients (83%) and gynaecomastia improved in 20/29 (69%).

Conclusions

Gynaecomastia was a frequently reported ADR in our setting, occurring with prolonged efavirenz exposure. Testosterone was low in the minority of tested cases. Most clinicians elected to switch patients off efavirenz, and gynaecomastia improved in the majority.

     

The effects of ‘activating’ almonds on consumer acceptance and gastrointestinal tolerance

Purpose

Recommendations to soak nuts prior to consumption to reduce phytate concentrations and improve gastrointestinal tolerance have received much attention in the popular press. This is despite no supporting scientific evidence for the practice. There is also a lack of information about how soaking nuts might affect consumer acceptability. This study primarily assessed the effects of soaking almonds on consumer acceptance and secondly assessed effects on gastrointestinal tolerance.

Methods

In this 8-week randomised crossover trial, 76 participants were allocated in balanced order to receive 30 g/day of four different preparations of almonds for 12 days: whole unsoaked, whole soaked, sliced unsoaked, and sliced soaked. Ratings of overall liking, desire to consume, and likelihood of future consumption, and severity of gastrointestinal symptoms were measured daily on visual analogue scales. The phytate concentrations were measured in all four nut types using high-performance liquid chromatography.

Results

Mean acceptance ratings of all nut types were above the neutral point indicating they were acceptable. However, sliced soaked almonds were rated significantly lower overall for all three acceptance scales compared to the other treatments (all P ≤ 0.003). The sliced unsoaked almonds were rated lower than both whole nut treatments (all P ≤ 0.006), while there were no significant differences between the two whole nut treatments (all P ≥ 0.511). Gastrointestinal symptoms were minimal, but flatulence was rated significantly higher for all time points combined for soaked whole nuts compared to unsoaked whole nuts (P = 0.005). Compared to the whole unsoaked nuts (mean [SD] 531 [9] mg/100 g), phytate concentration was higher for the whole soaked almonds (563 [38] mg/100 g, P = 0.016), with no evidence of a difference for the sliced soaked almonds (548 [27] mg/100 g, P = 0.197) and no difference between the soaked forms (P = 0.262).

Conclusions

This research supports previous results suggesting nuts, including different forms, are an acceptable food. They are also well tolerated gastrointestinally, but soaking does not improve gastrointestinal tolerance or acceptance as claimed in the lay literature.