The serum glucose response to glucagon suppression with somatostatin,insulin or antiglucagon serum in depancreatized rats

Summary Total immunoreactive glucagon (IRG) and immunoreactive glucagon of A cell origin (IRG_a) were measured in the serum of normal, sham-operated and depancreatized rats, after the administration of three glucagon antagonists: insulin (5–200 mU/rat/h), somatostatin (SRIF; 100 g/kg/h) and antiglucagon serum (AGS, enough to bind three times the calculated total amount of circulating IRG). Since no differences were noted between the responses of normal and sham-operated animals, the values were pooled and used as controls. Pancreatectomy caused a significant increase in serum glucose, IRG_a and total IRG and a significant decrease in serum insulin. AGS and SRIF significantly decreased serum glucose in control, but not in depancreatized rats, even though SRIF caused a significant decrease of IRG_a in all animals. SRIF significantly decreased plasma insulin in control rats, but did not modify total IRG secretion in either group. In control rats the minimum effective hypoglycaemic dose of insulin (5 mU/rat/h) may have decreased serum IRG_a, but not total IRG. At higher doses (20 mU/rat/h) insulin stimulated glucagon secretion. In depancreatized animals, higher doses of insulin (200 mU/rat/h) were needed to lower serum glucose. On the other hand, a dose of 100 U/rat/h was sufficient to lower the serum IRG. We conclude that although hyperglucagonaemia may contribute to the hyperglycaemia of the untreated depancreatized rats, the excessive secretion of glucagon is secondary to insulin insufficiency and that, at least in this animal model, the hypoglycaemic action of insulin is only minimally dependent upon its ability to suppress glucagon secretion.     

The role of calcium in glucagon release,interactions between glucose and calcium

Summary The interrelationships between glucose and calcium in glucagon release were investigated using the dynamic system of the in vitro perfused rat pancreas. When calcium deprivation was induced in the presence of fixed concentrations of glucose prevailing throughout the experiments (3.3, 5.5, 8.3 and 16.6 mM), an enhancement of glucagon release invariably occurred, the shape and amplitude of such response differing in relation to the environmental glucose concentration. Such enhancement of glucagon release was readily reversible upon restoration of normal calcium levels. By contrast, during the period of calcium deprivation itself, glucagon release was little influenced by either raised (from 3.3 to 16.6 mM) or decreased (from 16.6 to 3.3 mM) glucose concentrations. These results clearly indicate that calcium plays, at least, a dual role — both inhibitory and permissivein glucagon secretion, but the intimate mechanisms by which calcium exerts such a dual action are at present unknown.     

Islets and pancreatic ductal adenocarcinoma – An opportunity for translational research from the ‘Bench to the Bedside’

The islet-acinar axis is of prime importance to the optimal functioning of the human pancreas. Not only is this inter-relationship important for normal physiological processes, it is also relevant in diseased states, including chronic pancreatitis and pancreatic ductal adenocarcinoma (PDAC). Early experiments, nearly 4 decades ago, explored the role of islets in the development and progression of PDAC. These led to further studies that provided compelling evidence to support the role of islets and their hormones in PDAC. This association presents oncologists with therapeutic options not only for managing, but potentially preventing PDAC, a cancer that is well known for its poor patient outcomes. This review will discuss the accumulated evidence regarding the role of islets and their hormones in PDAC and highlight areas for future research.     

Next generation immunohistochemistry: Emerging substitutes to genetic testing?

The identification of at-risk kindreds facilitates screening and risk reduction strategies for patients with hereditary cancer predisposition syndromes. Recently, immunohistochemistry (IHC) has emerged as a cost-effective strategy for detecting or inferring the presence of mutations in both tumors and the germline of patients presenting with tumors associated with hereditary cancer predisposition syndromes. In this review we discuss the use of novel IHC markers, including PRKAR1A, β-catenin, SDHB, fumarate hydratase and 2SC, HRASQ61R, BAP1, parafibromin and glucagon, which have either established applications or show promise for surgical pathologists to complement morphological or clinical suspicion of hereditary cancer predisposition syndromes. Specifically, we focus on Carney complex, familial adenomatous polyposis (FAP)-associated cribriform-morular variant of papillary thyroid carcinoma, familial succinate dehydrogenase-related pheochromocytoma/paraganglioma syndromes, hereditary leiomyomatosis and renal cell cancer (HLRCC), medullary thyroid cancer and Multiple Endocrine Neoplasia 2 (MEN2), BAP1 hereditary cancer predisposition syndrome, Hyperparathyroidism-Jaw Tumor Syndrome (HPT-JT), and Pancreatic Neuroendocrine Tumor Syndrome (Mahvash disease).     

Nonobese Diabetic (NOD) Mouse Dendritic Cells Stimulate Insulin Secretion by Prediabetic Islets

In the Nonobese diabetic (NOD) mouse, a spontaneous model of type 1 diabetes, the pathogenic process is classically thought to start at 3-4 weeks of age with an accumulation of antigen-presenting cells (APC), especially CD11c⁺ dendritic cells (DC), around the pancreatic islets of Langerhans. Concomitantly, hyperinsulinemia and slight hyperglucagonemia are observed, which may be either the cause or consequence of the initial APC infiltration. To determine whether infiltrating DC can affect islet activity in control (C57BL/6) and NOD mice, we performed experiments in which islets and DC were isolated and co-cultured. We first showed that, immediately after isolation, islets from 8-week-old prediabetic NOD mice had significantly higher insulin and glucagon contents than those from C57BL/6 controls. Moreover, as is the case in vivo, prediabetic NOD mouse islets secrete more insulin in vitro at 11.1 mM glucose than C57BL/6 ones. In DC-islet co-cultures, insulin secretion was significantly increased for NOD mice only, while that of glucagon was not significantly affected. These findings indicate that NOD DC are good candidates for stimulating the NOD mouse &#103 -cell hyperactivity that is observed both in vivo and in vitro, and might, consequently, sensitize NOD islets to an autoimmune attack.     

A comparative study of the role of crocin and sitagliptin in attenuation of STZ-induced diabetes mellitus and the associated inflammatory and apoptotic changes in pancreatic β-islets

Type 1 diabetes mellitus (T1DM) describes a complex group of metabolic disorders associated with elevated blood glucose levels and increased risks of complications development. Exploring new drug therapies would reduce the increased diabetes-associated morbidity and mortality and will reduce the excessive health care costs. Crocin is the major active ingredient of saffron. In the current study, DM was induced by single intraperitoneal injection of streptozocin (50 mg/kg).DM progression was associated with a significant increase in blood glucose level with reduced insulin and increased glucagon secretion. Pancreatic malondialdehyde (MDA) content significantly escalated, while superoxide dismutase (SOD) activity, reduced glutathione (GSH) concentration, catalase activity, thioredoxin level and serum total antioxidant capacity significantly declined. This was associated with a significant increase in pancreatic caspase-3 contents and pancreatic infiltration with inflammatory cells in β-islets. Both sitagliptin and crocin significantly reduced blood glucose levels, enhanced pancreatic insulin expression and secretion and suppressed glucagon secretion with enhancement of anti-oxidant defenses and reduction of oxidative burden, with evident anti-inflammatory impacts. Interestingly, the effect of crocin on DM indices, inflammatory and apoptotic changes was comparable to that of sitagliptin; the standard oral hypoglycemic agent. Nevertheless, crocin had a superior effect compared to sitagliptin on blood sugar level, β-islets diameter and insulin immune-reactivity. In conclusion, crocin reduced blood glucose level mainly via reduction of oxidative burden, modulation of apoptotic pathway and attenuation of pancreatic inflammation.     

Relative insensitivity to glucagon of sterol synthesis in cultured rat aortic smooth muscle cells

Summary The smooth muscle cell plays an important role in the process of atherogenesis. In these experiments the effect of glucagon and dibutyryl cyclic AMP on sterol synthesis in cultured rat arterial smooth muscle cells was studied. Glucagon in concentrations of 1×10⁻⁹ mol/l inhibited the incorporation of sodium (2−¹⁴C)acetate into non-saponifiable lipids and digitonin precipitable sterols but lower concentrations of glucagon had no effect. In cells which were exposed to serum, dibutyryl cyclic AMP also resulted in a decrease in the incorporation of labelled acetate into sterols but when the cells were grown in serum free medium, dibutyryl cyclic AMP had no inhibitory effect on sterol synthesis. These results provide further evidence that sterol metabolism in arterial smooth cells may be influenced by hormones but suggest that glucagon is relatively less important than insulin in this respect.     

The nuclear bile acid receptor FXR is a PKA- and FOXA2-sensitive activator of fasting hepatic gluconeogenesis

1. Download high-res image (127KB)
2. Download full-size image