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Introduction In type 1 or type 2 diabetes mellitus, an absolute or relative deficiency of functional pancreatic [beta] cells underlies disease pathogenesis. Thus, investigations are focused on identifying native signaling [...], Inadequate pancreatic [beta] cell function underlies type 1 and type 2 diabetes mellitus. Strategies to expand functional cells have focused on discovering and controlling mechanisms that limit the proliferation of human [beta] cells. Here, we developed an engraftment strategy to examine age-associated human islet cell replication competence and reveal mechanisms underlying age-dependent decline of [beta] cell proliferation in human islets. We found that exendin-4 (Ex-4), an agonist of the glucagon-like peptide 1 receptor (GLP-1R), stimulates human [beta] cell proliferation in juvenile but not adult islets, This age-dependent responsiveness does not reflect loss of GLP-1R signaling in adult islets, since Ex-4 treatment stimulated insulin secretion by both juvenile and adult human [beta] cells. We show that the mitogenic effect of Ex-4 requires calcineurin/nuclear factor of activated T cells (NFAT) signaling. In juvenile islets, Ex-4 induced expression of calcineurin/ NFAT signaling components as well as target genes for proliferation-promoting factors, including NFATC1, FOXM1, and CCNA1. By contrast, expression of these factors in adult islet [beta] cells was not affected by Ex-4 exposure. These studies reveal age-dependent signaling mechanisms regulating human [beta] cell proliferation, and identify elements that could be adapted for therapeutic expansion of human [beta] cells.

Introduction Glucagon-like peptide-1 (GLP1) is a peptide produced both by intestinal enteroendocrine cells and a discrete population of hindbrain neurons. GLP1 acts through a G-protein-coupled receptor (GLP1R) expressed on pancreatic [...], Glucose control and weight loss are cornerstones of type 2 diabetes treatment. Currently, only glucagon-like peptide-1 (GLP1) analogs are able to achieve both weight loss and glucose tolerance. Both glucose and body weight are regulated by the brain, which contains GLP1 receptors (GLP1R). Even though the brain is poised to mediate the effects of GLP1 analogs, it remains unclear whether the glucose- and body weight-lowering effects of long-acting GLP1R agonists are via direct action on CNS GLP1R or the result of downstream activation of afferent neuronal GLP1R We generated mice with either neuronal or visceral nerve-specific deletion of Glp1r and then administered liraglutide, a long-acting GLP1R agonist. We found that neither reduction of GLP1R in the CNS nor in the visceral nerves resulted in alterations in body weight or food intake in animals fed normal chow or a high-fat diet. Liraglutide treatment provided beneficial glucose-lowering effects in both chow- and high-fat-fed mice lacking GLP1R in the CNS or visceral nerves; however, liraglutide was ineffective at altering food intake, body weight, or causing a conditioned taste aversion in mice lacking neuronal GLP1R These data indicate that neuronal GLP1Rs mediate body weight and anorectic effects of liraglutide, but are not required for glucose-lowering effects.

THE DIABETES Control and Complications Trial (National Institute of Diabetes and Digestive and Kidney Diseases 1994) established a strong link between [HbA.sub.1c] and the risk of long-term complications. The trial [...], Glucagon has been prescribed routinely on diagnosis of paediatric type 1 diabetes. A forum of paediatric diabetes specialist nurses sought to examine whether this practice is evidence based. Forum members audited their own caseloads, including the families and carers, their professional practices and those of other teams nationally. It was found that the prescription of glucagon varies and its use is often limited by lack of confidence. They found little evidence to support routine prescription on diagnosis and recommend that individual case assessment of risk and of the needs and preferences of families and carers would be more cost effective. Families and carers who do acquire a glucagon injection kit should receive regular training in its use. Keywords Glucagon injection, paediatric type 1 diabetes, training of caters

Introduction In individuals with type 1 diabetes, hypoglycemia is a common consequence of overinsulinization. The incidence of hypoglycemia is less frequent in individuals with type 2 diabetes, but as the [...], In individuals with type 1 diabetes, hypoglycemia is a common consequence of overinsulinization. Under conditions of insulin-induced hypoglycemia, glucagon is the most important stimulus for hepatic glucose production. In contrast, during euglycemia, insulin potently inhibits glucagon's effect on the liver. The first aim of the present study was to determine whether low blood sugar augments glucagon's ability to increase glucose production. Using a conscious catheterized dog model, we found that hypoglycemia increased glucagon's ability to overcome the inhibitory effect of insulin on hepatic glucose production by almost 3-fold, an effect exclusively attributable to marked enhancement of the effect of glucagon on net glycogen breakdown. To investigate the molecular mechanism by which this effect comes about, we analyzed hepatic biopsies from the same animals, and found that hypoglycemia resulted in a decrease in insulin signaling. Furthermore, hypoglycemia and glucagon had an additive effect on the activation of AMPK, which was associated with altered activity of the enzymes of glycogen metabolism.

Hepatic glucagon action increases in response to accelerated metabolic demands and is associated with increased whole body substrate availability, including circulating lipids. The hypothesis that increases in hepatic glucagon action stimulate AMP-activated protein kinase (AMPK) signaling and peroxisome proliferator-activated receptor-[alpha] (PPAR[alpha] and fibroblast growth factor 21 (FGF21) expression in a manner modulated by fatty acids was tested in vivo. Wild-type ([gcgr.sup.+/+]) and glucagon receptor-null ([gcgr.sup.-/-]) littermate mice were studied using an 18-h fast, exercise, and hyperglucagonemic-euglycemic clamps plus or minus increased circulating lipids. Fasting and exercise in [gcgr.sup.+/+], but not [gcgr.sup.-/-] mice, increased hepatic phosphorylated AMPK[alpha] at threonine 172 ([MATHEMATICAL EXPRESSION NOT REPRODUCIBLE IN ASCII]) and PPAR[alpha] and FGF21 mRNA. Clamp results in [gcgr.sup.+/+] mice demonstrate that hyperlipidemia does not independently impact or modify glucagon-stimulated increases in hepatic AMP/ATP, [MATHEMATICAL EXPRESSION NOT REPRODUCIBLE IN ASCII], or PPAR[alpha] and FGF21 mRNA. It blunted glucagon-stimulated acetyl-CoA carboxylase phosphorylation, a downstream target of AMPK, and accentuated PPAR[alpha] and FGF21 expression. All effects were absent in [gcgr.sup.-/-] mice. These findings demonstrate that glucagon exerts a critical regulatory role in liver to stimulate pathways linked to lipid metabolism in vivo and shows for the first time that effects of glucagon on PPARa and FGF21 expression are amplified by a physiological increase in circulating lipids. adenosine 5'-monophosphate-activated protein kinase; peroxisome proliferator-activated receptor-[alpha]; fibroblast growth factor 21 doi: 10.1152/ajpendo.00263.2010.

Byline: E. Hazouard (1), M. Ferrandiere (1), V. Lesire (1), F. Joye (1), D. Perrotin (1), B. de Toffol (2) Author Affiliation: (1) Reanimation medicale, CHU Bretonneau, 2 boulevard Tonnelle, F-37 044 Tours cedex 1, France Tel. + 3 32 47 47 37 18 Fax + 3 32 47 39 65 36, FR (2) Clinique de Neurologie, CHU Bretonneau, 2 boulevard Tonnelle, F-37 044 Tours cedex 1, France, FR Article note: Received: 28 August 1998 Accepted: 10 December 1998