sirolimus and exendin-(9-39)

Hyperinsulinemic hypoglycemia (HI) is the most common cause of hypoglycemia in children. Impairment of cellular pathways involved in insulin secretion from pancreatic β-cells, broadly classified as channelopathies and metabolopathies, have been discovered in the past two decades. The increasing use of NGS target panels, combined with clinical, biochemical and imaging findings allows differentiating the diagnostic management of children with focal forms, surgically curable, from those with diffuse forms, more conservatively treated with pharmacological and nutritional interventions. Specific approaches according to the subtype of HI have been established and novel therapies are currently under investigation. Despite diagnostic and therapeutic advances, HI remains an important cause of morbidity in children, still accounting for 26-44% of permanent intellectual disabilities, especially in neonatal-onset patients. Initial insult from recurrent hypoglycemia in early life greatly contributes to the poor outcomes. Therefore, patients need to be rapidly identified and treated aggressively, and require at follow-up a complex and regular monitoring, managed by a multidisciplinary HI team. This review gives an overview on the more recent diagnostic and therapeutic tools, on the novel drug and nutritional therapies, and on the long-term neurological outcomes.

Topics: Adenosine Triphosphate; Animals; Child; Child, Preschool; Congenital Hyperinsulinism; Diet, Ketogenic; Galactose; Glucagon; Humans; Hypoglycemia; Infant; Insulin; Insulin Secretion; Insulin-Secreting Cells; Mice; Nervous System Diseases; Peptide Fragments; Potassium Channels; Receptor, Insulin; Sirolimus; Somatostatin; Treatment Outcome

Glucagon-like peptide-1 (GLP-1) controls glucose metabolism in extrapancreatic tissues participating in glucose homeostasis, through receptors not associated to cAMP. In rat hepatocytes, activation of PI3K/PKB, PKC and PP-1 mediates the GLP-1-induced stimulation of glycogen synthase. We have investigated the effect of GLP-1 in normal human myocytes, and that of its structurally related peptides exendin-4 (Ex-4) and its truncated form 9-39 (Ex-9) upon glucose uptake, and the participation of cellular enzymes proposed to mediate insulin actions. GLP-1 and both exendins activated, like insulin, PI3K/PKB and p42/44 MAPK enzymes, but p70s6k was activated only by GLP-1 and insulin. GLP-1, Ex-4 and Ex-9, like insulin, stimulated glucose uptake; wortmannin blocked the action of GLP-1, insulin and Ex-9, and reduced that of Ex-4; PD98059 abolished the effect of all peptides/hormones, while rapamycin blocked that of insulin and partially prevented that of GLP-1. H-7 abolished the action of GLP-1, insulin and Ex-4, while Ro 31-8220 prevented only the Ex-4 and Ex-9 effect. In conclusion, GLP-1, like insulin, stimulates glucose uptake, and this involves activation of PI3K/PKB, p44/42 MAPKs, partially p70s6k, and possibly PKC; Ex-4 and Ex-9 both have GLP-1-like effect upon glucose transport, in which both share with GLP-1 an activation of PI3K/PKB--partially in the case of Ex-4--and p44/42 MAPKs but not p70s6k.

Topics: 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; Aged; Aged, 80 and over; Androstadienes; Biological Transport; Cells, Cultured; Enzyme Activation; Exenatide; Female; Flavonoids; Glucagon; Glucagon-Like Peptide 1; Glucose; Humans; Indoles; Insulin; Male; Mitogen-Activated Protein Kinase 1; Mitogen-Activated Protein Kinase 3; Muscle Cells; Peptide Fragments; Peptides; Phosphatidylinositol 3-Kinases; Phosphoinositide-3 Kinase Inhibitors; Protein Kinase C; Protein Precursors; Protein Serine-Threonine Kinases; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-akt; Ribosomal Protein S6 Kinases, 70-kDa; Signal Transduction; Sirolimus; Venoms; Wortmannin