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  • br Acknowledgements br Introduction Type diabetes


    Introduction Type 2 diabetes is a progressive metabolic disorder which is characterised by chronic hyperglycaemia due to relative insulin deficiency, insulin resistance and increased hepatic glucose production [1]. The metabolism of glucose by glycolysis increases the ATP:ADP ratio which results in the closure of the K+ATP sensitive channels, inducing membrane depolarisation [2] and the opening of voltage gated Ca2+ channels (VGCC) which augments the influx of Ca2+ and raises intracellular Ca2+ concentrations, prompting insulin secretion by exocytosis (Figure 1) [2]. G-protein coupled receptors (GPCRs) play a major role in the regulation of insulin secretion from islet β-cells []. The Gαs subunit activates the adenylyl cyclase pathway by the production of cAMP and binds to the key regulatory molecule protein kinase A (PKA) [4]. Gαi inhibits the adenylyl cyclase pathway and attenuates cAMP production and couples to other secondary messengers including phospholipase C (PLC) and K+ channels [3•, 4]. Gαq potentiates intracellular Ca2+ and PLC through diacylglycerol (DAG) which may activate protein kinase C (PKC) isoforms further downstream (Figure 1) [3•, 4].
    Glucagon-like peptide-1 (GLP-1) The proglucagon gene encodes for GLP-1 which is primarily synthesised by the L-cells of the ileum and colon (Table 1) []. Removal of the first 6 amino AZD 3965 synthesis yields the shorter biologically active GLP-1(7-36)amide and GLP-1(7-37) which have potent insulinotropic properties in response to elevated glucose [6]. GLP-1(7-36)amide and GLP-1(7-37) are degraded by the enzyme dipeptidylpeptidase-4 (DPP-4) to the biologically inactive isoforms GLP-1(9-36)amide and GLP-1(9-37) which are eliminated by the kidneys [7]. GLP-1 signalling in the pancreatic β-cell is regulated through the GLP-1 receptor (GLP-1R) which couples to Gαs thus activating the adenylyl cyclase pathway, producing cAMP to activate PKA (Figure 1) [5•, 8].
    Glucose-dependent insulinotropic polypeptide (GIP) GIP is a 42 amino acid peptide hormone which is released from the K-cells of the duodenum and jejunum of the small intestine in response to glucose, amino acids and lipids []. GIP stimulates glucose-induced insulin secretion, β-cell proliferation and prevents β-cell apoptosis [8]. GIP has an Ala at the penultimate N-terminal position that is a substrate favoured for DPP-4 degradation, which converts GIP(1-42) to the biologically inactive form GIP(3-42) []. The GIP receptor (GIPR,) like the GLP-1R, couples to Gαs activating the adenylyl cyclase pathway with cAMP accumulation and increased intracellular Ca2+, PKA and PKB (Figure 1) [8].
    Glucagon The main physiological function of pancreatic α-cells (15–20% of islet mass) is the secretion of glucagon which increases hepatic glucose production in response to hypoglycaemia [9]. The glucagon receptor once activated couples to Gαs and Gαq subunits resulting in cAMP (PKA) and intracellular Ca2+ (PLC) generation (Figure 1) [8]. Recently, a glucagon receptor antagonist LY2409021 has displayed potent anti-hyperglycaemic potential in type 2 diabetic patients in a phase II clinical trial [10].
    Somatostatin Somatostatin is secreted from pancreatic δ-cells which represents 5% of pancreatic islets and is an inhibitor of insulin secretion acting peripherally on islet cells but not mediated via the CNS [11]. Interestingly, omega-3 fatty acids that activate GPR120, were found to inhibit glucose-stimulated somatostatin secretion from isolated mouse islets []. There are five different human somatostatin receptors (SSTR1, SSTR2, SSTR3, SSTR4, SSTR5) which couple to Gαi proteins inhibiting the adenylyl cyclase pathway, lowering cAMP and intracellular Ca2+ generation [8].
    Pancreatic polypeptide Pancreatic polypeptide (PP) is 36 amino acids in length, synthesised by PP-cells of the islet which forms <2% of islet cell subtypes and is released in response to food intake [13]. PP secretion is augmented by glucose and PP inhibits glucagon release from α-cells via PPYR1 receptors [13]. PP activates Y1, Y2, Y4, Y5 neuropeptide receptors which decreases insulin release and once stimulated couple to Gαi inhibiting cAMP accumulation [8].