长期以来,胰岛β-细胞和胰岛素一直是糖代谢平衡调节和糖尿病发病与防治研究的“主角”。近年来由于细胞生物学和分子生物学的发展,提出胰腺α-细 胞在β-细胞的生长和胰岛素的分泌调节中,可能起着十分重要的作用。α-细胞可以产生和分泌两种不同的激素—Glucagon和GLP-1,前者可以抑制 β-细胞的生长和调节胰岛素分泌,升高血糖;后者则可促进β-细胞的增殖、存活和胰岛素分泌,降低血糖。他们是胰岛β-Cell和胰岛素的主要调节者,可 能是糖尿病发病和防治的重要靶点。一个以GLP-1为中心的α-细胞新时代正向我们阔步走来——Alpha Cells Come of Age:
目前GLP-1及其受体激动剂已经在临床用于防治II型糖尿病、肥胖症和一些心血管病。其中进入III期临床试验有 Exenatide、Lixisenatide、Taspoglutide和Liragluide;进入II期临床试验的有Albiglutide、 Semagluide和Exendin-4等,正在临床I期试验的有NN9068和NN9924等。但是GLP-1在体内极易被DPP-4酶所降解,半衰 期极短,亦难以口服,多需静脉注射。DPP-4抑制剂可以有效抑制GLP-1降解,还可以充分发挥内源性GLP-1的作用。此外,DPP-4抑制剂,还有 延长VIP、BNP、SDF-1a等活性多肽半衰期的作用,可促进血管活性多肽的促血管生成和细胞保护作用,现已在临床试用於糖尿病、急性冠脉综合症和心 功能不全等心血管病。主要的DPP-4抑制剂有Saxagliptin、Alogliptin、Sitagliptin、Linagliptin和 Vildagliptin等,且多可口服。此外,一些胰高血糖素受体拮抗剂和阻断剂,如BAY-27-905、MK-0893、LY-2409021等亦 已在临床试用。这为糖尿病和心血管病的防治开辟了一个新的有效途径。但是,这些药物的选择性、联合用药、确切疗效、毒付作用和远期效果,还需进一步观察。
糖尿病和心血管病有着密切的关系,它们都是代谢性炎症免疫性疾病,有着共同的复杂的发病机理。在继胰岛β-细胞和胰岛素以后,GLP和α-细胞又为我们提供了一个新的思路和途径。但是这还是初步的,更深入的作用和机理还需我们进一步研究:其主要问题有:
这些都是一个个复杂的相互调控的网络系统,都需要我们进行系统的分析。组织不同、细胞不同、条件不同、受体不同、信号途径不同,其作用也不相同。无论α-细胞,还是β-细胞,都需要我们应用整合医学和转化医学的概念、理论和方法,进行系统的组学研究,才能真正了解代谢性心血管病和糖尿病的发病机理,才能寻找到有效的防治措施。
Pancreatic islet cells——GLP-1: functional pancreatic effects
Putative paracrine and autocrine pathways in human pancreatic islets
Pathways of differentiation of the pancreatic endocrine lineage during development and during regeneration of beta cells in the adult mouse
The Formation of New Insulin-Producing Beta Cells in the Adult Pancreas
Role of islet transcription factors in endocrine differentiation in the developing pancreas
Differentiation of hES cells to maturing endocrine cells
the hierarchical activation of genes involved in islet endocrine cell subtypes specification
Pancreatic β Cell Dedifferentiation as a Mechanism of Diabetic β Cell Failure
Transcription factors important for pancreatic α-cell development
The structure and processing of proglucagon
Summary of effects of GLP-1
The major biological actions of glucagon, GLP-1, and GLP-2 on different target tissues
Main physiological regulators of α-cell function and glucagon secretion
Glucagon action in hepatic and extrahepatic tissues
The GIP gene is localized on human chromosome 17q21.3-q22 and comprises 6 exons. Proteolytic processing of preproGIP generates GIP that is secreted from K cells
Various biological functions of GIP and GLP-1
Secretion and metabolism of GIP and GLP-1
Molecular machinery underlying the insulinotropic effects of GIP and GLP-1.
Molecular machinery underlying the anti-apoptotic and proliferative effects of GIP and GLP-1.
Incretin secretion and action
proGIP and proglucagon
the main molecular events during incretin-induced insulin secretion from a β-cell
the incretin downstream signal transduction pathways in a β cell
Physiology of the incretin system.
GLP-1 effects on insulin secretion
GLP-1 effects on β-cell proliferation and survival
GLP-1R signals through distinct mechanisms in β-cell
Model depicting two hypothetical cell signaling pathways by which GLP-1 exerts insulinomimetic actions on insulin-sensitive target tissues
Summary of the cellular actions of GLP-1 that lead to stimulation of insulin secretion
GLP-1 activates PKA and Epac2 in pancreatic b cells
Glucose-stimulated insulin secretion under the control of GLP-1
Receptors structure for Other Glucagon Sequence-Containing Peptides
Paracrine signalling in the α-cell
Modulation of hepatic glucose production by β cells and α cells in different conditions
Role of glucokinase in various tissues
Glucose pathways during hyperglycemia resulting mainly in cell dysfunctions
Intracellular pathways proposed as mediators of the cardioprotective actions of glucagonlike peptide-1 (GLP-1).
GLP-1R-dependent intracellular signal transduction pathways in the cardiomyocyte
Antiatherosclerotic potential of GLP-1 action
Indirect cardiac actions of GLP-1
Proglucagon is a protein precursor of glucagon and GLPs
Amino acid sequences of GLP-1 and subpeptides generated by selective modifications by specific proteases
Pleiotropic effects of dipeptidyl peptidase-4 inhibitors
GLP-1R agonist and DPP-4 inhibitor cardiovascular outcomes trials
DPP-4 substrates that directly or indirectly regulate cardiovascular function
Substrates of DPP-4 and potential effects
DPP-4 cardioactive substrates and their effects on peripheral tissues that influence the cardiovascular system
Working hypothesis to investigate differences between DPP4i and GLP-1R agonist strategies in β-cell physiology
GLP-1 may exert its cardiovascular actions
Potential mechanisms whereby DPP-4 inhibitors can achieve cardiovascular protection
The possible effects of DPP4 targeting in ischemia/reperfusion injury (IRI).
GLP-1 targets multiple organs to improve glucose control in T2DM
Structure of native GLP-1, exenatide, liraglutide, sitagliptin, and vildagliptin
The role of microRNAs in b-cell function.
Timeline of evolution in therapies and equipment for diabetes management
Pathophysiological factors
International Diabetes Center (IDC) treatment algorithm for the management of type 2 diabetes center
Outstanding questions
Outstanding questions