Type 2 diabetes (T2D) has been known as 'bi-hormonal disorder' since decades ago, the role of glucagon from alpha-cell has languished whereas beta-cell taking center stage. Recently, numerous findings indicate that the defects of glucagon secretion get involve with development and exacerbation of hyperglycemia in T2D. Aberrant alpha-cell responses exhibit both fasting and postprandial states: hyperglucagonemia contributes to fasting hyperglycemia caused by inappropriate hepatic glucose production, and to postprandial hyperglycemia owing to blunted alpha-cell suppression. During hypoglycemia, insufficient counter-regulation response is also observed in advanced T2D. Though many debates still remained for exact mechanisms behind the dysregulation of alpha-cell in T2D, it is clear that the blockade of glucagon receptor or suppression of glucagon secretion from alpha-cell would be novel therapeutic targets for control of hyperglycemia. Whereas there have not been remarkable advances in developing new class of drugs, currently available glucagon-like peptide-1 and dipeptidyl peptidase-IV inhibitors could be options for treatment of hyperglucagonemia. In this review, we focus on alpha-cell dysfunction and therapeutic potentials of targeting alpha-cell in T2D.
Diabetes Mellitus, Type 2 ; Fasting ; Glucagon ; Glucagon-Like Peptide 1 ; Glucagon-Secreting Cells ; Glucose ; Hyperglycemia ; Hypoglycemia ; Insulin ; Insulin-Secreting Cells ; Receptors, Glucagon

The incretin hormones glucagon like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) have recently received much attention for their roles in type 2 diabetes therapy. GLP-1 stimulated insulin secretion in a glucose-dependent manner and is secreted by intestinal L cells. It also regulates blood glucose concentration, stomach motility, appetite, and body weight. These actions are mediated through G-protein-coupled receptors highly expressed on pancreatic beta cells and also exert indirect metabolic actions. Activation of GLP-1 receptors also produces nonglycemic effects in various tissues. The pleiotropic effects of GLP-1 have been recently reported. The mechanisms identified in preclinical studies have potential translational relevance for the treatment of disease. Here, the nonglycemic effects of GLP-1, especially those on the liver, central nervous system, and bone, were reviewed.
Appetite ; Blood Glucose ; Body Weight ; Central Nervous System ; Enteroendocrine Cells ; Glucagon ; Glucagon-Like Peptide 1 ; Incretins ; Insulin ; Insulin-Secreting Cells ; Liver ; Receptors, G-Protein-Coupled ; Stomach

Lycopene is an antioxidant which has potential anti-diabetic activity, but the cellular mechanisms have not been clarified. In this study, different concentrations of lycopene were used to treat pancreatic alpha and beta cell lines, and the changes of cell growth, cell apoptosis, cell cycle, reactive oxygen species (ROS), ATP levels and expression of related cytokines were determined. The results exhibited that lycopene did not affect cell growth, cell apoptosis, cell cycle, ROS and ATP levels of alpha cells, while it promoted the growth of beta cells, increased the ratio of S phase, reduced the ROS levels and increased the ATP levels of beta cells. At the same time, lycopene treatment elevated the mRNA expression levels of tnfα, tgfβ and hif1α in beta cells. These findings suggest that lycopene plays cell-specific role and activates pancreatic beta cells, supporting its application in diabetes therapy.
Adenosine Triphosphate ; metabolism ; Apoptosis ; Carotenoids ; pharmacology ; Cell Cycle ; Cells, Cultured ; Cytokines ; metabolism ; Glucagon-Secreting Cells ; drug effects ; Humans ; Insulin-Secreting Cells ; drug effects ; Lycopene ; pharmacology ; Reactive Oxygen Species ; metabolism

A putative polypeptide hormone identified as amylin[islet amyloid polypeptide] is synthesized and co-localized with insulin in B cells of pancreatic islets in several animal species including man. However, there is growing evidence that somatostatin cells are also expressed and contained amylin in the pancreatic islets of the rat The aim of the present study was to investigate the immunocytochemical expression of the amylin within the endocrine pancreas of the man, rabbit and guinea pig, with special reference to the possible ability of islet cells other than insulin cells to synthesize amylin. For this purpose serial sections of the pancreatic islets were stainedimmunocytochemically using anti-amylin, anti-insulin, anti-glucagon, anti-somatostatin antisera. In serial sections of pancreatic islets of the man and rabbit, it was shown that amylin immunoreactivity occurred in insulin-reactive B cells predominantly located in interior of the islets. In contrast, amylin immunoreacivity appeared in glucagon-reactive A cells peripherally located in the islets of the guinea pig. These results suggest that in both the man and rabbit, amylin is synthesized by B cells for subsequent co-secretion with insulin, and that in guinea pig, amylin is synthesized by A cells for co-secretion with glucagon. It thus appears that amylin release may be mediated by different secretory mechanisms according to animal species.
Amyloid ; Animals ; B-Lymphocytes ; Glucagon ; Guinea Pigs* ; Guinea* ; Immune Sera ; Immunohistochemistry ; Insulin ; Islet Amyloid Polypeptide* ; Islets of Langerhans* ; Rats ; Somatostatin-Secreting Cells

Diabetes Mellitus is a metabolic disease caused by impaired insulin secretion of pancreatic beta cells and increased insulin resistance of peripheral tissues. In Asian T2DM, progressive loss of beta cells mass and concomitant reduction of insulin secretion are more fundamental problems than peripheral insulin resistance. To solve this problem, research fields about investigation how stimulated islet cell growth and block the islet cell death is getting more important. Recently introduced drug, Glucagon like peptide-1 (GLP-1) has many beneficial roles in treatment of diabetes. GLP-1 stimulated glucose dependent insulin secretion and also can preserve beta cell mass through stimulation of beta cell growth and differentiation and protection of beta cell death from hyperglycemic stress. After treatment of GLP-1 or Exendin-4 (GLP-1 receptor agonist), beta cell mass is increased in animal models. This can be achieved through beta cell proliferation in islet or differentiation from intrapancreatic progenitor cells like ductal epithelium. The mechanism of beta cell proliferation is mediated by the PKA-CREB pathway. After activation of GLP-1 receptor, intracellular cAMP is elevated and then it activates PKA and CREB phosphorylation. Translocation of CREB into the nucleus up-regulates PDX-1 andIRS-2. Another pathway for beta cell proliferation is trans-activation of EGFR via c-Src after GLP-1 receptor activated. The notch pathway, major determinant of pancreas development in the embryonic stage, can be participate beta mass preservation through activation of gamma secretase in the beta cell membrane. Cleaved intracellular part of the notch translocates to the nucleus and binds to the pdx-1 promoter region. In hyperglycemia, oxidative and endoplasmic reticulum (ER) stress can be caused by apoptosis of the beta cell. Protection of apoptosis is another tool for beta cell mass preservation. After treatment of GLP-1 or exendin-4, beta cell apoptosis induced by oxidative and ER stress can be protected. GLP-1 can modulate JNK and GSK 3beta activation and ER chaperone and ER stress response. In treatment of diabetes, GLP-1 increases insulin secretion with glucose dependent manner and also preserves beta cell mass against progressive beta cell loss
Amyloid Precursor Protein Secretases ; Apoptosis ; Asian Continental Ancestry Group ; Cell Death ; Cell Membrane ; Cell Proliferation ; Diabetes Mellitus ; Endoplasmic Reticulum ; Epithelium ; Glucagon ; Glucagon-Like Peptide 1 ; Glucose ; Humans ; Hyperglycemia ; Insulin ; Insulin Resistance ; Insulin-Secreting Cells ; Islets of Langerhans ; Metabolic Diseases ; Models, Animal ; Pancreas ; Peptides ; Phosphorylation ; Promoter Regions, Genetic ; Receptors, Glucagon ; Stem Cells ; Venoms ; Glucagon-Like Peptide-1 Receptor

Nesidioblastosis is a term used to describe pathologic overgrowth of pancreatic islet cells. It also means maldistribution of islet cells within the ductules of exocrine pancreas. Generally, nesidioblastosis occurs in beta-cell and causes neonatal hyperinsulinemic hypoglycemia or adult noninsulinoma pancreatogenous hypoglycemia syndrome. Alpha-cell nesidioblastosis and hyperplasia is an extremely rare disorder. It often accompanies glucagon-producing marco- and mircoadenoma without typical glucagonoma syndrome. A 35-year-old female was referred to our hospital with recurrent acute pancreatitis. On radiologic studies, 1.5 cm sized mass was noted in pancreas tail. Cytological evaluation with EUS-fine-needle aspiration suggested serous cystadenoma. She received distal pancreatectomy. The histologic examination revealed a 1.7 cm sized neuroendocrine tumor positive for immunohistochemical staining with glucagon antibody. Multiple glucagon-producing micro endocrine cell tumors were scattered next to the main tumor. Additionally, diffuse hyperplasia of pancreatic islets and ectopic proliferation of islet cells in centroacinar area, findings compatible to nesidioblastosis, were seen. These hyperplasia and almost all nesidioblastic cells were positive for glucagon immunochemistry. Even though serum glucagon level still remained higher than the reference value, she has been followed-up without any evidence of recurrence or hormone related symptoms. Herein, we report a case of alpha-cell nesidioblastosis and hyperplasia combined with glucagon-producing neuroendocrine tumor with literature review.
Adult ; Chromogranin A/blood ; Female ; Glucagon/*metabolism ; Glucagon-Secreting Cells/metabolism ; Humans ; Hyperplasia/complications/*diagnosis ; Islets of Langerhans/metabolism/ultrasonography ; Nesidioblastosis/complications/*diagnosis ; Neuroendocrine Tumors/complications/*diagnosis/pathology ; Pancreas/*pathology ; Tomography, X-Ray Computed

INTRODUCTION: Cardiovascular diseases and diabetes mellitus (DM) are two disease entities that commonly coexist in a single patient. Ranolazine is an active piperazine derivative approved by FDA in 2006 as an anti-anginal medication. It was noted to have HbA1c lowering effects in the trials on angina. The proposed mechanism of action is the inhibition of glucagon secretion by blocking the Na v1.3 isoform of sodium channels in pancreatic alpha cells leading to glucagon- and glucose-lowering effects. HbA1c lowering to a target of 6.5% in type 2 diabetes patients has been shown to reduce risk of microvascular complications. The objective of this study is to determine the efficacy and safety of Ranolazine in HbA1c lowering as an add-on therapy to existing anti-diabetic regimen.

METHODS: A comprehensive literature search in PubMed, The Cochrane Central Register of Controlled Trials, the ClinicalTrials.gov website, Google Scholar databases and EMBASE databases were made using the search terms "Randomized controlled trial", "Ranolazine," "HbA1c," and "glycosylated hemoglobin", as well as various combinations of these, was done to identify randomized control trials. No restriction on language and time were done. The authors extracted data for characteristics, quality assessment and mean change in HbA1c after at least eight weeks of treatment with ranolazine. The program RevMan 5.3 was used to generate the statistical analysis of the data.

RESULTS: Six RCTs were included to make up a total of 1,650 diabetic patients. Five studies had moderate risk of bias assessment while one had low risk of bias assessment and hence was not included in the analysis. The overall analysis showed an HbA1c reduction of 0.35% 0.68 to -0.03, p-value=0.03) however, the population was heterogenous (I2=100%). The heterogeneity was not eliminated by sensitivity analysis.

DISCUSSION: The results showed a statistically significant lowering of HbA1c with ranolazine. However, the population was heterogenous. The sources of heterogeneity could be the (1) differences in the level of glycemic control among subjects as indicated by baseline HbA1c levels, (2) the current anti-diabetic regimen of the study patients, i.e. whether or not they are on insulin therapy, (3) the presence or absence of ischemic heart disease and (5) duration of ranolazine therapy, and (4) the presence or absence of chronic kidney disease. When the analysis excluded the population with combination insulin therapy and ranolazine, the effect becomes non-significant. Thus, the HbA1c lowering effect may have been from the insulin therapy rather than the ranolazine.

CONCLUSION: Ranolazine as anti-diabetic therapy shows statistically significant HbA1c lowering effect. It can be a potential treatment option for patients with both DM and angina pectoris. However, well-designed, prospective trials are still recommended to determine the effect on a less heterogenous population. Likewise, more studies are needed to determine its safety.

Human ; Hemoglobin A, Glycosylated ; Glucagon ; Glucagon-secreting Cells ; Diabetes Mellitus, Type 2 ; Ranolazine ; Insulin ; Language ; Prospective Studies ; Blood Glucose ; Angina Pectoris ; Coronary Artery Disease ; Myocardial Ischemia ; Renal Insufficiency, Chronic ; Pubmed ; Sodium Channels ; Protein Isoforms

BACKGROUND: The characteristic feature of pancreatic beta cells is highly developed endoplasmic reticulum (ER) due to a heavy engagement in insulin secretion. The ER serves several important function, including post-translational modification, folding, and assembly of newly synthesized secretory proteins, and its proper function is essential to cell survival. Various stress conditions can interfere with ER function. Pancreatic beta cells may be particularly vulnerable to ER stress that causes to impair insulin biosynthesis and beta cell survival through apoptosis. Glucagon like peptide-1 (GLP-1) is a new drug for treatment of type 2 diabetes and has effects on stimulation of insulin secretion and beta cell preservation. Also, it may have an antiapoptotic effect on beta cells, but detailed mechanisms are not proven. Therefore, we investigated the protective mechanism of GLP-1 in beta cells through ER stress response induced by 2-deoxy-D-glucose (2DG). METHODS: For induction of the ER stress, HIT-T15 cells (hamster beta cell line) were treated with 2DG (10 mM). Apoptosis was evaluated with MTT assay, hoechst 33342 staining and Annexin/PI flow cytometry. Expression of ER stress-related molecules was determined by real-time PCR or western blot. For blocking ER stress, we pretreated HIT-T15 cells with exendin-4 (Ex-4; GLP-1 receptor agonist) for 1 hour before stress induction. RESULTS: After induction with ER stress (2DG), beta cells were lost by apoptosis. We found that Ex-4 had a protective effect through ER stress related molecules (GRP78, GRP94, XBP-1, eIF2alpha, CHOP) modulation. Also, Ex-4 recovered the expression of insulin2 mRNA in beta cells. CONCLUSION: These results suggest that GLP-1 may protect beta cells apoptosis through ER stress modulation.
Apoptosis ; Benzimidazoles ; Blotting, Western ; Cell Survival ; Deoxyglucose ; Endoplasmic Reticulum ; Flow Cytometry ; Glucagon ; Glucagon-Like Peptide 1 ; Glucagon-Like Peptide-1 Receptor ; HSP70 Heat-Shock Proteins ; Insulin ; Insulin-Secreting Cells ; Membrane Proteins ; Peptides ; Protein Processing, Post-Translational ; Proteins ; Real-Time Polymerase Chain Reaction ; Receptors, Glucagon ; RNA, Messenger ; Venoms

BACKGROUND AND OBJECTIVES: Type 1 Diabetes Mellitus (T1DM) is an autoimmune disorder resulting out of T cell mediated destruction of pancreatic beta cells. Immunomodulatory properties of mesenchymal stem cells may help to regenerate beta cells and/or prevent further destruction of remnant, unaffected beta cells in diabetes. We have assessed the ability of umbilical cord derived MSCs (UCMSCs) to differentiate into functional islet cells in vitro. METHODS AND RESULTS: We have isolated UCMSCs and allowed sequential exposure of various inducing agents and growth factors. We characterized these cells for confirmation of the presence of islet cell markers and their functionality. The spindle shaped undifferentiated UCMSCs, change their morphology to become triangular in shape. These cells then come together to form the islet like structures which then grow in size and mature over time. These cells express pancreatic and duodenal homeobox -1 (PDX-1), neurogenin 3 (Ngn-3), glucose transporter 2 (Glut 2) and other pancreatic cell markers like glucagon, somatostatin and pancreatic polypeptide and lose expression of MSC markers like CD73 and CD105. They were functionally active as demonstrated by release of physiological insulin and C-peptide in response to elevated glucose concentrations. CONCLUSIONS: Pancreatic islet like cells with desired functionality can thus be obtained in reasonable numbers from undifferentiated UCMSCs in vitro. This could help in establishing a "very definitive source" of islet like cells for cell therapy. UCMSCs could thus be a game changer in treatment of diabetes.
C-Peptide ; Cell- and Tissue-Based Therapy* ; Diabetes Mellitus, Type 1 ; Genes, Homeobox ; Glucagon ; Glucose ; Glucose Transport Proteins, Facilitative ; Insulin* ; Insulin-Secreting Cells ; Intercellular Signaling Peptides and Proteins ; Islets of Langerhans ; Mesenchymal Stromal Cells* ; Pancreatic Polypeptide ; Somatostatin ; Stem Cells ; Umbilical Cord*

BACKGROUNDPancreatic islet cell transplantation is an effective approach to treat type 1 diabetes. However, this therapy is not widely used because of the severe shortage of transplantable donor islets. This study investigated whether mesenchymal stem cells (MSCs) derived from human umbilical cord blood (UCB) could be transdifferentiated into insulin producing cells in vitro and the role of extracellular matrix (ECM) gel in this procedure.

METHODSHuman UCB samples were collected and MSCs were isolated. MSCs specific marker proteins were analyzed by a flow cytometer. The capacities of osteoblast and adipocyte to differentiate were tested. Differentiation into islet like cell was induced by a 15-day protocol with or without ECM gel. Pancreatic characteristics were evaluated with immunofluorescence, reverse transcription polymerase chain reaction (RT-PCR) and flow cytometry. Insulin content and release in response to glucose stimulation were detected with chemiluminescent immunoassay system.

RESULTSSixteen MSCs were isolated from 42 term human UCB units (38%). Human UCB-MSCs expressed MSCs specific markers and could be induced in vitro into osteoblast and adipocyte. Islet like cell clusters appeared about 9 days after pancreatic differentiation in the inducing system with ECM gel. The insulin positive cells accounted for (25.2 +/- 3.4)% of the induced cells. The induced cells expressed islet related genes and hormones, but were not very responsive to glucose challenge. When MSCs were induced without ECM gel, clusters formation and secretion of functional islet proteins could not be observed.

CONCLUSIONSHuman UCB-MSCs can differentiate into islet like cells in vitro and ECM gel plays an important role in pancreatic endocrine cell maturation and formation of three dimensional structures.

C-Peptide ; analysis ; Cell Differentiation ; Cell Separation ; Cells, Cultured ; Extracellular Matrix ; physiology ; Fetal Blood ; cytology ; Flow Cytometry ; Fluorescent Antibody Technique ; Glucagon ; analysis ; Humans ; Insulin ; analysis ; secretion ; Insulin-Secreting Cells ; cytology ; Mesenchymal Stromal Cells ; cytology ; Reverse Transcriptase Polymerase Chain Reaction