Alpha-cell Glucagon Secretion Research Articles

Oral Glucose-Lowering Agent Treatments in Type 2 Diabetes Mellitus

Type 2 diabetes is manifested by impaired insulin secretion in pancreatic beta cells, increased glucagon secretion in alpha cells, and generally has a history of insulin resistance. The treatment of glucose metabolism disorder and the resulting hyperglycemia constitute an important part of the treatment of type 2 diabetes. Glycemic targets can be targeted with A1C

Glucagon-Like Peptide 1 Shows Glucose Dependence in Regulating Islet Hormone Secretion

Background: GLP-1, glucagon-like peptide 1, is an incretin secreted by intestinal L-cells, responsible for stimulating insulin and decreasing glucagon secretion. Analogs of this hormone such as Liraglutide are approved for treating Type II diabetes (T2D). Despite its clinical success, much about how GLP-1 inhibits the alpha-cell remains unknown. GLP-1 receptor is expressed in both beta and delta cells, but is absent from the alpha-cell. As somatostatin reduces alpha-cell Ca2+ influx, paracrine signaling between delta and alpha cells may contribute to GLP-1 mediated inhibition of glucagon secretion. Therefore, we hypothesize that altered delta-cell activity is involved in the inhibitory effects of GLP-1 on the alpha-cell. Methods: Genetically encoded cAMP indicator cADDIS or a Ca2+ dye together with mouse pancreatic islets that express red fluorescent protein in either alpha or delta cells were used. Islets were perfused in glucose with or without addition of Liraglutide while imaged in real-time on Zeiss LSm780. ImageJ was used for analysis. Results: GLP-1 reduced delta-cell Ca2+ influx in low glucose, possibly by enhancing electrical coupling between beta and delta cells. GLP-1 increased alpha-cell cAMP levels under low glucose, further suggesting that delta cell somatostatin secretion is also reduced in these conditions. In high glucose, we found increased synchronicity and frequency of Ca2+ oscillations between beta and delta cells but decreased alpha-cell cAMP. Conclusion: The data suggests that GLP-1 reduces delta-cell Ca2+ influx in low glucose and increases Ca2+ influx in high glucose, which may provide a mechanism for glucose-dependent modulation of alpha-cell glucagon secretion by GLP-1.

The Effects of Dual GLP-1/GIP Receptor Agonism on Glucagon Secretion-A Review.

The gut-derived incretin hormones glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are secreted after meal ingestion and work in concert to promote postprandial insulin secretion. Furthermore, GLP-1 inhibits glucagon secretion when plasma glucose concentrations are above normal fasting concentrations while GIP acts glucagonotropically at low glucose levels. A dual incretin receptor agonist designed to co-activate GLP-1 and GIP receptors was recently shown to elicit robust improvements of glycemic control (mean haemoglobin A1c reduction of 1.94%) and massive body weight loss (mean weight loss of 11.3 kg) after 26 weeks of treatment with the highest dose (15 mg once weekly) in a clinical trial including overweight/obese patients with type 2 diabetes. Here, we describe the mechanisms by which the two incretins modulate alpha cell secretion of glucagon, review the effects of co-administration of GLP-1 and GIP on glucagon secretion, and discuss the potential role of glucagon in the therapeutic effects observed with novel unimolecular dual GLP-1/GIP receptor agonists. For clinicians and researchers, this manuscript offers an understanding of incretin physiology and pharmacology, and provides mechanistic insight into future antidiabetic and obesity treatments.

Sympathetic Innervation of Human Alpha Cells

Autonomic input is critical for the regulation of glucagon secretion to maintain blood glucose levels. Glucagon secretion is abnormal in patients with type 1 diabetes (T1D) and we hypothesize this results from dysfunctional sympathetic innervation of alpha-cells and may be present in at-risk autoantibody positive (AAb+) individuals. To characterize alpha-cell sympathetic innervation, pancreas tail samples were used from age-matched organ donors in three groups: controls (n=6), AAb+ (4), and T1D (4). Fresh frozen 40μm sections or 1-2 cm optically cleared samples were stained with markers for neuroendocrine cells (GCG, INS), total (NCAM)/ sympathetic nerves (tyrosine hydroxylase (TH)), and vascular smooth muscle cells (SMA) followed by confocal and Lightsheet imaging. To determine whether sympathetic fibers were decreased in AAb+ and/or T1D donors, TH+ fiber numbers were counted within islets and the percentage (%) of TH+ fibers/NCAM+ fibers determined. The TH+ fibers/islet were not significantly different between controls (1.5 ± 0.36, n=6), AAb+ (1.2 ± 0.27 (4)), and T1D (1.8 ± 0.57 (4)) donors (p = 0.07, ANOVA) with similar results for TH+ %. TH+ fibers were observed at alpha-cells in all donors. TH+ nerve densities were also similar between islets and exocrine regions between groups. Microarray analysis of single islet transcriptomes obtained using laser microdissection (n=120 islets, 13 control, 12 T1D) showed decreased expression of VMAT2 in insulin+ islets from T1D donors compared to control islets (p=0.047) while insulin- islets in T1D donors had significantly reduced VMAT2 levels compared to control islets (p<0.0001). These data indicate a potential direct mechanism by which the sympathetic nervous system may regulate alpha-cell glucagon secretion with dysregulation of a vesicular monoamine transporter that accumulates monoamines in synaptic vesicles in islets without beta-cells in T1D donors. Sympathetic innervation of alpha-cells could play a direct role in exacerbation of dysregulated glucagon secretion in T1D. Disclosure E.A. Butterworth: None. L.H. Nasif: None. K. Nasif: None. K.N. Carty: None. C.E. Mathews: None. M.A. Atkinson: Other Relationship; Self; Patent Issued. I.C. Gerling: None. M. Campbell-Thompson: None.

Paracrine GABA and insulin regulate pancreatic alpha cell proliferation in a mouse model of type 1 diabetes.

This study aimed to elucidate the mechanism of increased proliferation of alpha cells in recent-onset type 1 diabetes. Pancreatic beta cells express GAD and produce γ-aminobutyric acid (GABA), which inhibits alpha cell secretion of glucagon. We explored the roles of GABA in alpha cell proliferation in conditions corresponding to type 1 diabetes in a mouse model and in vitro. Type 1 diabetes was induced by injecting the mice with streptozotocin (STZ). Some of the STZ-injected mice were treated with GABA (10mg/kg daily) for 12days. Isolated pancreatic islets were treated with STZ or STZ together with GABA for 2days. The effects of GABA treatment on STZ-induced alpha cell proliferation in vivo and in vitro were assessed. The effect of muscimol, a GABA receptor agonist, on αTC1-6 cell proliferation was also examined. STZ injection substantially decreased levels of GAD, GABA and insulin in pancreatic beta cells 12h after injection; this was followed by an upsurge of phosphorylated mechanistic target of rapamycin (p-mTOR) in the alpha cells at day 1, and a significant increase in alpha cell mass at day 3. Treating STZ-injected mice with GABA largely restored the immunodetectable levels of insulin and GAD in the beta cells and significantly decreased the number of aldehyde dehydrogenase 1 family, member A3 (ALDH1a3)-positive cells, alpha cell mass and hyperglucagonaemia. STZ treatment also increased alpha cell proliferation in isolated islets, which was reversed by co-treatment with GABA. Muscimol, together with insulin, significantly lowered the level of cytosolic Ca2+ and p-mTOR, and decreased the proliferation rate of αTC1-6 cells. GABA signalling critically controls the alpha cell population in pancreatic islets. Low intraislet GABA may contribute to alpha cell hyperplasia in early type 1 diabetes.

Lipocalin-type prostaglandin D2 synthase reduces glucagon secretion in alpha TC-1 clone 6 cells via the DP1 receptor

Diabetes is associated with disturbances in the normal levels of both insulin and glucagon, both of which play critical roles in the regulation of glycemia. Recent studies have found lipocalin-type prostaglandin D2 synthase (l-PGDS) to be an emerging target involved in the pathogenesis of type-2 diabetes. This study focused on the effect of l-PGDS on glucagon secretion from cultured pancreatic Alpha TC-1 Clone 6 cells. When cells were treated with various concentrations of l-PGDS (0, 10, 50, and 100ug/ml) for 2h in 1mM glucose; glucagon secretion decreased to 670±45, 838±38, 479±11, and 437±45pg/ml, respectively. In addition, pancreatic islets were isolated from C57BL/6 mice and stained for prostaglandin D2 receptors, DP1 and DP2, using immunohistochemistry. Our results showed that these islets express only the DP1 receptor. Pancreatic islets were then stained for alpha and beta cells, as well as DP1, to find the primary location of the receptor within the islets using immunofluorescence. Interestingly, DP1 receptor density was found primarily in alpha cells rather than in beta cells. Our study is the first to report a correlation between l-PGDS and glucagon secretion in alpha cells. Based on our obtained results, it can be concluded that higher concentrations of l-PGDS significantly reduced the secretion of glucagon in alpha cells, which may contribute to the pathogenesis of diabetes as well as offer a novel therapeutic site for the treatment of diabetes.

Zinc, Alpha Cells and Glucagon Secretion

Zinc concentrates in islet cells and is related to insulin secretion. Islet cells act as a unit within islets and hormone secretion in the islets is profoundly influenced by paracrine and autocrine regulation. Zinc has been recognised as a candidate paracrine inhibitor of glucagon secretion in alpha-cells. Further zinc fluxes may contribute to regulation of cell mass, Zn2+ may be cytotoxic and Zn2+ depletion by itself can cause cell death induced by oxidative stress. Recently, both free zinc ions and a number of zinc transporters have been localized in alpha-cells. These include zinc importers, ZIP1, ZIP10, and ZIP14 of the SLC39A family and zinc exporters, ZnT1, and ZnT4-8 of the SLC30A family. Furthermore, the redox state of thiol groups and Voltage Gated Ca2+ Channels (VGCC) add to the maintenance of a tight cytoplasmatic zinc homeostasis in the alpha-cells. The ZnT8 protein has emerged as particularly interesting since this zinc transporter has been identified as a genetic risk factor for the development of both type 1 and type 2 diabetes in which both alpha- and beta-cell functions are affected. Recent data discussed here suggest specific effects of Zn2+ on glucagon secretion and other alpha-cell functions.

Fluctuations of alpha cell calcium, potassium and sodium during amino acid perifusion of rat pancreatic islets.

Perifusion of rat pancreatic islets with a physiologic, 6-mM amino acid mixture resulted in typical acute and second phase glucagon secretion over 30 min. At various intervals, islets were acutely fixed and processed for scanning electron microscopy, identification of alpha cells, and measurements of single alpha cell content of calcium (Ca), potassium (K) and sodium (Na) with energy-dispersive x-ray analysis. Biphasic glucagon secretion was attended by corresponding biphasic Ca accumulation and a reciprocal, biphasic suppression of K content and acute phase suppression of Na in alpha cells. All secretory and cellular events were preceded by an evanescent upward spike in alpha cell K at 1 min. These results indicate that alpha cell glucagon secretion in response to amino acid mixtures may be initiated by a K signal and is coupled subsequently to phasic changes in alpha cell Ca content. Fluctuations of alpha cell K and Na appear to relate inversely to Ca, suggesting that transmembrane fluxes of the three cations are interrelated.

Effects of fasting and theophylline on alanine-stimulated glucagon secretion in neonatal and infant sheep

Plasma concentrations of glucose, alanine, and glucagon were measured after 24 hour fasting in newborn and infant sheep and in response to infusion of alanine alone and concurrently with theophylline. The plasma glucagon response to alanine was minimal in newborn sheep; in contrast, alanine produced a brisk response in plasma glucagon concentration in infant sheep. Glucose concentrations were unchanged in both groups. Theophylline enhanced blood glucagon and glucose responses to alanine in newborn animals but had minimal effects on the response of the infant sheep. These data, considered with earlier data in fetal sheep, suggest a progressive maturation of pancreatic islet alpha-cell glucagon secretion in the sheep during the postnatal period and suggest that the blunted glucagon response observed in the neonate is related to immaturity of the glucagon secretion mechanisms rather than deficient synthesis of the hormone. This immaturity may be related to impaired synthesis and/or enhanced degradation of cyclic adenosine monophosphate (cAMP) or to diminished responsiveness to cAMP.