| 1. |
- Kellard, J. A., et al.
(author)
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Reduced somatostatin signalling leads to hypersecretion of glucagon in mice fed a high-fat diet
- 2020
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In: Molecular Metabolism. - : Elsevier BV. - 2212-8778. ; 40
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Journal article (peer-reviewed)abstract
- Objectives: Elevated plasma glucagon is an early symptom of diabetes, occurring in subjects with impaired glucose regulation. Here, we explored alpha-cell function in female mice fed a high-fat diet (HFD). Methods: Female mice expressing the Ca2+ indicator GCaMP3 specifically in alpha-cells were fed a high-fat or control (CTL) diet. We then conducted in vivo phenotyping of these mice, as well as experiments on isolated (ex vivo) islets and in the in situ perfused pancreas. Results: In HFD-fed mice, fed plasma glucagon levels were increased and glucagon secretion from isolated islets and in the perfused mouse pancreas was also elevated. In mice fed a CTL diet, increasing glucose reduced intracellular Ca2+ ([Ca2+](i)) oscillation frequency and amplitude. This effect was also observed in HFD mice; however, both the frequency and amplitude of the [Ca2+](i) oscillations were higher than those in CTL alpha-cells. Given that alpha-cells are under strong paracrine control from neighbouring somatostatin-secreting delta-cells, we hypothesised that this elevation of alpha-cell output was due to a lack of somatostatin (SST) secretion. Indeed, SST secretion in isolated islets from HFD-fed mice was reduced but exogenous SST also failed to suppress glucagon secretion and [Ca2+](i) activity from HFD alpha-cells, in contrast to observations in CTL mice. Conclusions: These findings suggest that reduced delta-cell function, combined with intrinsic changes in alpha-cells including sensitivity to somatostatin, accounts for the hyperglucagonaemia in mice fed a HFD. (C) 2020 The Author(s). Published by Elsevier GmbH.
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| 2. |
- Vergari, Elisa, et al.
(author)
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Somatostatin secretion by Na+-dependent Ca2+-induced Ca2+ release in pancreatic delta-cells.
- 2020
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In: Nature metabolism. - : Springer Science and Business Media LLC. - 2522-5812. ; 2:1, s. 32-40
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Journal article (peer-reviewed)abstract
- Pancreatic islets are complex micro-organs consisting of at least three different cell types: glucagon-secreting α-, insulin-producing β- and somatostatin-releasing δ-cells1. Somatostatin is a powerful paracrine inhibitor of insulin and glucagon secretion2. In diabetes, increased somatostatinergic signalling leads to defective counter-regulatory glucagon secretion3. This increases the risk of severe hypoglycaemia, a dangerous complication of insulin therapy4. The regulation of somatostatin secretion involves both intrinsic and paracrine mechanisms5 but their relative contributions and whether they interact remains unclear. Here we show that dapagliflozin-sensitive glucose- and insulin-dependent sodium uptake stimulates somatostatin secretion by elevating the cytoplasmic Na+ concentration ([Na+]i) and promoting intracellular Ca2+-induced Ca2+ release (CICR). This mechanism also becomes activated when [Na+]i is elevated following the inhibition of the plasmalemmal Na+-K+ pump by reductions of the extracellular K+ concentration emulating those produced by exogenous insulin in vivo6. Islets from some donors with type-2 diabetes hypersecrete somatostatin, leading to suppression of glucagon secretion that can be alleviated by a somatostatin receptor antagonist. Our data highlight the role of Na+ as an intracellular second messenger, illustrate the significance of the intraislet paracrine network and provide a mechanistic framework for pharmacological correction of the hormone secretion defects associated with diabetes that selectively target the δ-cells.
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| 3. |
- Chanclón, Belén, et al.
(author)
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Peripancreatic adipose tissue protects against high-fat-diet-induced hepatic steatosis and insulin resistance in mice
- 2020
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In: International Journal of Obesity. - : Springer Science and Business Media LLC. - 0307-0565 .- 1476-5497. ; 44, s. 2323-2334
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Journal article (peer-reviewed)abstract
- Background/objectives Visceral adiposity is associated with increased diabetes risk, while expansion of subcutaneous adipose tissue may be protective. However, the visceral compartment contains different fat depots. Peripancreatic adipose tissue (PAT) is an understudied visceral fat depot. Here, we aimed to define PAT functionality in lean and high-fat-diet (HFD)-induced obese mice. Subjects/methods Four adipose tissue depots (inguinal, mesenteric, gonadal, and peripancreatic adipose tissue) from chow- and HFD-fed male mice were compared with respect to adipocyte size (n = 4-5/group), cellular composition (FACS analysis, n = 5-6/group), lipogenesis and lipolysis (n = 3/group), and gene expression (n = 6-10/group). Radioactive tracers were used to compare lipid and glucose metabolism between these four fat depots in vivo (n = 5-11/group). To determine the role of PAT in obesity-associated metabolic disturbances, PAT was surgically removed prior to challenging the mice with HFD. PAT-ectomized mice were compared to sham controls with respect to glucose tolerance, basal and glucose-stimulated insulin levels, hepatic and pancreatic steatosis, and gene expression (n = 8-10/group). Results We found that PAT is a tiny fat depot (similar to 0.2% of the total fat mass) containing relatively small adipocytes and many "non-adipocytes" such as leukocytes and fibroblasts. PAT was distinguished from the other fat depots by increased glucose uptake and increased fatty acid oxidation in both lean and obese mice. Moreover, PAT was the only fat depot where the tissue weight correlated positively with liver weight in obese mice (R = 0.65; p = 0.009). Surgical removal of PAT followed by 16-week HFD feeding was associated with aggravated hepatic steatosis (p = 0.008) and higher basal (p < 0.05) and glucose-stimulated insulin levels (p < 0.01). PAT removal also led to enlarged pancreatic islets and increased pancreatic expression of markers of glucose-stimulated insulin secretion and islet development (p < 0.05). Conclusions PAT is a small metabolically highly active fat depot that plays a previously unrecognized role in the pathogenesis of hepatic steatosis and insulin resistance in advanced obesity.
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| 4. |
- Dybjer, E., et al.
(author)
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Incretin hormones, insulin, glucagon and advanced glycation end products in relation to cognitive function in older people with and without diabetes, a population-based study
- 2020
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In: Diabetic Medicine. - : Wiley. - 0742-3071 .- 1464-5491. ; 37:7, s. 1157-1166
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Journal article (peer-reviewed)abstract
- Aim The aim of this observational study was to investigate relationships between physiological levels of glucometabolic biomarkers and cognitive test results in a population-based setting. Methods Cross-sectional data were obtained from the Swedish population-based Malmo Diet and Cancer Study Re-examination 2007-2012 comprising 3001 older people (mean age 72 years). Through oral glucose tolerance testing (OGTT), fasting and post-load levels of serum insulin, plasma glucagon, serum glucose-dependent insulinotropic peptide (GIP) and plasma glucagon-like peptide-1 (GLP-1) were measured. Insulin resistance and insulin sensitivity levels were calculated. In 454 participants, advanced glycation end products (AGEs) were estimated through skin autofluorescence. Associations between biomarkers and two cognitive tests, the Mini-Mental State Examination (MMSE) and A Quick Test of Cognitive Speed (AQT) respectively, were explored in multiple regression analyses. Results Positive associations following adjustments for known prognostic factors were found between MMSE scores and insulin sensitivity (B = 0.822, P = 0.004), 2-h plasma glucagon (B = 0.596, P = 0.026), 2-h serum GIP (B = 0.581, P = 0.040) and 2-h plasma GLP-1 (B = 0.585, P = 0.038), whereas negative associations were found between MMSE scores and insulin resistance (B = -0.734, P = 0.006), fasting plasma GLP-1 (B = -0.544, P = 0.033) and AGEs (B = -1.459, P = 0.030) were found. Conclusions Higher levels of insulin sensitivity, GIP and GLP-1 were associated with better cognitive outcomes, but AGEs were associated with worse outcomes, supporting evidence from preclinical studies. Glucagon was linked to better outcomes, which could possibly reflect neuroprotective properties similar to the related biomarker GLP-1 which has similar intracellular properties. Longitudinal and interventional studies are needed to further evaluate neuromodulating effects of these biomarkers. presented at the European Association for the Study of Diabetes (EASD) 2019, Barcelona, Spain
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| 5. |
- Hatamie, Amir, et al.
(author)
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Nanoscale Amperometry Reveals that Only a Fraction of Vesicular Serotonin Content is Released During Exocytosis from Beta Cells
- 2021
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In: Angewandte Chemie-International Edition. - : Wiley. - 1433-7851 .- 1521-3773. ; 60:14, s. 7593-7596
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Journal article (peer-reviewed)abstract
- Recent work has shown that chemical release during the fundamental cellular process of exocytosis in model cell lines is not all-or-none. We tested this theory for vesicular release from single pancreatic beta cells. The vesicles in these cells release insulin, but also serotonin, which is detectible with amperometric methods. Traditionally, it is assumed that exocytosis in beta cells is all-or-none. Here, we use a multidisciplinary approach involving nanoscale amperometric chemical methods to explore the chemical nature of insulin exocytosis. We amperometrically quantified the number of serotonin molecules stored inside of individual nanoscale vesicles (39 317 +/- 1611) in the cell cytoplasm before exocytosis and the number of serotonin molecules released from single cells (13 310 +/- 1127) for each stimulated exocytosis event. Thus, beta cells release only one-third of their granule content, clearly supporting partial release in this system. We discuss these observations in the context of type-2 diabetes.
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| 6. |
- Kim, Angela, et al.
(author)
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Arginine-vasopressin mediates counter-regulatory glucagon release and is diminished in type 1 diabetes.
- 2021
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In: eLife. - 2050-084X. ; 10
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Journal article (peer-reviewed)abstract
- Insulin-induced hypoglycemia is a major treatment barrier in type-1 diabetes (T1D). Accordingly, it is important that we understand the mechanisms regulating the circulating levels of glucagon. Varying glucose over the range of concentrations that occur physiologically between the fed and fuel-deprived states (8 to 4 mM) has no significant effect on glucagon secretion in the perfused mouse pancreas or in isolated mouse islets (in vitro), and yet associates with dramatic increases in plasma glucagon. The identity of the systemic factor(s) that elevates circulating glucagon remains unknown. Here, we show that arginine-vasopressin (AVP), secreted from the posterior pituitary, stimulates glucagon secretion. Alpha-cells express high levels of the vasopressin 1b receptor (V1bR) gene (Avpr1b). Activation of AVP neurons in vivo increased circulating copeptin (the C-terminal segment of the AVP precursor peptide) and increased blood glucose; effects blocked by pharmacological antagonism of either the glucagon receptor or V1bR. AVP also mediates the stimulatory effects of hypoglycemia produced by exogenous insulin and 2-deoxy-D-glucose on glucagon secretion. We show that the A1/C1 neurons of the medulla oblongata drive AVP neuron activation in response to insulin-induced hypoglycemia. AVP injection increased cytoplasmic Ca2+ in alpha-cells (implanted into the anterior chamber of the eye) and glucagon release. Hypoglycemia also increases circulating levels of AVP/copeptin in humans and this hormone stimulates glucagon secretion from human islets. In patients with T1D, hypoglycemia failed to increase both copeptin and glucagon. These findings suggest that AVP is a physiological systemic regulator of glucagon secretion and that this mechanism becomes impaired in T1D.
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| 7. |
- Muratore, Massimo, et al.
(author)
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The vascular architecture of the pancreatic islets: A homage to August Krogh
- 2021
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In: Comparative Biochemistry and Physiology -Part A : Molecular and Integrative Physiology. - : Elsevier BV. - 1095-6433. ; 252
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Journal article (peer-reviewed)abstract
- The vascular network supporting the islets of Langerhans represents a highly specialised system of arterioles, capillaries and venules. Several features of the islet vasculature (density and fenestration of the capillaries) ensure rapid exchange of nutrients and hormones, which is central to the islets' capacity to control of systemic metabolism via reciprocal changes of insulin and glucagon secretion. Here we discuss how changes in islet blood flow may underlie pulsatile insulin secretion, which becomes impaired in type-2 diabetes. Improved understanding of the architecture and regulation of pancreas/islet blood flow may therefore illuminate the causes underlying this common metabolic disorder. The pioneering work of August Krogh on blood flow, oxygen diffusion and capillary anatomy (that was awarded with the Nobel Prize in 1920) is a cornerstone in these efforts and remains relevant to today's research. © 2020 The Authors
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| 8. |
- Oduori, O. S., et al.
(author)
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Gs/Gq signaling switch in beta cells defines incretin effectiveness in diabetes
- 2020
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In: Journal of Clinical Investigation. - : American Society for Clinical Investigation. - 0021-9738 .- 1558-8238. ; 130:12, s. 6639-6655
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Journal article (peer-reviewed)abstract
- By restoring glucose-regulated insulin secretion, glucagon-like peptide-1-based (GLP-1-based) therapies are becoming increasingly important in diabetes care. Normally, the incretins GLP-1 and glucose-dependent insulinotropic polypeptide (GIP) jointly maintain normal blood glucose levels by stimulation of insulin secretion in pancreatic beta cells. However, the reason why only GLP-1-based drugs are effective in improving insulin secretion after presentation of diabetes has not been resolved. ATP-sensitive K+ (K-ATP) channels play a crucial role in coupling the systemic metabolic status to beta cell electrical activity for insulin secretion. Here, we have shown that persistent membrane depolarization of beta cells due to genetic cell-specific Kcnj11(-/-)mice) or pharmacological (long-term exposure to sulfonylureas) inhibition of the K-ATP channel led to a switch from Gs to Gq in a major amplifying pathway of insulin secretion. The switch determined the relative insulinotropic effectiveness of GLP-1 and GIP, as GLP-1 can activate both Gq and Gs, while GIP only activates Gs. The findings were corroborated in other models of persistent depolarization: a spontaneous diabetic KK-Ay mouse and nondiabetic human and mouse beta cells of pancreatic islets chronically treated with high glucose. Thus, a Gs/Gq signaling switch in beta cells exposed to chronic hyperglycemia underlies the differential insulinotropic potential of incretins in diabetes.
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| 9. |
- Peterson, Q. P., et al.
(author)
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A method for the generation of human stem cell-derived alpha cells
- 2020
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In: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 11:1
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Journal article (peer-reviewed)abstract
- The generation of pancreatic cell types from renewable cell sources holds promise for cell replacement therapies for diabetes. Although most effort has focused on generating pancreatic beta cells, considerable evidence indicates that glucagon secreting alpha cells are critically involved in disease progression and proper glucose control. Here we report on the generation of stem cell-derived human pancreatic alpha (SC-alpha) cells from pluripotent stem cells via a transient pre-alpha cell intermediate. These pre-alpha cells exhibit a transcriptional profile similar to mature alpha cells and although they produce proinsulin protein, they do not secrete significant amounts of processed insulin. Compound screening identified a protein kinase c activator that promotes maturation of pre-alpha cells into SC-alpha cells. The resulting SC-alpha cells do not express insulin, share an ultrastructure similar to cadaveric alpha cells, express and secrete glucagon in response to glucose and some glucagon secretagogues, and elevate blood glucose upon transplantation in mice. Deriving functional pancreatic cell types from human stem cells may have important clinical applications. Building on previous work, here the authors generate stem cell-derived alpha cells via a polyhormonal intermediate, which have a gene expression pattern similar to human islet alpha cells and behave as such when transplanted into mice.
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| 10. |
- Satin, L. S., et al.
(author)
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"Take Me To Your Leader": An Electrophysiological Appraisal of the Role of Hub Cells in Pancreatic Islets
- 2020
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In: Diabetes. - : American Diabetes Association. - 0012-1797 .- 1939-327X. ; 69:5, s. 830-836
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Journal article (peer-reviewed)abstract
- The coordinated electrical activity of beta-cells within the pancreatic islet drives oscillatory insulin secretion. A recent hypothesis postulates that specially equipped "hub" or "leader" cells within the beta-cell network drive islet oscillations and that electrically silencing or optically ablating these cells suppresses coordinated electrical activity (and thus insulin secretion) in the rest of the islet. In this Perspective, we discuss this hypothesis in relation to established principles of electrophysiological theory. We conclude that whereas electrical coupling between beta-cells is sufficient for the propagation of excitation across the islet, there is no obvious electrophysiological mechanism that explains how hyperpolarizing a hub cell results in widespread inhibition of islet electrical activity and disruption of their coordination. Thus, intraislet diffusible factors should perhaps be considered as an alternate mechanism.
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