scholarly journals Arginine-vasopressin mediates counter-regulatory glucagon release and is diminished in type 1 diabetes

eLife ◽  
2021 ◽  
Vol 10 ◽  
Author(s):  
Angela Kim ◽  
Jakob G Knudsen ◽  
Joseph C Madara ◽  
Anna Benrick ◽  
Thomas Hill ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
Blood Glucose ◽  
Arginine Vasopressin ◽  
Glucagon Secretion ◽  
Glucagon Release ◽  
Alpha Cells ◽  
Major Barrier ◽  
Circulating Levels

Insulin-induced hypoglycemia is a major barrier to the treatment of type-1 diabetes (T1D). Accordingly, it is important that we understand the mechanisms regulating the circulating levels of glucagon - the body's principal blood glucose-elevating hormone which is secreted from alpha-cells of the pancreatic islets. Varying glucose over the range of concentrations that occur physiologically between the fed and fuel-deprived states (from 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 changes in plasma glucagon in vivo. The identity of the systemic factor(s) that stimulates glucagon secretion remains unknown. Here, we show that arginine-vasopressin (AVP), secreted from the posterior pituitary, stimulates glucagon secretion. Glucagon-secreting alpha-cells express high levels of the vasopressin 1b receptor gene (Avpr1b). Activation of AVP neurons in vivo increased circulating copeptin (the C-terminal segment of the AVP precursor peptide, a stable surrogate marker of AVP) and increased blood glucose; effects blocked by pharmacological antagonism of either the glucagon receptor or vasopressin 1b receptor. 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. Exogenous injection of AVP in vivo increased cytoplasmic Ca2+ in alpha-cells (implanted into the anterior chamber of the eye) and glucagon release. Hypoglycemia also increases circulating levels of AVP in humans and this hormone stimulates glucagon secretion from isolated human islets. In patients with T1D, hypoglycemia failed to increase both plasma copeptin and glucagon levels. These findings suggest that AVP is a physiological systemic regulator of glucagon secretion and that this mechanism becomes impaired in T1D.

scholarly journals AVP-induced counter-regulatory glucagon is diminished in type 1 diabetes

2020 ◽  
Author(s):  
Angela Kim ◽  
Jakob G. Knudsen ◽  
Joseph C. Madara ◽  
Anna Benrick ◽  
Thomas Hill ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
Glucagon Secretion ◽  
Human Islets ◽  
Alpha Cells ◽  
Glucagon Receptor ◽  
Major Barrier ◽  
Neuron Activation ◽  
Circulating Levels

AbstractHypoglycaemia is a major barrier to the treatment of diabetes. Accordingly, it is important that we understand the mechanisms regulating the circulating levels of glucagon – the body’s principle blood glucose-elevating hormone which is secreted from alpha-cells of the pancreatic islets. In isolated islets, varying glucose over the range of concentrations that occur physiologically between the fed and fuel-deprived states (from 8 to 4 mM) has no significant effect on glucagon secretion and yet associates with dramatic changes in plasma glucagon in vivo. The identity of the systemic factor that stimulates glucagon secretion in vivo remains unknown. Here, we show that arginine-vasopressin (AVP), secreted from the posterior pituitary, stimulates glucagon secretion. Glucagon-secreting alpha-cells express high levels of the vasopressin 1b receptor (V1bR). Activation of AVP neurons in vivo increased circulating AVP, stimulated glucagon release and evoked hyperglycaemia; effects blocked by pharmacological antagonism of either the glucagon receptor or vasopressin 1b receptor. AVP also mediates the stimulatory effects of dehydration and hypoglycaemia produced by exogenous insulin and 2-deoxy-D-glucose on glucagon secretion. We show that the A1/C1 neurons of the medulla oblongata, which are known to be activated by hypoglycaemia, drive AVP neuron activation in response to insulin-induced hypoglycaemia. Hypoglycaemia also increases circulating levels of copeptin (derived from the same pre-pro hormone as AVP) levels in humans and this hormone stimulates glucagon secretion from isolated human islets. In patients with type 1 diabetes, hypoglycaemia failed to increase both plasma copeptin and glucagon. These findings provide a new mechanism for the central regulation of glucagon secretion in both health and disease.

scholarly journals The mathematician's control toolbox for management of type 1 diabetes

2014 ◽  
Vol 4 (5) ◽  
pp. 20140042 ◽  
Author(s):  
Marie Csete ◽  
John Doyle
Keyword(s):  
Type 1 Diabetes ◽  
Blood Glucose ◽  
Feedback Loop ◽  
Artificial Pancreas ◽  
Glucagon Release ◽  
Control Engineering ◽  
Glucose Levels ◽  
Blood Glucose Levels ◽  
Physiological Feedback

Blood glucose levels are controlled by well-known physiological feedback loops: high glucose levels promote insulin release from the pancreas, which in turn stimulates cellular glucose uptake. Low blood glucose levels promote pancreatic glucagon release, stimulating glycogen breakdown to glucose in the liver. In healthy people, this control system is remarkably good at maintaining blood glucose in a tight range despite many perturbations to the system imposed by diet and fasting, exercise, medications and other stressors. Type 1 diabetes mellitus (T1DM) results from loss of the insulin-producing cells of the pancreas, the beta cells. These cells serve as both sensor (of glucose levels) and actuator (insulin/glucagon release) in a control physiological feedback loop. Although the idea of rebuilding this feedback loop seems intuitively easy, considerable control mathematics involving multiple types of control schema were necessary to develop an artificial pancreas that still does not function as well as evolved control mechanisms. Here, we highlight some tools from control engineering used to mimic normal glucose control in an artificial pancreas, and the constraints, trade-offs and clinical consequences inherent in various types of control schemes. T1DM can be viewed as a loss of normal physiologic controls, as can many other disease states. For this reason, we introduce basic concepts of control engineering applicable to understanding pathophysiology of disease and development of physiologically based control strategies for treatment.

Early hyperglycemia following alloxan administration in vivo is not associated with altered hepatic mitochondrial function: acceptable model for type 1 diabetes?

2011 ◽  
Vol 89 (7) ◽  
pp. 477-484 ◽  
Author(s):  
Dairo A. Rendon ◽  
Jose A. Alvarez-Bustamante
Keyword(s):  
Type 1 Diabetes ◽  
Blood Glucose ◽  
Mitochondrial Dysfunction ◽  
Glucose Concentration ◽  
Alloxan Diabetes ◽  
Blood Glucose Concentration ◽  
Diabetic State ◽  
Acceptable Model

Alloxan and oxidative stress, which have been detected in livers of laboratory animals shortly after in vivo alloxan administration, cause in vitro mitochondrial dysfunction, thus questioning alloxan diabetes as an acceptable model for type 1 diabetes, a model that cannot legitimately be used to investigate mitochondrial metabolism in a diabetic state. In the current study, the blood glucose concentration increased in the drug-treated group of Sprague–Dawley rats (compared with the placebo group) 45 or 60 min after alloxan treatment, whereas at 30 min the blood glucose concentration was unchanged. State 4, state 3, respiratory control, efficiency of oxidative phosphorylation, and mitochondrial ATP synthase activity, assayed using glutamate plus malate, pyruvate plus malate, or succinate as a substrate, were not negatively altered during the entire study. These results indicated that early increases of blood glucose concentration, after in vivo alloxan administration, did not lead to liver mitochondrial dysfunction, suggesting that alloxan diabetes can be used for the study of liver mitochondrial respiration in a diabetic state.

scholarly journals Systemic Delivery of TNF-Related Apoptosis-Inducing Ligand (TRAIL) Elevates Levels of Tissue Inhibitor of Metalloproteinase-1 (TIMP-1) and Prevents Type 1 Diabetes in Nonobese Diabetic Mice

Endocrinology ◽  
2010 ◽  
Vol 151 (12) ◽  
pp. 5638-5646 ◽  
Author(s):  
Soojeong Kang ◽  
Eun-Jin Park ◽  
Yeonsoo Joe ◽  
Eunhui Seo ◽  
Mi-Kyoung Park ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
Blood Glucose ◽  
Gelatin Zymography ◽  
Nod Mice ◽  
Tissue Inhibitor Of Metalloproteinase ◽  
Tissue Inhibitor ◽  
Nonobese Diabetic ◽  
Induced Apoptosis

Recent studies have demonstrated that TNF-related apoptosis-inducing ligand (TRAIL) is a modulator of the immune response. The relation between TRAIL and type 1 diabetes (T1D) as an autoimmune inflammatory disease in vivo is relatively unknown. To explore the potential role of TRAIL in the development of T1D, we examined its in vivo effects in nonobese diabetic (NOD) mice. NOD mice at 7 wk of age were iv injected with an adenovirus carrying either human TRAIL (Ad.hTRAIL) or β-galactosidase genes. Blood glucose was monitored weekly, and the expression of hTRAIL was evaluated in plasma and liver of mice. To investigate whether hTRAIL elicits its effect through the induction of tissue inhibitor of metalloproteinase-1 (TIMP-1), we examined the concentration of plasma TIMP-1 by ELISA and the inhibition of matrix metalloproteinase (MMP) by gelatin zymography. Here, we show that Ad.hTRAIL-transduced mice had significantly reduced blood glucose levels and markedly increased production of TIMP-1 compared with control β-galactosidase animals. Pancreatic tissue isolated from Ad.hTRAIL-treated NOD mice showed reduced MMP activities associated with significantly improved insulitis. In addition, TIMP-1 in vitro suppressed cytokine-induced apoptosis in insulin-producing INS-1 cells. These results indicate that T1D can be prevented by TRAIL overexpression through enhancement of TIMP-1 function. Elevated TIMP-1 production inhibits the activity of MMPs, which may contribute to suppress the transmigration of diabetogenic T cells into the pancreatic islets and protects pancreatic β-cells from cytokine-induced apoptosis. Therefore, TRAIL and TIMP-1 induction may be potential targets to prevent development of T1D.

scholarly journals Circulating insulin inhibits glucagon secretion induced by arginine in type 1 diabetes

2000 ◽  
pp. 30-34 ◽  
Author(s):  
PR Oskarsson ◽  
PE Lins ◽  
B Ahre ◽  
UC Adamson
Keyword(s):  
Growth Hormone ◽  
Type 1 Diabetes ◽  
Blood Glucose ◽  
Blood Glucose Level ◽  
Glucose Level ◽  
Glucagon Secretion ◽  
Suppressive Effect ◽  
C Peptide ◽  
Dose Infusion

OBJECTIVE: To evaluate if insulin has a suppressive effect on the glucagon secretion stimulated by arginine in type 1 diabetes. RESEARCH DESIGN AND METHODS: The alpha-cell response to an i.v. bolus of arginine (150mgkg(-1)) followed by an infusion of arginine (10mgkg(-1)min(-1)) was studied in random order during either low dose infusion (LDT) or high dose infusion (HDT) of insulin in ten patients with type 1 diabetes. The blood glucose level was clamped at an arterialized level of 5mmoll(-1) by a variable infusion of glucose. Venous C-peptide, glucagon, growth hormone, and insulin were analyzed. RESULTS: The mean plasma concentration of insulin was four times higher during the HDT. The C-peptide level did not differ between the LDT and the HDT. During the LDT in response to arginine the blood glucose level increased from 5.0 to 5.8mmol l(-1) although the glucose infusion was markedly reduced, while no change was seen during the HDT. A significantly smaller increase in the glucagon levels during the HDT was seen (area under the curve of 413+/-45 vs 466+/-44pgml(-1)h(-1), P=0.03) while the growth hormone levels were almost identical. CONCLUSION: This study demonstrates that a high level of circulating insulin exerts an inhibitory effect on the glucagon response to arginine in type 1 diabetes. Thus, the suppressive effect of insulin on the glucagon release from the alpha-cell seems to be general and not only dependent on stimulation by hypoglycemia.

A fully implantable device for intraperitoneal drug delivery refilled by ingestible capsules

2021 ◽  
Vol 6 (57) ◽  
pp. eabh3328
Author(s):  
Veronica Iacovacci ◽  
Izadyar Tamadon ◽  
Emanuele Federico Kauffmann ◽  
Stefano Pane ◽  
Virginia Simoni ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
Blood Glucose ◽  
Control Unit ◽  
Robotic Device ◽  
Physiological Processes ◽  
Critical Issues ◽  
And Control ◽  
Integrated Device

Creating fully implantable robots that replace or restore physiological processes is a great challenge in medical robotics. Restoring blood glucose homeostasis in patients with type 1 diabetes is particularly interesting in this sense. Intraperitoneal insulin delivery could revolutionize type 1 diabetes treatment. At present, the intraperitoneal route is little used because it relies on accessing ports connecting intraperitoneal catheters to external reservoirs. Drug-loaded pills transported across the digestive system to refill an implantable reservoir in a minimally invasive fashion could open new possibilities in intraperitoneal delivery. Here, we describe PILLSID (PILl-refiLled implanted System for Intraperitoneal Delivery), a fully implantable robotic device refillable through ingestible magnetic pills carrying drugs. Once refilled, the device acts as a programmable microinfusion system for precise intraperitoneal delivery. The robotic device is grounded on a combination of magnetic switchable components, miniaturized mechatronic elements, a wireless powering system, and a control unit to implement the refilling and control the infusion processes. In this study, we describe the PILLSID prototyping. The device key blocks are validated as single components and within the integrated device at the preclinical level. We demonstrate that the refilling mechanism works efficiently in vivo and that the blood glucose level can be safely regulated in diabetic swine. The device weights 165 grams and is 78 millimeters by 63 millimeters by 35 millimeters, comparable with commercial implantable devices yet overcoming the urgent critical issues related to reservoir refilling and powering.

scholarly journals FAILURE OF PANCREATIC ALPHA CELLS TO RESPOND TO HYPOGLYCEMIA IS LINKED TO IMPAIRED GLUTAMATE RECEPTOR SIGNALING IN DIABETES

2021 ◽  
Author(s):  
Julia Katharina Panzer ◽  
Alejandro Tamayo ◽  
Alejandro Caicedo
Keyword(s):  
Type 1 Diabetes ◽  
Glucagon Secretion ◽  
Kainate Receptors ◽  
Kainate Receptor ◽  
Allosteric Modulators ◽  
Alpha Cells ◽  
Receptor Signaling ◽  
Pancreatic Alpha Cells ◽  
Positive Allosteric Modulators

Glucagon secretion from the pancreatic alpha cells is crucial to prevent hypoglycemia. People with type 1 diabetes, however, lose this glucoregulatory mechanism and are susceptible to dangerous insulin treatment-induced hypoglycemia. We established that activating glutamate receptors of the AMPA/kainate type in alpha cells is needed for decreases in glucose levels to elicit full glucagon responses from mouse and human islets. We performed functional studies using living pancreas slices from donors with type 1 diabetes and found that alpha cells had normal glucagon content and responded typically to KCl depolarization, but failed to respond to decreases in glucose concentration and had severely impaired AMPA/kainate receptor signaling. Reactivating residual AMPA/kainate receptor function with the positive allosteric modulators cyclothiazide and aniracetam partially rescued glucagon secretion in response to hypoglycemia. Positive allosteric modulators of AMPA/kainate receptors already approved to treat other conditions could thus be repurposed to prevent hypoglycemia and improve management of diabetes.

Partial ablation of leptin signaling in mouse pancreatic α-cells does not alter either glucose or lipid homeostasis

2014 ◽  
Vol 306 (7) ◽  
pp. E748-E755 ◽  
Author(s):  
Eva Tudurí ◽  
Heather C. Denroche ◽  
Jenna A. Kara ◽  
Ali Asadi ◽  
Jessica K. Fox ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
Leptin Receptor ◽  
Pathological Condition ◽  
Immunohistochemical Analysis ◽  
Glucagon Secretion ◽  
Inhibitory Effect ◽  
Leptin Resistance ◽  
Lipid Homeostasis

The role of glucagon in the pathological condition of diabetes is gaining interest, and it has been recently reported that its action is essential for hyperglycemia to occur. Glucagon levels, which are elevated in some diabetic models, are reduced following leptin therapy. Likewise, hyperglycemia is corrected in type 1 diabetic mice treated with leptin, although the mechanisms have not been fully determined. A direct inhibitory effect of leptin on mouse and human α-cells has been demonstrated at the levels of electrical activity, calcium signaling, and glucagon secretion. In the present study we employed the Cre- loxP strategy to generate Lepr flox/flox Gcg-cre mice, which specifically lack leptin receptors in glucagon-secreting α-cells, to determine whether leptin resistance in α-cells contributes to hyperglucagonemia, and also whether leptin action in α-cells is required to improve glycemia in type 1 diabetes with leptin therapy. Immunohistochemical analysis of pancreas sections revealed Cre-mediated recombination in ∼43% of the α-cells. We observed that in vivo Lepr flox/flox Gcg-cre mice display normal glucose and lipid homeostasis. In addition, leptin administration in streptozotocin-induced diabetic Lepr flox/flox Gcg-cre mice restored euglycemia similarly to control mice. These findings suggest that loss of leptin receptor signaling in close to one-half of α-cells does not alter glucose metabolism in vivo, nor is it sufficient to prevent the therapeutic action of leptin in type 1 diabetes.

scholarly journals Brain Glycogen Content and Metabolism in Subjects with Type 1 Diabetes and Hypoglycemia Unawareness

2011 ◽  
Vol 32 (2) ◽  
pp. 256-263 ◽  
Author(s):  
Gülin Öz ◽  
Nolawit Tesfaye ◽  
Anjali Kumar ◽  
Dinesh K Deelchand ◽  
Lynn E Eberly ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
Blood Glucose ◽  
Glycogen Content ◽  
Blood Glucose Concentration ◽  
Occipital Lobe ◽  
Resonance Spectroscopy ◽  
Hypoglycemia Unawareness ◽  
Brain Glycogen

Supercompensated brain glycogen may contribute to the development of hypoglycemia unawareness in patients with type 1 diabetes by providing energy for the brain during periods of hypoglycemia. Our goal was to determine if brain glycogen content is elevated in patients with type 1 diabetes and hypoglycemia unawareness. We used in vivo13C nuclear magnetic resonance spectroscopy in conjunction with [1-13C]glucose administration in five patients with type 1 diabetes and hypoglycemia unawareness and five age-, gender-, and body mass index-matched healthy volunteers to measure brain glycogen content and metabolism. Glucose and insulin were administered intravenously over ∼51 hours at a rate titrated to maintain a blood glucose concentration of 7 mmol/L. 13C-glycogen levels in the occipital lobe were measured at ∼5, 8, 13, 23, 32, 37, and 50 hours, during label wash-in and wash-out. Newly synthesized glycogen levels were higher in controls than in patients ( P<0.0001) for matched average blood glucose and insulin levels, which may be due to higher brain glycogen content or faster turnover in controls. Metabolic modeling indicated lower brain glycogen content in patients than in controls ( P=0.07), implying that glycogen supercompensation does not contribute to the development of hypoglycemia unawareness in humans with type 1 diabetes.

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