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Diabetes Oct 2023Whole-body glucose homeostasis is coordinated through secretion of glucagon and insulin from pancreatic islets. When glucose is low, glucagon is released from α-cells...
UNLABELLED
Whole-body glucose homeostasis is coordinated through secretion of glucagon and insulin from pancreatic islets. When glucose is low, glucagon is released from α-cells to stimulate hepatic glucose production. However, the mechanisms that regulate glucagon secretion from pancreatic α-cells remain unclear. Here we show that in α-cells, the interaction between fatty acid oxidation and glucose metabolism controls glucagon secretion. The glucose-dependent inhibition of glucagon secretion relies on pyruvate dehydrogenase and carnitine palmitoyl transferase 1a activity and lowering of mitochondrial fatty acid oxidation by increases in glucose. This results in reduced intracellular ATP and leads to membrane repolarization and inhibition of glucagon secretion. These findings provide a new framework for the metabolic regulation of the α-cell, where regulation of fatty acid oxidation by glucose accounts for the stimulation and inhibition of glucagon secretion.
ARTICLE HIGHLIGHTS
It has become clear that dysregulation of glucagon secretion and α-cell function plays an important role in the development of diabetes, but we do not know how glucagon secretion is regulated. Here we asked whether glucose inhibits fatty acid oxidation in α-cells to regulate glucagon secretion. We found that fatty acid oxidation is required for the inhibitory effects of glucose on glucagon secretion through reductions in ATP. These findings provide a new framework for the regulation of glucagon secretion by glucose.
Topics: Adenosine Triphosphate; Blood Glucose; Fatty Acids; Glucagon; Glucagon-Secreting Cells; Glucose; Insulin; Islets of Langerhans; Humans; Animals; Mice
PubMed: 37494670
DOI: 10.2337/db23-0056 -
Diabetes Sep 2023Carboxypeptidase E (CPE) facilitates the conversion of prohormones into mature hormones and is highly expressed in multiple neuroendocrine tissues. Carriers of CPE...
UNLABELLED
Carboxypeptidase E (CPE) facilitates the conversion of prohormones into mature hormones and is highly expressed in multiple neuroendocrine tissues. Carriers of CPE mutations have elevated plasma proinsulin and develop severe obesity and hyperglycemia. We aimed to determine whether loss of Cpe in pancreatic β-cells disrupts proinsulin processing and accelerates development of diabetes and obesity in mice. Pancreatic β-cell-specific Cpe knockout mice (βCpeKO; Cpefl/fl x Ins1Cre/+) lack mature insulin granules and have elevated proinsulin in plasma; however, glucose-and KCl-stimulated insulin secretion in βCpeKO islets remained intact. High-fat diet-fed βCpeKO mice showed weight gain and glucose tolerance comparable with those of Wt littermates. Notably, β-cell area was increased in chow-fed βCpeKO mice and β-cell replication was elevated in βCpeKO islets. Transcriptomic analysis of βCpeKO β-cells revealed elevated glycolysis and Hif1α-target gene expression. On high glucose challenge, β-cells from βCpeKO mice showed reduced mitochondrial membrane potential, increased reactive oxygen species, reduced MafA, and elevated Aldh1a3 transcript levels. Following multiple low-dose streptozotocin injections, βCpeKO mice had accelerated development of hyperglycemia with reduced β-cell insulin and Glut2 expression. These findings suggest that Cpe and proper proinsulin processing are critical in maintaining β-cell function during the development of hyperglycemia.
ARTICLE HIGHLIGHTS
Carboxypeptidase E (Cpe) is an enzyme that removes the carboxy-terminal arginine and lysine residues from peptide precursors. Mutations in CPE lead to obesity and type 2 diabetes in humans, and whole-body Cpe knockout or mutant mice are obese and hyperglycemic and fail to convert proinsulin to insulin. We show that β-cell-specific Cpe deletion in mice (βCpeKO) does not lead to the development of obesity or hyperglycemia, even after prolonged high-fat diet treatment. However, β-cell proliferation rate and β-cell area are increased, and the development of hyperglycemia induced by multiple low-dose streptozotocin injections is accelerated in βCpeKO mice.
Topics: Animals; Mice; Carboxypeptidase H; Diabetes Mellitus, Type 2; Glucose; Hyperglycemia; Insulin; Insulin-Secreting Cells; Islets of Langerhans; Mice, Knockout; Obesity; Proinsulin; Streptozocin
PubMed: 37364047
DOI: 10.2337/db22-0945 -
International Journal of Pharmaceutics Mar 2024As the 100th anniversary of glucagon's discovery approaches, we reflect on the remarkable journey of understanding its pivotal role in glucose regulation. Advancements... (Review)
Review
As the 100th anniversary of glucagon's discovery approaches, we reflect on the remarkable journey of understanding its pivotal role in glucose regulation. Advancements in glucagon delivery systems for managing hypoglycemia are unfolding with promise, albeit accompanied by formulation and implementation challenges. Recent developments include non-injectable methods like BAQSIMI® (Nasal glucagon) offers a user-friendly option, but stability, bioavailability, and rapid onset remain formulation hurdles. Closed-loop systems, combining glucagon with insulin, aim to automate glucose control, demanding stable and precise formulations compatible with complex algorithms. However, achieving co-delivery harmony and effective dual-hormone responses poses substantial challenges. Ogluo® and Gvoke HypoPen® are auto-injector pens, a ready-to-use solution that can rapidly control hypoglycemia and eliminate the need for mixing powder and liquid. GlucaGen® Hypokit® and Glucagon Emergency Kits are traditional deliveries that possess complexity during administration and are still widely used in clinical practice. In addition to this advancement, we have covered the recent patents and clinical trials of glucagon delivery. The synergy of patent innovation and clinical validation offers a glimpse into the transformative potential of glucagon delivery yet underscores the intricate path toward widespread adoption and improved diabetes care. Finally, this review will help the formulation scientist, clinicians, healthcare providers, and patient to manage hypoglycemia using glucagon.
Topics: Humans; Glucagon; Hypoglycemia; Insulin; Diabetes Mellitus; Blood Glucose; Diabetes Mellitus, Type 1
PubMed: 38224759
DOI: 10.1016/j.ijpharm.2024.123785 -
The New England Journal of Medicine Nov 2023Mahvash disease is an exceedingly rare genetic disorder of glucagon signaling characterized by hyperglucagonemia, hyperaminoacidemia, and pancreatic α-cell hyperplasia....
Mahvash disease is an exceedingly rare genetic disorder of glucagon signaling characterized by hyperglucagonemia, hyperaminoacidemia, and pancreatic α-cell hyperplasia. Although there is no known definitive treatment, octreotide has been used to decrease systemic glucagon levels. We describe a woman who presented to our medical center after three episodes of small-volume hematemesis. She was found to have hyperglucagonemia and pancreatic hypertrophy with genetically confirmed Mahvash disease and also had evidence of portal hypertension (recurrent portosystemic encephalopathy and variceal hemorrhage) in the absence of cirrhosis. These findings established a diagnosis of portosinusoidal vascular disease, a presinusoidal type of portal hypertension previously known as noncirrhotic portal hypertension. Liver transplantation was followed by normalization of serum glucagon and ammonia levels, reversal of pancreatic hypertrophy, and resolution of recurrent encephalopathy and bleeding varices.
Topics: Female; Humans; Esophageal and Gastric Varices; Gastrointestinal Hemorrhage; Glucagon; Hypertension, Portal; Hypertrophy; Liver Cirrhosis; Liver Transplantation; Genetic Diseases, Inborn; Pancreatic Diseases; Glucagon-Secreting Cells
PubMed: 37991855
DOI: 10.1056/NEJMoa2303226 -
International Journal of Molecular... Jan 2024Diabetes mellitus is a devastating chronic metabolic disease. Since the majority of type 2 diabetes mellitus patients are overweight or obese, a novel term-diabesity-has... (Review)
Review
Diabetes mellitus is a devastating chronic metabolic disease. Since the majority of type 2 diabetes mellitus patients are overweight or obese, a novel term-diabesity-has emerged. The gut-brain axis plays a critical function in maintaining glucose and energy homeostasis and involves a variety of peptides. Amylin is a neuroendocrine anorexigenic polypeptide hormone, which is co-secreted with insulin from β-cells of the pancreas in response to food consumption. Aside from its effect on glucose homeostasis, amylin inhibits homeostatic and hedonic feeding, induces satiety, and decreases body weight. In this narrative review, we summarized the current evidence and ongoing studies on the mechanism of action, clinical pharmacology, and applications of amylin and its analogs, pramlintide and cagrilintide, in the field of diabetology, endocrinology, and metabolism disorders, such as obesity.
Topics: Humans; Islet Amyloid Polypeptide; Diabetes Mellitus, Type 2; Hypoglycemic Agents; Insulin; Obesity; Glucose; Amyloid
PubMed: 38338796
DOI: 10.3390/ijms25031517 -
Diabetes, Obesity & Metabolism Jan 2024The development of pancreatic islet endocrine cells is a tightly regulated process leading to the generation of distinct cell types harbouring different hormones in... (Review)
Review
The development of pancreatic islet endocrine cells is a tightly regulated process leading to the generation of distinct cell types harbouring different hormones in response to small changes in environmental stimuli. Cell differentiation is driven by transcription factors that are also critical for the maintenance of the mature islet cell phenotype. Alteration of the insulin-secreting β-cell transcription factor set by prolonged metabolic stress, associated with the pathogenesis of diabetes, obesity or pregnancy, results in the loss of β-cell identity through de- or transdifferentiation. Importantly, the glucose-lowering effects of approved and experimental antidiabetic agents, including glucagon-like peptide-1 mimetics, novel peptides and small molecules, have been associated with preventing or reversing β-cell dedifferentiation or promoting the transdifferentiation of non-β-cells towards an insulin-positive β-cell-like phenotype. Therefore, we review the manifestations of islet cell plasticity in various experimental settings and discuss the physiological and therapeutic sides of this phenomenon, focusing on strategies for preventing β-cell loss or generating new β-cells in diabetes. A better understanding of the molecular mechanisms underpinning islet cell plasticity is a prerequisite for more targeted therapies to help prevent β-cell decline in diabetes.
Topics: Humans; Cell Plasticity; Islets of Langerhans; Insulin; Insulin-Secreting Cells; Diabetes Mellitus; Cell Transdifferentiation
PubMed: 37845573
DOI: 10.1111/dom.15300 -
International Journal of Molecular... Dec 2023Type 1 diabetes (T1D) is a chronic autoimmune disease characterized by the destruction of insulin-producing pancreatic β-cells by the immune system. Although... (Review)
Review
Type 1 diabetes (T1D) is a chronic autoimmune disease characterized by the destruction of insulin-producing pancreatic β-cells by the immune system. Although conventional therapeutic modalities, such as insulin injection, remain a mainstay, recent years have witnessed the emergence of novel treatment approaches encompassing immunomodulatory therapies, such as stem cell and β-cell transplantation, along with revolutionary gene-editing techniques. Notably, recent research endeavors have enabled the reshaping of the T-cell repertoire, leading to the prevention of T1D development. Furthermore, CRISPR-Cas9 technology has demonstrated remarkable potential in targeting endogenous gene activation, ushering in a promising avenue for the precise guidance of mesenchymal stem cells (MSCs) toward differentiation into insulin-producing cells. This innovative approach holds substantial promise for the treatment of T1D. In this review, we focus on studies that have developed T1D models and treatments using gene-editing systems.
Topics: Humans; Diabetes Mellitus, Type 1; Autoimmune Diseases; Insulin, Regular, Human; Insulin; Technology
PubMed: 38203514
DOI: 10.3390/ijms25010344 -
Journal of Diabetes Science and... Sep 2023Open-source Automated Insulin Dosing (OS-AID) algorithms are made publicly accessible so that every facet of their operation can be understood. Currently, commercial AID...
Open-source Automated Insulin Dosing (OS-AID) algorithms are made publicly accessible so that every facet of their operation can be understood. Currently, commercial AID algorithms are kept proprietary trade secrets, despite the role they take in making life and death decisions for people living with type 1 diabetes. Loop was the second OS-AID algorithm, developed initially by Nate Racklyeft and Pete Schwamb. In 2018, the nonprofit organization Tidepool (Palo Alto, CA) announced the launch of the "Tidepool Loop" initiative with the aim to generate real-world evidence and obtain regulatory clearance. By the end of 2020, the U.S. Food and Drug Administration received Tidepool's application for an interoperable automated glycemic controller based on Loop. After 2 years, the FDA approved the Tidepool Loop on January 23, 2023.
Topics: Humans; Insulin; Blood Glucose; Diabetes Mellitus, Type 1; Insulin, Regular, Human; Algorithms; Insulin Infusion Systems; Hypoglycemic Agents
PubMed: 37051947
DOI: 10.1177/19322968231164166 -
Diabetes, Obesity & Metabolism Aug 2023Insulin action in the brain influences cognitive processes, peripheral metabolism and eating behaviour. However, the influence of age and peripheral insulin sensitivity...
AIMS
Insulin action in the brain influences cognitive processes, peripheral metabolism and eating behaviour. However, the influence of age and peripheral insulin sensitivity on brain insulin action remains unclear.
MATERIALS AND METHODS
We used intranasal administration of insulin and functional magnetic resonance imaging in a randomized, placebo-controlled within-subject design in 110 participants (54 women, body mass index 18-49 kg/m , age 21-74 years). Cerebral blood flow was measured before and after nasal spray application to assess brain insulin action. Peripheral insulin sensitivity was assessed by a five-point oral glucose tolerance test. Linear regressions were used to investigate associations between age and peripheral insulin sensitivity with brain insulin action in predefined region of interests (i.e. insulin-sensitive brain regions).
RESULTS
We found significant negative associations between age and insulin action in the hippocampus (β = -0.215; p = .017) and caudate nucleus (β = -0.184; p = .047); and between peripheral insulin sensitivity and insulin action in the amygdala (β = -0.190, p = .023). Insulin action in the insular cortex showed an interaction effect between age and peripheral insulin sensitivity (β = -0.219 p = .005). Furthermore, women showed the strongest negative association between age and hippocampal insulin action, while men showed the strongest associations with peripheral insulin sensitivity and age in reward-related brain regions.
CONCLUSION
We could show a region-specific relationship between brain insulin responsiveness, age and peripheral insulin sensitivity. Our findings underline the need to study brain insulin action in both men and women and further substantiate that brain insulin sensitivity is a possible link between systemic metabolism and neurocognitive functions.
Topics: Male; Humans; Female; Young Adult; Adult; Middle Aged; Aged; Insulin; Insulin Resistance; Brain; Insulin, Regular, Human; Glucose Tolerance Test
PubMed: 37046367
DOI: 10.1111/dom.15094 -
Peptides Jun 2024Circulating insulin levels are known to be increased in people with higher body mass index (BMI) due to effects of adiposity on insulin resistance, whilst gut hormones...
Circulating insulin levels are known to be increased in people with higher body mass index (BMI) due to effects of adiposity on insulin resistance, whilst gut hormones have a more complex relationship, with fasting peptideYY (PYY) reported to be inversely related to BMI. This study aimed to further explore fasting and post prandial pancreatic and gut hormone concentrations in plasma samples from obese and non-obese participants. Participants with healthy BMI (n=15), overweight BMI (n=29) and obesity (n=161) had samples taken fasting and 30 min post mixed liquid meal for analysis of glucagon-like peptide-1 (GLP-1), PYY, glucose-dependent insulinotropic polypeptide (GIP), insulin and glucagon. Data visualiation used linear discriminant analysis for dimensionality reduction, to visualise the data and assess scaling of each hormone. Fasting levels of insulin, GIP and PYY were shown to be key classifiers between the 3 groups on ANCOVA analysis, with an observation of increased GIP levels in overweight, but not obese participants. In non-obese subjects, fasting GIP, PYY and insulin correlated with BMI, whereas in subjects with obesity only the pancreatic hormones glucagon and insulin correlated with BMI. Concentrations of total GLP-1 in the fasting state correlated strongly with glucagon levels, highlighting potential assay cross-reactivities. The study, which included a relatively large number of subjects with severe obesity, supported previous evidence of BMI correlating negatively with fasting PYY and positively with fasting insulin. The observation of increased fasting GIP levels in overweight but not obese participants deserves further validation and mechanistic investigation.
Topics: Humans; Obesity; Male; Female; Adult; Fasting; Peptide YY; Middle Aged; Glucagon-Like Peptide 1; Gastric Inhibitory Polypeptide; Body Mass Index; Insulin; Postprandial Period; Glucagon; Gastrointestinal Hormones
PubMed: 38490484
DOI: 10.1016/j.peptides.2024.171186