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Diabetes & Metabolism Journal Sep 2021The year 2021 marks the 100th anniversary of the discovery of insulin, which has greatly changed the lives of people with diabetes and become a cornerstone of advances... (Review)
Review
The year 2021 marks the 100th anniversary of the discovery of insulin, which has greatly changed the lives of people with diabetes and become a cornerstone of advances in medical science. A rapid bench-to-bedside application of the lifesaving pancreatic extract and its immediate commercialization was the result of a promising idea, positive drive, perseverance, and collaboration of Banting and colleagues. As one of the very few proteins isolated in a pure form at that time, insulin also played a key role in the development of important methodologies and in the beginning of various fields of modern science. Since its discovery, insulin has evolved continuously to optimize the care of people with diabetes. Since the 1980s, recombinant DNA technology has been employed to engineer insulin analogs by modifying their amino acid sequence, which has resulted in the production of insulins with various profiles that are currently used. However, unmet needs in insulin treatment still exist, and several forms of future insulins are under development. In this review, we discuss the past, present, and future of insulin, including a history of ceaseless innovations and collective intelligence. We believe that this story will be a solid foundation and an unerring guide for the future.
Topics: Amino Acid Sequence; Diabetes Mellitus; Humans; Insulin; Insulin, Regular, Human; Insulins
PubMed: 34610718
DOI: 10.4093/dmj.2021.0163 -
Physiological Reviews Apr 2015The preproglucagon gene (Gcg) is expressed by specific enteroendocrine cells (L-cells) of the intestinal mucosa, pancreatic islet α-cells, and a discrete set of neurons... (Review)
Review
The preproglucagon gene (Gcg) is expressed by specific enteroendocrine cells (L-cells) of the intestinal mucosa, pancreatic islet α-cells, and a discrete set of neurons within the nucleus of the solitary tract. Gcg encodes multiple peptides including glucagon, glucagon-like peptide-1, glucagon-like peptide-2, oxyntomodulin, and glicentin. Of these, glucagon and GLP-1 have received the most attention because of important roles in glucose metabolism, involvement in diabetes and other disorders, and application to therapeutics. The generally accepted model is that GLP-1 improves glucose homeostasis indirectly via stimulation of nutrient-induced insulin release and by reducing glucagon secretion. Yet the body of literature surrounding GLP-1 physiology reveals an incompletely understood and complex system that includes peripheral and central GLP-1 actions to regulate energy and glucose homeostasis. On the other hand, glucagon is established principally as a counterregulatory hormone, increasing in response to physiological challenges that threaten adequate blood glucose levels and driving glucose production to restore euglycemia. However, there also exists a potential role for glucagon in regulating energy expenditure that has recently been suggested in pharmacological studies. It is also becoming apparent that there is cross-talk between the proglucagon derived-peptides, e.g., GLP-1 inhibits glucagon secretion, and some additive or synergistic pharmacological interaction between GLP-1 and glucagon, e.g., dual glucagon/GLP-1 agonists cause more weight loss than single agonists. In this review, we discuss the physiological functions of both glucagon and GLP-1 by comparing and contrasting how these peptides function, variably in concert and opposition, to regulate glucose and energy homeostasis.
Topics: Animals; Blood Glucose; Diabetes Mellitus; Energy Metabolism; Enteroendocrine Cells; Gene Expression Regulation; Glucagon; Glucagon-Like Peptide 1; Glucagon-Secreting Cells; Homeostasis; Humans; Signal Transduction
PubMed: 25834231
DOI: 10.1152/physrev.00013.2014 -
Expert Opinion on Pharmacotherapy Nov 2016Neuroendocrine tumors(NETs), once thought rare, are increasing in frequency in most countries and receiving increasing-attention. NETs present two-treatment problems. A... (Review)
Review
Neuroendocrine tumors(NETs), once thought rare, are increasing in frequency in most countries and receiving increasing-attention. NETs present two-treatment problems. A proportion is aggressive and a proportion has a functional, hormone-excess-state(F-NET), each of which must be treated. Recently, there have been many advances, well-covered in reviews/consensus papers on imaging-NETs; new, novel anti-tumor treatments and understanding their pathogenesis. However, little attention has been paid to advances in the treatment of the hormone-excess-state. These advances are usually reported in case-series, and case-reports with few large studies. In this paper these advances are reviewed. Areas covered: Advances in the last 5-years are concentrated on, but a review of literature from the last 10-years was performed. PubMed and other databases (Cochrane, etc.) were searched for F-NET-syndromes including carcinoid-syndrome, as well as meeting-abstracts on NETs. All advances that controlled hormone-excess-states or facilitated-control were covered. These include new medical-therapies [serotonin-synthesis inhibitors(telotristat), Pasireotide, new agents for treating ACTHomas], increased dosing with conventional therapies (octreotide-LAR, Lanreotide-Autogel), mTor inhibitors(everolimus), Tyrosine-kinase inhibitors(sunitinib),cytoreductive surgery, liver-directed therapies (embolization, chemoembolization, radioembolization, RFA), peptide radio-receptor-therapy(PRRT) and I-MIBG, ablation of primary F-NETs. Expert opinion: Although many of the newer therapies controlling the hormone-excess-states in F-NETs are reported in relatively few patients, all the approaches show promise. Their description also generates some controversies/unresolved areas,such as the order of these new treatments, their longterm-efficacy, and effectiveness of combinations which may require large,controlled studies.
Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Everolimus; Humans; Indoles; Molecular Targeted Therapy; Neuroendocrine Tumors; Octreotide; Pyrroles; Somatostatin; Sunitinib; Syndrome; Treatment Outcome
PubMed: 27635672
DOI: 10.1080/14656566.2016.1236916 -
Annals of Medicine Dec 2021Many patients with type 2 diabetes will ultimately require the inclusion of basal insulin in their treatment regimen. Since most people with type 2 diabetes are managed... (Review)
Review
Many patients with type 2 diabetes will ultimately require the inclusion of basal insulin in their treatment regimen. Since most people with type 2 diabetes are managed in the community, it is important that primary care providers understand and correctly manage the initiation and titration of basal insulins, and help patients to self-manage insulin injections. Newer, long-acting basal insulins provide greater stability and flexibility than older preparations and improved delivery systems. Basal insulin is usually initiated at a conservative dose of 10 units/day or 0.1-0.2 units/kg/day, then titrated thereafter over several weeks or months, based on patients' self-measured fasting plasma glucose, to achieve an individualized target (usually 80-130 mg/dL). Through a shared decision-making process, confirmation of appropriate goals and titration methods should be established, including provisions for events that might alter scheduled titration (e.g. travel, dietary change, illness, hospitalization, etc.). Although switching between basal insulins is usually easily accomplished, pharmacokinetic and pharmacodynamic differences between formulations require clinicians to provide explicit guidance to patients. Basal insulin is effective long-term, but overbasalization (continuing to escalate dose without a meaningful reduction in fasting plasma glucose) should be avoided.Key messagesPrimary care providers often initiate basal insulin for people with type 2 diabetes.Basal insulin is recommended to be initiated at 10 units/day or 0.1-0.2 units/kg/day, and doses must be titrated to agreed fasting plasma glucose goals, usually 80-130 mg/dL. A simple rule is to gradually increase the initial dose by 1 unit per day (NPH, insulin detemir, and glargine 100 units/mL) or 2-4 units once or twice per week (NPH, insulin detemir, glargine 100 and 300 units/mL, and degludec) until FPG levels remain consistently within the target range. If warranted, switching between basal insulins can be done using simple regimens.The dose of basal insulin should be increased as required up to approximately 0.5-1.0 units/kg/day in some cases. Overbasalization (continuing to escalate dose without a meaningful reduction in fasting plasma glucose) is not recommended; rather re-evaluation of individual therapy, including consideration of more concentrated basal insulin preparations and/or short-acting prandial insulin as well as other glucose-lowering therapies, is suggested.
Topics: Blood Glucose; Diabetes Mellitus, Type 2; Humans; Hypoglycemic Agents; Insulin; Insulin Detemir; Insulin Glargine; Insulin, Long-Acting; Primary Health Care
PubMed: 34165382
DOI: 10.1080/07853890.2021.1925148 -
The Journal of Endocrinology Sep 2023Since the discovery of glucagon 100 years ago, the hormone and the pancreatic islet alpha cells that produce it have remained enigmatic relative to insulin-producing...
Since the discovery of glucagon 100 years ago, the hormone and the pancreatic islet alpha cells that produce it have remained enigmatic relative to insulin-producing beta cells. Canonically, alpha cells have been described in the context of glucagon's role in glucose metabolism in liver, with glucose as the primary nutrient signal regulating alpha cell function. However, current data reveal a more holistic model of metabolic signalling, involving glucagon-regulated metabolism of multiple nutrients by the liver and other tissues, including amino acids and lipids, providing reciprocal feedback to regulate glucagon secretion and even alpha cell mass. Here we describe how various nutrients are sensed, transported and metabolised in alpha cells, providing an integrative model for the metabolic regulation of glucagon secretion and action. Importantly, we discuss where these nutrient-sensing pathways intersect to regulate alpha cell function and highlight key areas for future research.
Topics: Glucagon; Glucagon-Secreting Cells; Glucose; Signal Transduction; Liver; Insulin
PubMed: 37523232
DOI: 10.1530/JOE-23-0081 -
Signal Transduction and Targeted Therapy Apr 2023Disease modifying therapies aiming to preserve β-cell function in patients with adult-onset autoimmune type 1 diabetes are lacking. Here, we conducted a multi-centre,... (Randomized Controlled Trial)
Randomized Controlled Trial
Disease modifying therapies aiming to preserve β-cell function in patients with adult-onset autoimmune type 1 diabetes are lacking. Here, we conducted a multi-centre, randomized, controlled trial to assess the β-cell preservation effects of saxagliptin alone and saxagliptin combined with vitamin D as adjunctive therapies in adult-onset autoimmune type 1 diabetes. In this 3-arm trial, 301 participants were randomly assigned to a 24-month course of the conventional therapy (metformin with or without insulin) or adjunctive saxagliptin or adjunctive saxagliptin plus vitamin D to the conventional therapy. The primary endpoint was the change from baseline to 24 months in the fasting C-peptide. The secondary endpoints included the area under the concentration-time curve (AUC) for C-peptide level in a 2-h mixed-meal tolerance test, glycemic control, total daily insulin use and safety, respectively. The primary endpoint was not achieved in saxagliptin plus vitamin D group (P = 0.18) and saxagliptin group (P = 0.26). However, compared with the conventional therapy, 2-h C-peptide AUC from 24 months to baseline decreased less with saxagliptin plus vitamin D (-276 pmol/L vs. -419 pmol/L; P = 0.01), and not to the same degree with saxagliptin alone (-314 pmol/L; P = 0.14). Notably, for participants with higher glutamic acid decarboxylase antibody (GADA) levels, the decline of β-cell function was much lower in saxagliptin plus vitamin D group than in the conventional therapy group (P = 0.001). Insulin dose was significantly reduced in both active treatment groups than in the conventional therapy group despite all groups having similar glycemic control. In conclusion, the combination of saxagliptin and vitamin D preserves pancreatic β-cell function in adult-onset autoimmune type 1 diabetes, an effect especially efficacious in individuals with higher GADA levels. Our results provide evidence for a novel adjunct to insulin and metformin as potential initial treatment for adult-onset type 1 diabetes. (ClinicalTrials.gov identifier: NCT02407899).
Topics: Humans; Adult; Hypoglycemic Agents; Diabetes Mellitus, Type 1; Vitamin D; C-Peptide; Blood Glucose; Drug Therapy, Combination; Diabetes Mellitus, Type 2; Metformin; Insulin
PubMed: 37076476
DOI: 10.1038/s41392-023-01369-9 -
Peptides Feb 2022Glucose homeostasis is maintained by the glucoregulatory hormones, glucagon, insulin and somatostatin, secreted from the islets of Langerhans. Glucagon is the body's... (Review)
Review
Glucose homeostasis is maintained by the glucoregulatory hormones, glucagon, insulin and somatostatin, secreted from the islets of Langerhans. Glucagon is the body's most important anti-hypoglycemic hormone, mobilizing glucose from glycogen stores in the liver in response to fasting, thus maintaining plasma glucose levels within healthy limits. Glucagon secretion is regulated by both circulating nutrients, hormones and neuronal inputs. Hormones that may regulate glucagon secretion include locally produced insulin and somatostatin, but also urocortin-3, amylin and pancreatic polypeptide, and from outside the pancreas glucagon-like peptide-1 and 2, peptide tyrosine tyrosine and oxyntomodulin, glucose-dependent insulinotropic polypeptide, neurotensin and ghrelin, as well as the hypothalamic hormones arginine-vasopressin and oxytocin, and calcitonin from the thyroid. Each of these hormones have distinct effects, ranging from regulating blood glucose, to regulating appetite, stomach emptying rate and intestinal motility, which makes them interesting targets for treating metabolic diseases. Awareness regarding the potential effects of the hormones on glucagon secretion is important since secretory abnormalities could manifest as hyperglycemia or even lethal hypoglycemia. Here, we review the effects of each individual hormone on glucagon secretion, their interplay, and how treatments aimed at modulating the plasma levels of these hormones may also influence glucagon secretion and glycemic control.
Topics: Animals; Blood Glucose; Calcitonin; Gastric Inhibitory Polypeptide; Ghrelin; Glucagon; Glucagon-Like Peptide 1; Glucagon-Like Peptide 2; Humans; Insulin; Islet Amyloid Polypeptide; Neurotensin; Oxyntomodulin; Oxytocin; Pancreas; Pancreatic Polypeptide; Somatostatin; Urocortins; Vasopressins
PubMed: 34748791
DOI: 10.1016/j.peptides.2021.170683 -
Frontiers in Immunology 2022Glucagon-like peptide-1 (GLP-1) is a 30-amino acid hormone secreted by L cells in the distal ileum, colon, and pancreatic α cells, which participates in blood sugar... (Review)
Review
Glucagon-like peptide-1 (GLP-1) is a 30-amino acid hormone secreted by L cells in the distal ileum, colon, and pancreatic α cells, which participates in blood sugar regulation by promoting insulin release, reducing glucagon levels, delaying gastric emptying, increasing satiety, and reducing appetite. GLP-1 specifically binds to the glucagon-like peptide-1 receptor (GLP-1R) in the body, directly stimulating the secretion of insulin by pancreatic β-cells, promoting proliferation and differentiation, and inhibiting cell apoptosis, thereby exerting a glycemic lowering effect. The glycemic regulating effect of GLP-1 and its analogues has been well studied in human and murine models in the circumstance of many diseases. Recent studies found that GLP-1 is able to modulate innate immune response in a number of inflammatory diseases. In the present review, we summarize the research progression of GLP-1 and its analogues in immunomodulation and related signal pathways.
Topics: Mice; Humans; Animals; Glucagon-Like Peptide-1 Receptor; Insulin; Glucagon-Like Peptide 1; Blood Glucose; Immunity, Innate
PubMed: 36569936
DOI: 10.3389/fimmu.2022.997578 -
Peptides Oct 2020Amylin is a peptide hormone that is mainly known to be produced by pancreatic β-cells in response to a meal but amylin is also produced by brain cells in discrete brain... (Review)
Review
Amylin is a peptide hormone that is mainly known to be produced by pancreatic β-cells in response to a meal but amylin is also produced by brain cells in discrete brain areas albeit in a lesser amount. Amylin receptor (AMY) is composed of the calcitonin core-receptor (CTR) and one of the 3 receptor activity modifying protein (RAMP), thus forming AMY1-3; RAMP enhances amylin binding properties to the CTR. However, amylin receptor agonist such as salmon calcitonin is able to bind CTR alone. Peripheral amylin's main binding site is located in the area postrema (AP) which then propagate the signal to the nucleus of the solitary tract and lateral parabrachial nucleus (LPBN) and it is then transmitted to the forebrain areas such as central amygdala and bed nucleus of the stria terminalis. Amylin's activation of these different brain areas mediates eating and other metabolic pathways controlling energy expenditure and glucose homeostasis. Peripheral amylin can also bind in the arcuate nucleus of the hypothalamus where it acts independently of the AP to activate POMC and NPY neurons. Amylin activation of NPY neurons has been shown to be transmitted to LPBN neurons to act on eating while amylin POMC signaling affects energy expenditure and locomotor activity. While a large amount of experiments have already been conducted, future studies will have to further investigate how amylin is taken up by forebrain areas and deepen our understanding of amylin action on peripheral metabolism.
Topics: Animals; Appetite Depressants; Brain; Eating; Humans; Islet Amyloid Polypeptide; Pancreatic Hormones; Signal Transduction
PubMed: 32634450
DOI: 10.1016/j.peptides.2020.170366 -
Frontiers in Endocrinology 2021Initially discovered as an impurity in insulin preparations, our understanding of the hyperglycaemic hormone glucagon has evolved markedly over subsequent decades. With... (Review)
Review
Initially discovered as an impurity in insulin preparations, our understanding of the hyperglycaemic hormone glucagon has evolved markedly over subsequent decades. With description of the precursor proglucagon, we now appreciate that glucagon was just the first proglucagon-derived peptide (PGDP) to be characterised. Other bioactive members of the PGDP family include glucagon-like peptides -1 and -2 (GLP-1 and GLP-2), oxyntomodulin (OXM), glicentin and glicentin-related pancreatic peptide (GRPP), with these being produced tissue-specific processing of proglucagon by the prohormone convertase (PC) enzymes, PC1/3 and PC2. PGDP peptides exert unique physiological effects that influence metabolism and energy regulation, which has witnessed several of them exploited in the form of long-acting, enzymatically resistant analogues for treatment of various pathologies. As such, intramuscular glucagon is well established in rescue of hypoglycaemia, while GLP-2 analogues are indicated in the management of short bowel syndrome. Furthermore, since approval of the first GLP-1 mimetic for the management of Type 2 diabetes mellitus (T2DM) in 2005, GLP-1 therapeutics have become a mainstay of T2DM management due to multifaceted and sustainable improvements in glycaemia, appetite control and weight loss. More recently, longer-acting PGDP therapeutics have been developed, while newfound benefits on cardioprotection, bone health, renal and liver function and cognition have been uncovered. In the present article, we discuss the physiology of PGDP peptides and their therapeutic applications, with a focus on successful design of analogues including dual and triple PGDP receptor agonists currently in clinical development.
Topics: Diabetes Mellitus, Type 2; Glucagon; Glucagon-Like Peptide 1; Glucagon-Like Peptide 2; Humans; Proglucagon
PubMed: 34093449
DOI: 10.3389/fendo.2021.689678