Glucagon - a forgotten pancreatic hormone
Glucagon is a hormone that is mostly produced by pancreatic alpha cells. It is clinically utilized as first aid for hypoglycemia due to its insulin-regulatory properties. In all types of diabetes, plasma glucagon concentrations are high, As a result, compounds that lower glucagon concentrations or block glucagon activity have been discovered to treat type 2 diabetics (T2D). Aside from glucoregulation, glucagon has a significant impact on lipid metabolism, energy expenditure, and satiety. Novel treatments combine glucagon receptors with other receptors, such as GLP1 and GIP receptors. These multi agonist's preclinical findings are quite promising, Furthermore, these novel multiagonists may give much-needed new avenues for treating metabolic disorders such as obesity and T2D.
Hormones are derived from preproglucagon (amino acids 1–160) (9). In the pancreas, the action of prohormone convertase 2 (PK-2) results in the production of a glicentin-related pancreatic polypeptide (GRPP), glucagon, and a proglucagon fragment. In the gut, the action of PK-1/3 results in the production of glicentin, GLP-1, and GLP-2. In addition, several glucagon variants have been identified in plasma, of which proglucagon 1-61 is the most common.
Glucagon physiological
Glucagon is mainly secreted by pancreatic alpha cells. It causes hyperglycemia by increasing glycogen breakdown, or glycogenolysis, in the liver, and on the other hand, it increases gluconeogenesis. This is a major protective mechanism against hypoglycemia, and low glucose directly stimulates glucagon secretion. Insulin and high glucose, on the other hand, inhibit glucagon secretion.
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Effects of glucagon on different organ groups by way of example. In fat cells, glucagon increases lipolysis by stimulating hormone-sensitive lipase. The classical glucagon effect of the liver is an increase in glycogenolysis and glucose production and acts as a protective mechanism against hypoglycemia.
Glucagon also increases lipid oxidation and ketogenesis in the liver and decreases triglyceride synthesis. Glucagon acts centrally as a saturation factor and increases energy consumption and thermogenesis. In addition, centrally administered glucagon reduces hepatic glucose production and improves glucose tolerance in experimental animals (2.5).
Acutely administered glucagon increases plasma glucose levels, which is utilized in the first aid for hypoglycemia. Given the other beneficial metabolic effects of glucagon, the stable glucagon receptor agonists under development, which also combine the agonism of receptors with other intestinal peptides (such as GLP-1 and GIP), offer entirely new possibilities for the treatment of obesity and type 2 diabetes (2,3,32). ↑ = increase, ↓ = decrease Given the other beneficial metabolic effects of glucagon, the stable glucagon receptor agonists under development, which also combine the agonism of receptors with other intestinal peptides (such as GLP-1 and GIP), offer entirely new possibilities for the treatment of obesity and type 2 diabetes.
Plasma glucagon levels are increased in all forms of diabetes. Drugs that reduce or inhibit plasma glucagon levels alleviate hyperglycemia, and interventions affecting glucagon have been the subject of intense research.
In addition to glucose metabolism, glucagon has fundamental effects on fat metabolism. Glucagon increases lipolysis, fatty acid oxidation, and ketogenesis. It increases heat production, ie thermogenesis, and energy consumption. Central glucagon infusion into the mediobasal hypothalamus has the opposite effect to the peripheral effect of glucagon, as centrally administered glucagon reduces hepatic glucose production and improves glucose tolerance. In addition, glucagon acts as a satiety factor: its appetite suppressant effect was identified as early as six decades ago. However, for years, this phenomenon was left out of the saturation study.
Excretion of glucagon from outside the pancreas
A new, highly accurate analytical system has been investigated by a Danish research team to investigate the possible extrapancreatic secretion of glucagon. The study involved a number of patients whose pancreas had been completely removed due to the disease. Subjects were examined twice. On the first study visit, they took glucose orally. In a second study visit, researchers infused them intravenously with as much glucose as needed to increase plasma glucose levels to the same extent as with oral glucose.
As expected, plasma glucose levels in pancreatic patients were elevated and diabetic. A classical incretin effect was observed in healthy controls, as C-peptide secretion, which reflects insulin secretion, was significantly higher when oral glucose was administered compared to intravenous administration.
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The C-peptide value of pancreatic patients was not measurable, indicating absolute insulin deficiency. Another indication of the completeness of pancreatic removal was the immeasurably low pancreatic polypeptide content. In healthy subjects, plasma glucagon levels decreased after oral administration of glucose, and the same was observed after intravenous glucose infusion.
However, glucagon levels decreased with a delay after oral administration of glucose compared to intravenous administration. Plasma glucagon levels in measurable patients were measurable, and intravenous glucose infusion rapidly reduced their glucagon levels. In contrast, after oral glucose, plasma glucagon levels in pancreatectomy patients increased markedly.
This study unequivocally shows that in humans, glucagon of 29 amino acids is also excreted outside the pancreas. However, based on the study, the tissue responsible for glucagon secretion in pancreatic patients cannot be precisely located. However, different responses to oral (increased glucagon) and intravenous (decreased) glucose suggest that glucagon is excreted from the gastrointestinal tract outside the pancreas. The hyperglucagonemic response to oral glucose appears to affect postprandial hyperglycemia in pancreatic patients.
Utilizing the latest proteomic techniques, several glucagon variants have been identified from human plasma. The most common of these is proglucagon 1-61 (PG 1-61), which includes amino acids 1-61 of the proglucagon molecule. Concentrations of PG 1-61 are increased in patients with renal insufficiency, obesity, and type 2 diabetes, but in normal-weight healthy subjects, it is below the limit of quantification (9). Concentrations of PG 1-61 decrease after renal transplantation, suggesting that PG 1-61 is eliminated by the kidneys. PG 1-61 levels in type 2 diabetics increase after a meal. Ingestion of fats or proteins increases PG 1-61 levels in obese people.
Clinical use of glucagon
As first aid for hypoglycemia, glucagon 1 mg may be administered intramuscularly if there are difficulties in opening the vascular access. Glucagon mobilizes glucose from the liver into the bloodstream by stimulating glycogenolysis. The effect is usually seen within ten minutes of the injection. Thus, the effect of glucagon is too slow if the patient cramps or is unconscious as a result of hypoglycemia.
Indeed, a patient who is convulsive or unconscious due to hypoglycemia is given glucose intravenously. While waiting for vascular contact, glucose, such as honey, may be administered to the oral mucosa. Diabetics who are prone to hypoglycemia should take glucagon with them as first aid.
Glucagon has also been tested as first aid for hypoglycemia as a nasal spray. A study conducted outside the study laboratory in an everyday setting included 69 types 1 diabetic with a total of 157 moderate to severe hypoglycemias.
Hypoglycemia in almost all participants returned to normal within 30 minutes of nasal glucagon injection. Severe hypoglycemia was experienced by seven participants and they recovered within 15 minutes of taking glucagon. Nasal glucagon seems to be a viable alternative to the intramuscular or subcutaneous glucagon pens currently in use.
Continuous glucagon infusion to prevent hypoglycemia. A study reported so far only as a congressional abstract (American Diabetes Association 76th Scientific Sessions, New Orleans, 2016) investigated the efficacy of continuous glucagon infusion in preventing hypoglycemia in type 1 diabetics. Twenty-two adult type 1 diabetics with impaired knowledge of hypoglycemia were recruited for the study.
In the intervention group, subjects used a bihormonal pump that sensitized the patient's glucose level for a week (only the glucagon chamber was filled), which delivered a small glucagon bolus if hypoglycemia was detected by a continuous real-time glucose sensor. Patients used either their own insulin pump or insulin multi-injection therapy as usual. The results were promising, with a 75% reduction in the time patients had hypoglycemia (plasma glucose below 3.3 mmol / l) in the intervention group.
More importantly, nocturnal hypoglycemias were reduced by 91%. Glucose sensing revealed that the mean plasma glucose concentration in the glucagon group did not differ from the placebo group (8.5 vs 8.4 mmol / l). Treatment was well tolerated. that in the glucagon group, the mean plasma glucose concentration did not differ from the placebo group (8.5 vs 8.4 mmol / l). Treatment was well tolerated . that in the glucagon group, the mean plasma glucose concentration did not differ from the placebo group (8.5 vs 8.4 mmol / l). Treatment was well tolerated.
Glucagon as part of insulin pump therapy. Glucagon infusion has also been tested as part of concomitant insulin pump therapy. The bihormonary pump system (bionic pancreas) has been infused with both insulin and small amounts of glucagon based on continuous glucose sensing under the control of an automatically adaptive algorithm.
In the past, the method has been used for a short time inward conditions. The research team tested the bionic pancreas for five days outside the hospital in adult and adolescent type 1 diabetics. During the comparison period, subjects used their own insulin pump. Treatment was initiated by entering only patient weight information.
No information about the patient's previous insulin therapy was entered into the algorithm, but the algorithm began to automatically adjust the insulin dose of the pump based on glucose sensing and the declared meal (breakfast, lunch, or dinner, and a smaller, normal, or larger amount of food).
The use of the bionic pancreas clearly improved mean glycemic control and reduced episodes of hypoglycemia in adult patients. Blood glucose balance also improved in young patients. The use of the bionic pancreas clearly improved mean glycemic control and reduced episodes of hypoglycemia in adult patients
The same study group published the first results of home use of bionic pancreas in 2017. Bionic pancreas used for 11 days at home improved glycemic control and reduced episodes of hypoglycemia in adults compared with conventional insulin pump therapy.
The results of the use of bionic pancreas, i.e. the simultaneous infusion of insulin and glucagon, in the treatment of type 1 diabetics are very promising. One problem with the development work has been the poor shelf life of the available glucagon: the glucagon tank has had to be filled daily with fresh glucagon solution. In the future, the bionic pancreas is likely to be of particular benefit to type 1 diabetic with high daily variability in glucose levels and frequent episodes of hypoglycemia.
Pathogenesis of glucagon and diabetic ketoacidosis
Ketosis occurs in a situation where the oxidation of fatty acids is mainly responsible for energy production. In diabetic ketoacidosis, absolute insulin deficiency leads to accelerated lipolysis and an increased supply of free fatty acids to the liver. Increased glucagon concentration promotes fatty acid oxidation and ketone formation.
In experimental animal studies, non-insulin-deficient mice with medically destroyed beta cells do not develop diabetic ketoacidosis (or hyperglycemia) if the glucagon effect is inhibited. This suggests that in addition to insulin deficiency, increased glucagon levels are a very significant factor in the development of diabetic ketoacidosis.
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