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Article ; Online: Glucagon 100 years. Important, but still enigmatic.

Holst, Jens Juul

2023 Volume 161, Page(s) 170942

Abstract: Glucagon was discovered in 1923 as a contaminant of early insulin preparations, and its hormonal status was not established until its structure was established in the 1950 s and when the first radioimmunoassay was developed by Roger Unger, providing ... ...

Abstract	Glucagon was discovered in 1923 as a contaminant of early insulin preparations, and its hormonal status was not established until its structure was established in the 1950 s and when the first radioimmunoassay was developed by Roger Unger, providing information about its secretion. Its role in hepatic glucose production was soon established and it was proposed as an essential factor in diabetic hyperglycemia. However, even today a number of issues remain unsolved. For instance, the assays for glucagon are not straightforward, although the development of sandwich ELISAs allowed reasonably accurate measurements also in rodents. The tools for evaluation of glucagon physiology include pancreatectomy, but studies in both humans and experimental animals pointed towards extrapancreatic sources of glucagon. It was demonstrated that glucagon receptor knockout animals do not develop diabetes upon destruction of their beta cells with streptozotocin. However, in patients with type 1 diabetes, glucagon antagonists do not normalize glucose levels; but antagonists do lower glucose levels in patients with in type 2 diabetes. Recent studies in animals and humans have confirmed the essential role of glucagon in glucose metabolism, but have suggested that it may be at least equally important for amino acid and lipid metabolism. In spite of the 100 years, glucagon research is very much alive.
MeSH term(s)	Animals ; Humans ; Blood Glucose/metabolism ; Diabetes Mellitus, Type 2/drug therapy ; Glucagon/metabolism ; Glucose/metabolism ; Hyperglycemia/metabolism ; Insulin
Chemical Substances	Blood Glucose ; Glucagon (9007-92-5) ; Glucose (IY9XDZ35W2) ; Insulin
Language	English
Publishing date	2023-01-07
Publishing country	United States
Document type	Journal Article
ZDB-ID	769028-9
ISSN	1873-5169 ; 0196-9781
ISSN (online)	1873-5169
ISSN	0196-9781
DOI	10.1016/j.peptides.2023.170942
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Incretin-based therapy of metabolic disease.

Holst, Jens Juul

Danish medical journal

2022 Volume 70, Issue 1

Abstract: Recent studies show that incretin hormone analogues effectively control blood glucose while producing major weight losses and reducing the risk of all-cause mortality, myocardial infarction, stroke and kidney function impairment. Furthermore, the risk of ...

Abstract	Recent studies show that incretin hormone analogues effectively control blood glucose while producing major weight losses and reducing the risk of all-cause mortality, myocardial infarction, stroke and kidney function impairment. Furthermore, the risk of dementia and cognitive impairment is reduced. A monomolecular coagonist (tirzepatide) of receptors for both incretin hormones (glucagon-like peptide-1 and glucose-dependent insulinotropic polypeptide) produced HbA1c values below 5.7% in 50% of the treated patients and weight losses exceeding 20% in obese individuals. These new agents will radically change our approach to the treatment of T2DM and obesity alike.
MeSH term(s)	Humans ; Blood Glucose/metabolism ; Diabetes Mellitus, Type 2/complications ; Diabetes Mellitus, Type 2/drug therapy ; Gastric Inhibitory Polypeptide/metabolism ; Glucagon-Like Peptide 1 ; Incretins/therapeutic use ; Metabolic Diseases/drug therapy ; Obesity/complications ; Obesity/drug therapy ; Weight Loss
Chemical Substances	Blood Glucose ; Gastric Inhibitory Polypeptide (59392-49-3) ; Glucagon-Like Peptide 1 (89750-14-1) ; Incretins
Language	English
Publishing date	2022-12-21
Publishing country	Denmark
Document type	Journal Article
ZDB-ID	2648771-8
ISSN	2245-1919 ; 2245-1919
ISSN (online)	2245-1919
ISSN	2245-1919
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article: Glucagon and other proglucagon-derived peptides in the pathogenesis of obesity.

Holst, Jens Juul

Frontiers in nutrition

2022 Volume 9, Page(s) 964406

Abstract: Because of differential processing of the hormone precursor, proglucagon, numerous peptide products are released from the pancreatic alpha cells and the intestinal L-cells in which the (pro)glucagon gene is expressed. Of particular interest in relation ... ...

Abstract	Because of differential processing of the hormone precursor, proglucagon, numerous peptide products are released from the pancreatic alpha cells and the intestinal L-cells in which the (pro)glucagon gene is expressed. Of particular interest in relation to obesity are glucagon from the pancreas and oxyntomodulin and GLP-1 from the gut, all of which inhibit food intake, but the other products are also briefly discussed, because knowledge about these is required for selection and evaluation of the methods for measurement of the hormones. The distal intestinal L-cells also secrete the appetite-inhibiting hormone PYY. Characteristics of the secretion of the pancreatic and intestinal products are described, and causes of the hypersecretion of glucagon in obesity and type 2 diabetes are discussed. In contrast, the secretion of the products of the L-cells is generally impaired in obesity, raising questions about their role in the development of obesity. It is concluded that the impairment probably is secondary to obesity, but the lower plasma levels may contribute to the development.
Language	English
Publishing date	2022-08-04
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2776676-7
ISSN	2296-861X
ISSN	2296-861X
DOI	10.3389/fnut.2022.964406
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Discovery of the GI Effects of GLP-1: An Historical Perspective.

Holst, Jens Juul

Digestive diseases and sciences

2022 Volume 67, Issue 7, Page(s) 2716–2720

Abstract: In 1993, my laboratory published an article in Digestive Diseases and Sciences that clearly demonstrated the pronounced effects of the newly discovered intestinal hormone, glucagon-like peptide-1 (GLP-1), on a number of gastrointestinal functions, ... ...

Abstract	In 1993, my laboratory published an article in Digestive Diseases and Sciences that clearly demonstrated the pronounced effects of the newly discovered intestinal hormone, glucagon-like peptide-1 (GLP-1), on a number of gastrointestinal functions, including gastric emptying rate, gastric acid secretion, and pancreatic enzyme secretion. The gut hormone is released in response to nutrient intake, and in further experiments, its release from the ileum paralleled inhibition of both gastric and pancreatic secretions. Based on these studies, it was concluded that GLP-1 is an important regulator of the so-called ileal brake, a term given for the observation that ileal perfusion of lipids delayed gastric emptying, reduced food intake, and induced satiety Welch et al. (1985), in addition to its functions as an incretin hormone. GLP-1 was subsequently identified as a physiological inhibitor of appetite and food intake, and based on these actions, the GLP-1 receptor agonists are today considered among the most powerful and effective antiobesity and antidiabetic agents available, with the added benefits of reducing the risk of the cardiovascular and renal complications associated with these conditions.
MeSH term(s)	Appetite ; Eating ; Gastrointestinal Hormones ; Glucagon-Like Peptide 1 ; Humans ; Hypoglycemic Agents ; Peptide Fragments/pharmacology
Chemical Substances	Gastrointestinal Hormones ; Hypoglycemic Agents ; Peptide Fragments ; Glucagon-Like Peptide 1 (89750-14-1)
Language	English
Publishing date	2022-05-30
Publishing country	United States
Document type	Journal Article ; Review ; Research Support, Non-U.S. Gov't
ZDB-ID	304250-9
ISSN	1573-2568 ; 0163-2116
ISSN (online)	1573-2568
ISSN	0163-2116
DOI	10.1007/s10620-022-07519-3
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: What combines best with GLP-1 for obesity treatment: GIP receptor agonists or antagonists?

Holst, Jens Juul

Cell reports. Medicine

2021 Volume 2, Issue 5, Page(s) 100284

Abstract: Lu et al. ...

Abstract	Lu et al.
MeSH term(s)	Animals ; Gastric Inhibitory Polypeptide ; Glucagon-Like Peptide 1 ; Glucagon-Like Peptide-1 Receptor ; Obesity/drug therapy ; Receptors, Gastrointestinal Hormone
Chemical Substances	Glucagon-Like Peptide-1 Receptor ; Receptors, Gastrointestinal Hormone ; Gastric Inhibitory Polypeptide (59392-49-3) ; Glucagon-Like Peptide 1 (89750-14-1) ; gastric inhibitory polypeptide receptor (D6H00MV7K8)
Language	English
Publishing date	2021-05-18
Publishing country	United States
Document type	Journal Article ; Comment
ISSN	2666-3791
ISSN (online)	2666-3791
DOI	10.1016/j.xcrm.2021.100284
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Article ; Online: Glucagon 100 years. Important, but still enigmatic

Holst, Jens Juul

Peptides. 2023 Mar., v. 161 p.170942-

2023

Abstract	Glucagon was discovered in 1923 as a contaminant of early insulin preparations, and its hormonal status was not established until its structure was established in the 1950 s and when the first radioimmunoassay was developed by Roger Unger, providing information about its secretion. Its role in hepatic glucose production was soon established and it was proposed as an essential factor in diabetic hyperglycemia. However, even today a number of issues remain unsolved. For instance, the assays for glucagon are not straightforward, although the development of sandwich ELISAs allowed reasonably accurate measurements also in rodents. The tools for evaluation of glucagon physiology include pancreatectomy, but studies in both humans and experimental animals pointed towards extrapancreatic sources of glucagon. It was demonstrated that glucagon receptor knockout animals do not develop diabetes upon destruction of their beta cells with streptozotocin. However, in patients with type 1 diabetes, glucagon antagonists do not normalize glucose levels; but antagonists do lower glucose levels in patients with in type 2 diabetes. Recent studies in animals and humans have confirmed the essential role of glucagon in glucose metabolism, but have suggested that it may be at least equally important for amino acid and lipid metabolism. In spite of the 100 years, glucagon research is very much alive.
Keywords	amino acids ; enzyme-linked immunosorbent assay ; glucagon ; glucagon receptors ; glucose ; hyperglycemia ; insulin ; insulin-dependent diabetes mellitus ; lipid metabolism ; noninsulin-dependent diabetes mellitus ; radioimmunoassays ; secretion ; streptozotocin
Language	English
Dates of publication	2023-03
Publishing place	Elsevier Inc.
Document type	Article ; Online
Note	Use and reproduction
ZDB-ID	769028-9
ISSN	1873-5169 ; 0196-9781
ISSN (online)	1873-5169
ISSN	0196-9781
DOI	10.1016/j.peptides.2023.170942
Database	NAL-Catalogue (AGRICOLA)

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Zs.A 1649: Show issues

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Article ; Online: Treatment of Type 2 Diabetes and Obesity on the Basis of the Incretin System: The 2021 Banting Medal for Scientific Achievement Award Lecture.

Holst, Jens Juul

Diabetes

2021 Volume 70, Issue 11, Page(s) 2468–2475

Abstract: In my lecture given on the occasion of the 2021 Banting Medal for Scientific Achievement, I briefly described the history of the incretin effect and summarized some of the developments leading to current therapies of obesity and diabetes based on the ... ...

Abstract	In my lecture given on the occasion of the 2021 Banting Medal for Scientific Achievement, I briefly described the history of the incretin effect and summarized some of the developments leading to current therapies of obesity and diabetes based on the incretin hormones, glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). In the text below, I discuss in further detail the role of these two hormones for postprandial insulin secretion in humans on the basis of recent studies with antagonists. Their direct and indirect actions on the β-cells are discussed next as well as their contrasting actions on glucagon secretion. After a brief discussion of their effect on insulin sensitivity, I describe their immediate actions in patients with type 2 diabetes and emphasize the actions of GLP-1 on β-cell glucose sensitivity, followed by a discussion of their extrapancreatic actions, including effects on appetite and food intake in humans. Finally, possible mechanisms of action of GIP-GLP-1 coagonists are discussed, and it is concluded that therapies based on incretin actions are likely to change the current hesitant therapy of both obesity and diabetes.
MeSH term(s)	Awards and Prizes ; Diabetes Mellitus, Type 2/drug therapy ; Diabetes Mellitus, Type 2/metabolism ; Gastric Inhibitory Polypeptide/agonists ; Gastric Inhibitory Polypeptide/metabolism ; Glucagon-Like Peptide 1/agonists ; Glucagon-Like Peptide 1/metabolism ; Humans ; Incretins/metabolism ; Insulin/metabolism ; Insulin-Secreting Cells/metabolism ; Obesity/drug therapy ; Obesity/metabolism
Chemical Substances	Incretins ; Insulin ; Gastric Inhibitory Polypeptide (59392-49-3) ; Glucagon-Like Peptide 1 (89750-14-1)
Language	English
Publishing date	2021-10-27
Publishing country	United States
Document type	Address ; Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	80085-5
ISSN	1939-327X ; 0012-1797
ISSN (online)	1939-327X
ISSN	0012-1797
DOI	10.2337/dbi21-0026
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Article: Long-acting glucagon-like peptide-1 receptor agonist-status December 2018.

Holst, Jens Juul

Annals of translational medicine

2019 Volume 7, Issue 5, Page(s) 83

Language	English
Publishing date	2019-02-06
Publishing country	China
Document type	Editorial ; Comment
ZDB-ID	2893931-1
ISSN	2305-5847 ; 2305-5839
ISSN (online)	2305-5847
ISSN	2305-5839
DOI	10.21037/atm.2019.01.09
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Article ; Online: Which to choose, an oral or an injectable glucagon-like peptide-1 receptor agonist?

Holst, Jens Juul

Lancet (London, England)

2019 Volume 394, Issue 10192, Page(s) 4–6

MeSH term(s)	Diabetes Mellitus, Type 2 ; Double-Blind Method ; Glucagon-Like Peptide-1 Receptor ; Glucagon-Like Peptides ; Humans ; Hypoglycemic Agents ; Liraglutide
Chemical Substances	Glucagon-Like Peptide-1 Receptor ; Hypoglycemic Agents ; semaglutide (53AXN4NNHX) ; Glucagon-Like Peptides (62340-29-8) ; Liraglutide (839I73S42A)
Language	English
Publishing date	2019-06-08
Publishing country	England
Document type	Journal Article ; Comment
ZDB-ID	3306-6
ISSN	1474-547X ; 0023-7507 ; 0140-6736
ISSN (online)	1474-547X
ISSN	0023-7507 ; 0140-6736
DOI	10.1016/S0140-6736(19)31350-9
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Article ; Online: Dietary impact on fasting and stimulated GLP-1 secretion in different metabolic conditions - a narrative review.

Huber, Hanna / Schieren, Alina / Holst, Jens Juul / Simon, Marie-Christine

The American journal of clinical nutrition

2024 Volume 119, Issue 3, Page(s) 599–627

Abstract: Glucagon-like peptide 1 (GLP-1), a gastrointestinal peptide and central mediator of glucose metabolism, is secreted by L cells in the intestine in response to food intake. Postprandial secretion of GLP-1 is triggered by nutrient-sensing via transporters ... ...

Abstract	Glucagon-like peptide 1 (GLP-1), a gastrointestinal peptide and central mediator of glucose metabolism, is secreted by L cells in the intestine in response to food intake. Postprandial secretion of GLP-1 is triggered by nutrient-sensing via transporters and G-protein-coupled receptors (GPCRs). GLP-1 secretion may be lower in adults with obesity/overweight (OW) or type 2 diabetes mellitus (T2DM) than in those with normal glucose tolerance (NGT), but these findings are inconsistent. Because of the actions of GLP-1 on stimulating insulin secretion and promoting weight loss, GLP-1 and its analogs are used in pharmacologic preparations for the treatment of T2DM. However, physiologically stimulated GLP-1 secretion through the diet might be a preventive or synergistic method for improving glucose metabolism in individuals who are OW, or have impaired glucose tolerance (IGT) or T2DM. This narrative review focuses on fasting and postprandial GLP-1 secretion in individuals with different metabolic conditions and degrees of glucose intolerance. Further, the influence of relevant diet-related factors (e.g., specific diets, meal composition, and size, phytochemical content, and gut microbiome) that could affect fasting and postprandial GLP-1 secretion are discussed. Some studies showed diminished glucose- or meal-stimulated GLP-1 response in participants with T2DM, IGT, or OW compared with those with NGT, whereas other studies have reported an elevated or unchanged GLP-1 response in T2DM or IGT. Meal composition, especially the relationship between macronutrients and interventions targeting the microbiome can impact postprandial GLP-1 secretion, although it is not clear which macronutrients are strong stimulants of GLP-1. Moreover, glucose tolerance, antidiabetic treatment, grade of overweight/obesity, and sex were important factors influencing GLP-1 secretion. The results presented in this review highlight the potential of nutritional and physiologic stimulation of GLP-1 secretion. Further research on fasting and postprandial GLP-1 concentrations and the resulting metabolic consequences under different metabolic conditions is needed.
MeSH term(s)	Adult ; Humans ; Glucagon-Like Peptide 1/metabolism ; Diabetes Mellitus, Type 2/metabolism ; Glucose Tolerance Test ; Insulin/metabolism ; Blood Glucose/metabolism ; Overweight ; Diet ; Fasting ; Glucose Intolerance/metabolism ; Obesity ; Postprandial Period/physiology
Chemical Substances	Glucagon-Like Peptide 1 (89750-14-1) ; Insulin ; Blood Glucose
Language	English
Publishing date	2024-01-11
Publishing country	United States
Document type	Journal Article ; Review
ZDB-ID	280048-2
ISSN	1938-3207 ; 0002-9165
ISSN (online)	1938-3207
ISSN	0002-9165
DOI	10.1016/j.ajcnut.2024.01.007
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