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Jens J Holst - One of the best experts on this subject based on the ideXlab platform.

  • determinants of fasting Hyperglucagonemia in patients with type 2 diabetes and nondiabetic control subjects
    Metabolic Syndrome and Related Disorders, 2018
    Co-Authors: Mia Demant, Jonatan I Bagger, Malte P Suppli, Asger Lund, Mette Gyldenlove, Katrine B Hansen, Kristine J Hare, Mikkel B Christensen, David P Sonne, Jens J Holst
    Abstract:

    Abstract Background: Fasting Hyperglucagonemia can be detrimental to glucose metabolism in patients with type 2 diabetes (T2D) and may contribute to metabolic disturbances in obese and/or prediabet...

  • Hyperglucagonemia correlates with plasma levels of non branched chain amino acids in patients with liver disease independent of type 2 diabetes
    American Journal of Physiology-gastrointestinal and Liver Physiology, 2018
    Co-Authors: Nicolai Wewer J Albrechtsen, Anders E Junker, Mette Christensen, Sofie Haedersdal, Flemming Wibrand, Allan M Lund, Katrine D Galsgaard, Jens J Holst, Filip K Knop, Tina Vilsboll
    Abstract:

    Hypersecretion of glucagon (Hyperglucagonemia) has been suggested to be linked to type 2 diabetes. Here, we show that levels of amino acids correlate with levels of glucagon. Hyperglucagonemia may ...

  • pancreatic α cell hyperplasia and Hyperglucagonemia due to a glucagon receptor splice mutation
    Endocrinology Diabetes & Metabolism Case Reports, 2016
    Co-Authors: Etienne Larger, Nicolai Wewer J Albrechtsen, Lars H Hansen, Richard W Gelling, Jacqueline Capeau, Carolyn F Deacon, Ole D Madsen, Fumiatsu Yakushiji, Pierre De Meyts, Jens J Holst
    Abstract:

    : Glucagon stimulates hepatic glucose production by activating specific glucagon receptors in the liver, which in turn increase hepatic glycogenolysis as well as gluconeogenesis and ureagenesis from amino acids. Conversely, glucagon secretion is regulated by concentrations of glucose and amino acids. Disruption of glucagon signaling in rodents results in grossly elevated circulating glucagon levels but no hypoglycemia. Here, we describe a patient carrying a homozygous G to A substitution in the invariant AG dinucleotide found in a 3' mRNA splice junction of the glucagon receptor gene. Loss of the splice site acceptor consensus sequence results in the deletion of 70 nucleotides encoded by exon 9, which introduces a frame shift and an early termination signal in the receptor mRNA sequence. The mutated receptor neither bound 125I-labeled glucagon nor induced cAMP production upon stimulation with up to 1 µM glucagon. Despite the mutation, the only obvious pathophysiological trait was Hyperglucagonemia, hyperaminoacidemia and massive hyperplasia of the pancreatic α-cells assessed by histology. Our case supports the notion of a hepato-pancreatic feedback system, which upon disruption leads to Hyperglucagonemia and α-cell hyperplasia, as well as elevated plasma amino acid levels. Together with the glucagon-induced hypoaminoacidemia in glucagonoma patients, our case supports recent suggestions that amino acids may provide the feedback link between the liver and the pancreatic α-cells. LEARNING POINTS: Loss of function of the glucagon receptor may not necessarily lead to the dysregulation of glucose homeostasis.Loss of function of the glucagon receptor causes hyperaminoacidemia, Hyperglucagonemia and α-cell hyperplasia and sometimes other pancreatic abnormalities.A hepato-pancreatic feedback regulation of the α-cells, possibly involving amino acids, may exist in humans.

  • the biology of glucagon and the consequences of Hyperglucagonemia
    Biomarkers in Medicine, 2016
    Co-Authors: Nicolai Wewer J Albrechtsen, Filip K Knop, Rune E Kuhre, Jens Pedersen, Jens J Holst
    Abstract:

    The proglucagon-derived peptide hormone, glucagon, comprises 29 amino acids. Its secretion from the pancreatic α cells is regulated by several factors. Glucagon increases blood glucose levels through gluconeogenesis and glycogenolysis. Elevated plasma concentrations of glucagon, Hyperglucagonemia, may contribute to diabetes. However, Hyperglucagonemia is also observed in other clinical conditions than diabetes, including nonalcoholic fatty liver disease, glucagon-producing tumors and after gastric bypass surgery. Here, we review the current literature on Hyperglucagonemia in disease with a particular focus on diabetes, and finally speculate that the primary physiological importance of glucagon may not reside in glucose homeostasis but in regulation of amino acid metabolism exerted via a hitherto unrecognized hepato-pancreatic feedback loop.

Masaaki Yoshikawa - One of the best experts on this subject based on the ideXlab platform.

  • proadrenomedullin n terminal 20 peptide pamp elevates blood glucose levels via bombesin receptor in mice
    FEBS Letters, 2000
    Co-Authors: Kousaku Ohinata, Estuko Wada, Keiji Wada, Akihiro Asakawa, Akio Inui, Masaaki Yoshikawa
    Abstract:

    We found a potent hyperglycemic effect of proadrenomedullin N-terminal 20 peptide (PAMP) after intra-third cerebroventricular administration at a dose of 10 nmol in fasted mice. PAMP has four homologous residues with bombesin (BN), a hyperglycemic peptide. PAMP showed affinity for gastrin-releasing peptide preferring receptor (GRP-R) and neuromedin B preferring receptor. The PAMP-induced hyperglycemic effect was inhibited by [D-Phe6, Leu-NHEt13, des-Met14]-BN (6–14), GRP-R specific antagonist, indicating that the hyperglycemic effect is mediated at least in part via GRP-R. Furthermore, pretreatment of α-adrenergic blocker inhibited the PAMP-induced hyperglycemia and Hyperglucagonemia, suggesting that the increase of glucagon secretion through α-adrenergic activation is involved in this hyperglycemic effect of PAMP.

  • Proadrenomedullin N‐terminal 20 peptide (PAMP) elevates blood glucose levels via bombesin receptor in mice
    FEBS Letters, 2000
    Co-Authors: Kousaku Ohinata, Estuko Wada, Keiji Wada, Akihiro Asakawa, Akio Inui, Masaaki Yoshikawa
    Abstract:

    We found a potent hyperglycemic effect of proadrenomedullin N-terminal 20 peptide (PAMP) after intra-third cerebroventricular administration at a dose of 10 nmol in fasted mice. PAMP has four homologous residues with bombesin (BN), a hyperglycemic peptide. PAMP showed affinity for gastrin-releasing peptide preferring receptor (GRP-R) and neuromedin B preferring receptor. The PAMP-induced hyperglycemic effect was inhibited by [D-Phe6, Leu-NHEt13, des-Met14]-BN (6–14), GRP-R specific antagonist, indicating that the hyperglycemic effect is mediated at least in part via GRP-R. Furthermore, pretreatment of α-adrenergic blocker inhibited the PAMP-induced hyperglycemia and Hyperglucagonemia, suggesting that the increase of glucagon secretion through α-adrenergic activation is involved in this hyperglycemic effect of PAMP.

Ravi Retnakaran - One of the best experts on this subject based on the ideXlab platform.

  • effect of short term intensive insulin therapy on post challenge Hyperglucagonemia in early type 2 diabetes
    The Journal of Clinical Endocrinology and Metabolism, 2015
    Co-Authors: Caroline K Kramer, Bernard Zinman, Haysook Choi, Ravi Retnakaran
    Abstract:

    Context: Hyperglucagonemia is a characteristic feature of type 2 diabetes (T2DM) that has been postulated to be due to β-cell dysfunction and the resultant loss of insulin-mediated α-cell suppression. When administered in early T2DM, short-term intensive insulin therapy (IIT) can improve β-cell function, resulting in reduced glycemic variability. Objective: To evaluate the impact of IIT on Hyperglucagonemia and its associations with β-cell function and glycemic variability. Design/Setting/Participants/Intervention: Sixty-two patients with T2DM of mean 3.0 ± 2.1 years duration and glycated hemoglobin of 6.8 ± 0.7% underwent 4 weeks of IIT, consisting of basal detemir and premeal insulin aspart. Main Outcome Measures: Glucagon response was measured by area under the glucagon curve (AUCglucagon) on oral glucose tolerance test at baseline and 1 day post-IIT. β-Cell function before and after IIT was assessed by Insulin Secretion-Sensitivity Index-2 and ΔISR0–120/Δglucose0–120*Matsuda index (where ISR is the pr...

Tina Vilsboll - One of the best experts on this subject based on the ideXlab platform.

  • Hyperglucagonemia correlates with plasma levels of non branched chain amino acids in patients with liver disease independent of type 2 diabetes
    American Journal of Physiology-gastrointestinal and Liver Physiology, 2018
    Co-Authors: Nicolai Wewer J Albrechtsen, Anders E Junker, Mette Christensen, Sofie Haedersdal, Flemming Wibrand, Allan M Lund, Katrine D Galsgaard, Jens J Holst, Filip K Knop, Tina Vilsboll
    Abstract:

    Hypersecretion of glucagon (Hyperglucagonemia) has been suggested to be linked to type 2 diabetes. Here, we show that levels of amino acids correlate with levels of glucagon. Hyperglucagonemia may ...

  • Glucagon and Type 2 Diabetes: the Return of the Alpha Cell
    Current Diabetes Reports, 2014
    Co-Authors: Asger Lund, Filip K Knop, Jonatan I Bagger, Mikkel Christensen, Tina Vilsboll
    Abstract:

    In normal physiology, glucagon from pancreatic alpha cells plays an important role in maintaining glucose homeostasis via its regulatory effect on hepatic glucose production. Patients with type 2 diabetes suffer from fasting and postprandial Hyperglucagonemia, which stimulate hepatic glucose production and, thus, contribute to the hyperglycemia characterizing these patients. Although this has been known for years, research focusing on alpha cell (patho)physiology has historically been dwarfed by research on beta cells and insulin. Today the mechanisms behind type 2 diabetic Hyperglucagonemia are still poorly understood. Preclinical and clinical studies have shown that the gastrointestinal hormone glucose-dependent insulinotropic polypeptide (GIP) might play an important role in this pathophysiological phenomenon. Furthermore, it has become apparent that suppression of glucagon secretion or antagonization of the glucagon receptor constitutes potentially effective treatment strategies for patients with type 2 diabetes. In this review, we focus on the regulation of glucagon secretion by the incretin hormones glucagon-like peptide-1 (GLP-1) and GIP. Furthermore, potential advantages and limitations of suppressing glucagon secretion or antagonizing the glucagon receptor, respectively, in the treatment of patients with type 2 diabetes will be discussed.

Michael H Torosian - One of the best experts on this subject based on the ideXlab platform.

  • reversal of tumor associated Hyperglucagonemia as treatment for cancer cachexia
    Surgery, 1995
    Co-Authors: David L Bartlett, Scott L Charland, Michael H Torosian
    Abstract:

    Background. The tumor-bearing state is associated with increased circulating glucagon levels that may play an etiologic role in cancer cachexia. The secretion of glucagon can be inhibited with long-term somatostatin analogs, and, in combination with insulin, should maximally reverse the low insulin/glucagon ratio seen in cancer cachexia. The goal of this study is to examine the effect of somatostatin (octreotide) and insulin in a model of cancer cachexia and to determine whether inhibition of glucagon secretion will reverse some of the abnormalities in carbohydrate metabolism to selectively benefit host versus tumor metabolism Methods. Sixty-seven female Lewis rats were subcutaneously inoculated with 1 × 106 metastasizing mammary adenocarcinoma tumor cells. On day 30 the animals were randomized into four groups to receive (1) tumor-bearing control (saline injections); (2) octreotide, 150 μg/kg intraperitoneally twice a day; (3) neutral protamine Hagedorn insulin, 5 units/kg subcutaneously twice a day; or (4) both insulin and octreotide injections. A fifth group of non-tumor-bearing controls was included. The animals received treatment for 5 days and were then killed. Results. The tumor-bearing state was found to be associated with an increase in glucagon levels and a significant decrease in the insulin/glucagon ratio. The combination of somatostatin + insulin resulted in a 23-fold increase in the insulin/glucagon ratio without causing significant host morbidity from hypoglycemia. This increased insulin/glucagon ratio was associated with increased carcass weight, increased muscle weight, increased muscle protein, increased liver cellular protein, increased liver microsomal P-450 content, and decreased tumor protein content compared with the tumor-bearing controls. These results were not seen with insulin or somatostatin alone. Hepatic lactate dehydrogenase, glucose-6-phosphatase, and fructose-1,6-diphosphatase activities were increased as a result of combination hormone treatment. Conclusions. Combination hormone treatment with somatostatin and insulin results in a marked increase in the insulin/glucagon ratio and a selective nutritional benefit to the host. The inhibition of tumor-associated Hyperglucagonemia should be considered in the treatment of cancer cachexia