A5075350597- Pancreatic function and diabetes
- Diabetes Treatment and Management
- Diabetes Management and Research
- Metabolism, Diabetes, and Cancer
- Receptor Mechanisms and Signaling
- Neuropeptides and Animal Physiology
- Diabetes and associated disorders
- Biomedical Research and Pathophysiology
- Hyperglycemia and glycemic control in critically ill and hospitalized patients
- Growth Hormone and Insulin-like Growth Factors
- Pain Mechanisms and Treatments
- Amino Acid Enzymes and Metabolism
- Adipose Tissue and Metabolism
- Monoclonal and Polyclonal Antibodies Research
- Cancer, Stress, Anesthesia, and Immune Response
- Cardiovascular Function and Risk Factors
- Pharmacological Receptor Mechanisms and Effects
- PI3K/AKT/mTOR signaling in cancer
- Glycosylation and Glycoproteins Research
- Luminescence and Fluorescent Materials
- Drug Transport and Resistance Mechanisms
- Neuroendocrine Tumor Research Advances
- Pregnancy-related medical research
- Adrenal Hormones and Disorders
- Protein Interaction Studies and Fluorescence Analysis
Novo Nordisk (Denmark)
2013-2024
Profu (Sweden)
2024
Novo Nordisk (United Kingdom)
2023
Jikei University Kashiwa hospital
2018
Jikei University School of Medicine
2014
Albert Einstein College of Medicine
2003
Mexican Social Security Institute
2003
Dorn Research Institute
1998
Steno Diabetes Centers
1995
Salk Institute for Biological Studies
1987
Glucagon, the counter-regulatory hormone to insulin, is secreted from pancreatic α cells in response low blood glucose. To examine role of glucagon glucose homeostasis, mice were generated with a null mutation receptor (Gcgr −/− ). These display lower levels throughout day and improved tolerance but similar insulin compared control animals. Gcgr displayed supraphysiological associated postnatal enlargement pancreas hyperplasia islets due predominantly cell, lesser extent, δ cell...
Introduction Insulin icodec is a novel, long-acting insulin analog designed to cover basal requirements with once-weekly subcutaneous administration. Here we describe the molecular engineering and biological pharmacological properties of icodec. Research design methods A number in vitro assays measuring receptor binding, intracellular signaling as well cellular metabolic mitogenic responses were used characterize To evaluate individuals type 2 diabetes, randomized, double-blind,...
We have studied the distribution of activin receptor gene expression in brain, pituitary, ovary, and testis adult rat by situ hybridization, using probes complementary to mRNAs encoding mouse subtypes II IIB (ActRII ActRIIB). Throughout ActRII mRNA was stronger than that ActRIIB, patterns were similar, although not identical. The most intense sites hippocampal formation, especially dentate gyrus (ActRII), taenia tecta, induseum griseum; amygdala, particularly amygdaloid-hippocampal...
Here, we describe the molecular engineering of insulin icodec to achieve a plasma half-life 196 h in humans, suitable for once-weekly subcutaneously administration. Insulin is based on re-engineering ultra-long oral basal OI338 with 70 humans. This systematic was accomplished by (1) further increasing albumin binding changing fatty diacid from 1,18-octadecanedioic acid (C18) 1,20-icosanedioic (C20) and (2) reducing receptor affinity B16Tyr → His substitution. selected screening long...
The risk of inducing hypoglycaemia (low blood glucose) constitutes the main challenge associated with insulin therapy for diabetes
In previous studies, glucagon receptor knockout mice (Gcgr(-/-)) display reduced blood glucose and increased tolerance, with hyperglucagonemia levels of glucagon-like peptide (GLP)-1. However, the role signaling for regulation islet function insulin sensitivity is unknown. We therefore explored beta-cell in Gcgr(-/-) wild-type mice. The steady-state infusion rate during hyperinsulinemic-euglycemic clamp was elevated mice, indicating enhanced sensitivity. Furthermore, acute response (AIR) to...
Mice genetically deficient in the glucagon receptor (Gcgr−/−) show improved glucose tolerance, insulin sensitivity, and α-cell hyperplasia. In addition, Gcgr−/− mice do not develop diabetes after chemical destruction of β-cells. Since fibroblast growth factor 21 (FGF21) has insulin-independent glucose-lowering properties, we investigated whether FGF21 was contributing to resistance insulin-deficient mice. Plasma 25-fold higher than wild-type found be expressed pancreatic β- α-cells, with...
Abstract Recently, the clinical proof of concept for first ultra-long oral insulin was reported, showing efficacy and safety similar to subcutaneously administered glargine. Here, we report molecular engineering as well biological pharmacological properties these analogues. Molecules were designed have pharmacokinetic profile minimize variability in plasma exposure. Elimination half-life ~20 h dogs ~70 man is achieved by a strong albumin binding, lowering receptor affinity 500-fold slow down...
Insulin icodec is a once-weekly insulin analogue that has long half-life of approximately 7 days, making it suitable for once weekly dosing. The molecule was developed based on the hypothesis lowering receptor affinity and introducing strong albumin-binding moiety would result in half-life, provided non-receptor-mediated clearance diminished. Here, we report an mechanism, resulting splitting molecules into its A-chain B-chain by thiol-disulphide exchange reaction. Even though substitutions...
Peroxisome proliferator-activated receptor-γ coactivator-1α and -1β (PGC-1α PGC-1β) were overexpressed by adenovirus-mediated gene transfer in cultures of primary rat skeletal muscle cells derived from neonatal myoblasts. Effects on fiber type transition metabolism studied days 5 to 22 culture. PGC-1α PGC-1β overexpression caused a three- fourfold increase mRNA level, doubling enzymatic activity citrate synthase, slight short-chain acyl-CoA dehydrogenase mRNA, the 30–50%...
Endogenous insulin secretion exposes the liver to three times higher concentrations than rest of body. Because subcutaneous delivery eliminates this gradient and is associated with metabolic abnormalities, functionally restoring physiologic may provide therapeutic benefits. The effects recombinant human (HI) delivered intraportally or peripherally were compared an acylated model compound (insulin-327) in dogs. During somatostatin basal portal vein glucagon infusion, was infused portally...
Peripheral hyperinsulinemia resulting from subcutaneous insulin injection is associated with metabolic defects that include abnormal glucose metabolism. The first aim of this study was to quantify the impairments in liver and muscle metabolism occur when delivered via a peripheral vein compared it given through its endogenous secretory route (the hepatic portal vein) overnight-fasted conscious dogs. second determine if delivery hepato-preferential analog could restore physiologic response...
In type 2 diabetes, glucagon levels are elevated in relation to the prevailing insulin and glucose levels. The relative hyperglucagonemia is linked increased hepatic output (HGO) hyperglycemia. Antagonizing effects of therefore considered an attractive target for treatment diabetes. current study, eliminating signaling with a monoclonal antibody (mAb) were investigated diabetic ob/ob mouse. Acute inhibiting action studied by oral tolerance test (OGTT) measurement HGO. addition, subchronic (5...
In addition to its primary role in regulating glucose production from the liver, glucagon has many other actions, reflected by wide tissue distribution of receptor (Gcgr). To investigate regulation insulin secretion and whole body homeostasis vivo, we generated mice overexpressing Gcgr specifically on pancreatic beta-cells (RIP-Gcgr). vivo vitro response was increased 1.7- 3.9-fold RIP-Gcgr compared with controls. Consistent observed increase release glucose, excursion resulting both a...
In type 2 Diabetes (T2D) free fatty acids (FFAs) in plasma are increased and hepatic insulin resistance is “selective”, the sense that insulin-mediated decrease of glucose production blunted while insulin's effect on stimulating lipogenesis maintained. We investigated molecular mechanisms underlying this pathogenic paradox. Primary rat hepatocytes were exposed to palmitate for twenty hours. To establish physiological relevance vitro findings, we also studied insulin-resistant Zucker Diabetic...
Glucagon stimulates hepatic glucose production by activating specific glucagon receptors in the liver, which turn increase glycogenolysis as well gluconeogenesis and ureagenesis from amino acids. Conversely, secretion is regulated concentrations of Disruption signaling rodents results grossly elevated circulating levels but no hypoglycemia. Here, we describe a patient carrying homozygous G to A substitution invariant AG dinucleotide found 3' mRNA splice junction receptor gene. Loss site...
The distribution of atrial natriuretic factor (ANF) binding sites in Wistar rat tissues, as well tissues from other species was studied. Using autoradiography slide mounted tissue sections incubated with 125 I-labelled ANF, high densities were found the renal glomeruli and papilla, aortic smooth muscle, iliac vein, choroid plexus, anterior pituitary, lung, adrenal zona glomerulosa. Results renal, aortic, adrenal, lung spontaneously hypertensive rats did not differ those rats. Binding also...
In the liver, insulin suppresses hepatic gluconeogenesis by activating Akt, which inactivates key gluconeogenic transcription factor FoxO1 (Forkhead Box O1). Recent studies have implicated hyperactivity of Akt phosphatase Protein Phosphatase 2A (PP2A) and impaired signaling as a molecular defect underlying resistance. We therefore hypothesized that PP2A inhibition would enhance insulin-stimulated activity decrease glucose production. inhibitors increased phosphorylation inhibited FoxO1in...