Jens Juul Holst | University of Copenhagen (original) (raw)

Papers by Jens Juul Holst

American Journal of Physiology-Regulatory, Integrative and Comparative Physiology, 1999

The aim of the present study was to assess the effect of glucagon-like peptide-1 (GLP-1) on solid... more The aim of the present study was to assess the effect of glucagon-like peptide-1 (GLP-1) on solid gastric emptying and the subsequent release of pancreatic and intestinal hormones. In eight men [age 33.6 ± 2.5 yr, body mass index 24.1 ± 0.9 (means ± SE)], scintigraphic solid gastric emptying during infusion of GLP-1 (0.75 pmol ⋅ kg−1 ⋅ min−1) or saline was studied for 180 min. Concomitantly, plasma concentrations of C- and N-terminal GLP-1, glucose, insulin, C-peptide, glucagon, and peptide YY (PYY) were assessed. Infusion of GLP-1 resulted in a profound inhibition of both the lag phase (GLP-1: 91.5, range 73.3–103.6 min vs. saline: 19.5, range 10.2–43.4 min) and emptying rate (GLP-1: 0.34, range 0.06–0.56 %/min vs. saline: 0.84, range 0.54–1.33 %/min; P< 0.01 for both) of solid gastric emptying. Concentrations of both intact and total GLP-1 were elevated to supraphysiological levels. Plasma glucose and glucagon concentrations were below baseline during infusion of GLP-1 in contr...

Diabetes Care, 2001

OBJECTIVE—To investigate whether features of the insulin resistance syndrome are associated with ... more OBJECTIVE—To investigate whether features of the insulin resistance syndrome are associated with altered incretin responses to food intake. RESEARCH DESIGN AND METHODS—From a population-based study, 35 men were recruited, representing a wide spectrum of insulin sensitivity and body weight. Each subject underwent a hyperinsulinemic-euglycemic clamp to determine insulin sensitivity. A mixed meal was given, and plasma levels of gastric inhibitory polypeptide (GIP) and glucagon-like peptide 1 (GLP-1), as well as insulin, glucagon, and glucose were measured. RESULTS—Insulin resistance was associated with impaired GIP and GLP-1 responses to a mixed meal. The total area under the curve (AUC) of the GIP response after the mixed meal was associated with insulin sensitivity (r = 0.54, P < 0.01). There was a significant difference between the highest and the lowest tertile of insulin sensitivity (P < 0.05). GLP-1 levels 15 min after food intake were significantly lower in the most insuli...

Diabetes, Obesity and Metabolism

Diabetologia, 2022

Aim/hypothesis Urocortin-3 (UCN3) is a glucoregulatory peptide produced in the gut and pancreatic... more Aim/hypothesis Urocortin-3 (UCN3) is a glucoregulatory peptide produced in the gut and pancreatic islets. The aim of this study was to clarify the acute effects of UCN3 on glucose regulation following an oral glucose challenge and to investigate the mechanisms involved. Methods We studied the effect of UCN3 on blood glucose, gastric emptying, glucose absorption and secretion of gut and pancreatic hormones in male rats. To supplement these physiological studies, we mapped the expression of UCN3 and the UCN3-sensitive receptor, type 2 corticotropin-releasing factor receptor (CRHR2), by means of fluorescence in situ hybridisation and by gene expression analysis. Results In rats, s.c. administration of UCN3 strongly inhibited gastric emptying and glucose absorption after oral administration of glucose. Direct inhibition of gastrointestinal motility may be responsible because UCN3’s cognate receptor, CRHR2, was detected in gastric submucosal plexus and in interstitial cells of Cajal. Des...

Endocrine Connections, 2021

Diabetes, 2020

Background: Altered meal-associated secretion of gut peptides is key for the metabolic changes an... more Background: Altered meal-associated secretion of gut peptides is key for the metabolic changes and weight-loss observed after Roux-en-Y gastric bypass (RYGB). Parenteral administration of the gut peptide neurotensin (NT) reduces food intake in rodents, and, like glucagon-like peptide-1 and peptide YY, the secretion of NT is markedly increased after RYGB. We therefore investigated the effect of intravenous (IV) NT on ad libitum food intake and appetite sensations. Design: Using a double-blinded, randomized placebo-controlled design, NT (2.5pmol/kg/min) or saline was infused IV in healthy young men to obtain NT concentrations similar to NT levels observed postprandially after RYGB. Four visits were performed in random order, after an acclimatization visit, to evaluate the main outcomes - ad libitum food intake and appetite sensations (visual analogue scale (VAS) questionnaires). Blood samples were collected for plasma and serum analyses (including entero-pancreatic peptides and glucos...

American Journal of Physiology-Gastrointestinal and Liver Physiology, 2020

Postprandial gut hormone responses change after Roux-en-Y gastric bypass (RYGB), and we investiga... more Postprandial gut hormone responses change after Roux-en-Y gastric bypass (RYGB), and we investigated the impact of glucose, protein, and fat (with and without pancreas lipase inhibition) on plasma responses of gut and pancreas hormones, bile acids, and fibroblast growth factor 21 (FGF-21) after RYGB and in nonoperated control subjects. In a randomized, crossover study 10 RYGB operated and 8 healthy weight-matched control subjects were administered 4 different 4-h isocaloric (200 kcal) liquid meal tests containing >90 energy (E)% of either glucose, protein (whey protein), or fat (butter with and without orlistat). The primary outcome was glucagon-like peptide-1 (GLP-1) secretion (area under the curve above baseline). Secondary outcomes included responses of peptide YY (PYY), glucose-dependent insulinotropic polypeptide (GIP), cholecystokinin (CCK), glicentin, neurotensin, ghrelin, insulin, glucagon, bile acids, and FGF-21. In the RYGB group the responses of GLP-1, GIP, glicentin, ...

The American Journal of Clinical Nutrition, 2019

Background Altered meal-related gut hormone secretion seems important for weight loss and diabete... more Background Altered meal-related gut hormone secretion seems important for weight loss and diabetes remission after Roux-en-Y gastric bypass (RYGB). Elucidating the responsible meal components and receptors could aid discovery of new treatments of obesity and diabetes. Enteroendocrine cells respond to digestion products of dietary triacylglycerol, especially long-chain fatty acids (LCFAs) and 2-oleoyl-glycerol (2-OG), but not medium-chain fatty acids (MCFAs). Objective We examined the impact of olive oil (20 mL) and its derivates, LCFAs and 2-OG, on enteroendocrine secretions [glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP), cholecystokinin (CCK), peptide YY (PYY), and neurotensin (NT)] and on glucose, lipid, and bile acid metabolism in RYGB-operated and unoperated individuals. Methods In an exploratory randomized crossover design, 10 RYGB-operated patients and 10 matched controls ingested 3 equimolar triacylglycerol formulations on separate days: ...

ObjectiveGastrointestinal hormones contribute to the beneficial effects of Roux-en-Y gastric bypa... more ObjectiveGastrointestinal hormones contribute to the beneficial effects of Roux-en-Y gastric bypass surgery (RYGB) on glycemic control. Secretin is secreted from duodenal S-cells in response to low luminal pH, but it is unknown whether its secretion is altered after RYGB and if secretin contributes to the post-operative improvement in glycemic control. We hypothesized that secretin secretion increases after RYGB as a result of the diversion of nutrients to more distal parts of the small intestine, and thereby affects islet hormone release.MethodsA specific secretin radioimmunoassay was developed, evaluated biochemically, and used to quantify plasma concentrations of secretin in 13 obese individuals before, 1 week after and 3 months after RYGB. Distribution of secretin and its receptor was assessed by RNA-sequencing, mass-spectrometry andin situhybridization in human and rat tissues. Isolated, perfused rat intestine and pancreas were used to explore the molecular mechanism underlying...

JBMR Plus, 2019

ABSTRACTBones have been suggested to be a target for glucagon‐like peptide ‐1 (GLP‐1); however, s... more ABSTRACTBones have been suggested to be a target for glucagon‐like peptide ‐1 (GLP‐1); however, studies of the effects on human bones so far have given diverging results. We hypothesized that GLP‐1, together with glucagon‐like peptide‐2 and glucose‐dependent insulinotropic polypeptide, plays a role in the gut–bone axis. We examined the acute effect of three GLP‐1 receptor ligands [GLP‐1 (7‐36)amide, GLP‐1 (9‐36)amide, and exenatide] on markers of bone remodeling. Eight healthy, normal‐weight participants, with a mean age of 24.3 years, were studied for 4 days in a double‐blinded, randomized clinical trial. Blood was collected before and after s.c. injection of GLP‐1 (7‐36)amide (1.5 nmol/kg), GLP‐1 (9‐36)amide (1.5 nmol/kg), exenatide (2.4 nmol/subject), or saline. Plasma was analyzed for bone markers and for osteoprotegerin (OPG), PTH, and IGF‐1 levels. All ligands were tested in vitro for their cAMP‐inducing activity on the human GLP‐1 receptor. GLP‐1 (7‐36)amide decreased CTX‐lev...

Physiological reports, 2018

A serious complication to the laparoscopic Roux-en-Y gastric bypass (RYGB) is internal hernia, wh... more A serious complication to the laparoscopic Roux-en-Y gastric bypass (RYGB) is internal hernia, which can lead to massive bowel necrosis that may result in short bowel syndrome. We determined postprandial enteropancreatic hormonal responses and metabolites in a 22-year-old nondiabetic woman with a history of RYGB experiencing severe internal herniation with widespread bowel necrosis. Extensive resections were performed leaving her with a saliva fistula from the pouch-enteric anastomosis, an intact duodenum, 15 cm of jejunum, 35 cm of ileum, and intact colon. Parenteral nutrition was initiated and 10 months after the bowel resection, intestinal continuity was re-established. After 6 weeks the patient reached parenteral nutrition independence. She underwent standardized liquid mixed meal tests before, 3 months after and 2 years after intestinal continuity was re-established. Gut hormone responses were completely restored postoperatively leading to very high concentrations in plasma. Af...

The British journal of nutrition, 2018

The aim of the study was to assess whether a simple substitution of carbohydrate in the conventio... more The aim of the study was to assess whether a simple substitution of carbohydrate in the conventionally recommended diet with protein and fat would result in a clinically meaningful reduction in postprandial hyperglycaemia in subjects with type 2 diabetes mellitus (T2DM). In all, sixteen subjects with T2DM treated with metformin only, fourteen male, with a median age of 65 (43-70) years, HbA1c of 6·5 % (47 mmol/l) (5·5-8·3 % (37-67 mmol/l)) and a BMI of 30 (sd 4·4) kg/m2 participated in the randomised, cross-over study. A carbohydrate-reduced high-protein (CRHP) diet was compared with an iso-energetic conventional diabetes (CD) diet. Macronutrient contents of the CRHP/CD diets consisted of 31/54 % energy from carbohydrate, 29/16 % energy from protein and 40/30 % energy from fat, respectively. Each diet was consumed on 2 consecutive days in a randomised order. Postprandial glycaemia, pancreatic and gut hormones, as well as satiety, were evaluated at breakfast and lunch. Compared with ...

Nutrition & diabetes, Jan 12, 2018

After digestion, dietary triacylglycerol stimulates incretin release in humans, mainly through ge... more After digestion, dietary triacylglycerol stimulates incretin release in humans, mainly through generation of 2-monoacylglycerol, an agonist for the intestinal G protein-coupled receptor 119 (GPR119). Enhanced incretin release may have beneficial metabolic effects. However, dietary fat may promote weight gain and should therefore be restricted in obesity. We designed C4-dietary oil (1,3-di-butyryl-2-oleoyl glycerol) as a 2-oleoyl glycerol (2-OG)-generating fat type, which would stimulate incretin release to the same extent while providing less calories than equimolar amounts of common triglycerides, e.g., olive oil. We studied the effect over 180 min of (a) 19 g olive oil plus 200 g carrot, (b) 10.7 g C4 dietary oil plus 200 g carrot and (c) 200 g carrot, respectively, on plasma responses of gut and pancreatic hormones in 13 overweight patients with type 2 diabetes (T2D). Theoretically, both oil meals result in formation of 7.7 g 2-OG during digestion. Both olive oil and C4-dietary o...

American journal of physiology. Endocrinology and metabolism, Jan 18, 2017

Glucagon-like peptide-1 (GLP-1) is an incretin hormone secreted from the gastrointestinal tract. ... more Glucagon-like peptide-1 (GLP-1) is an incretin hormone secreted from the gastrointestinal tract. It is best known for its glucose-dependent insulinotropic effects GLP-1 is secreted in its intact (active) form (7-36NH2) but is rapidly degraded by the dipeptidyl peptidase 4 (DPP-4) enzyme, converting >90% to the primary metabolite (9-36NH2) before reaching the targets via the circulation. Although originally thought to be inactive or antagonistic, GLP-1 9-36NH2 may have independent actions, and it is therefore relevant to be able to measure it. Because reliable assays were not available, we developed a sandwich ELISA recognizing both GLP-1 9-36NH2 and non-amidated GLP-1 9-37. The ELISA was validated using analytical assay validation guidelines and by comparing it to a subtraction-based method, hitherto employed for estimation of GLP-1 9-36NH2 Its accuracy was evaluated from measurements of plasma obtained during intravenous infusions (1.5 pmol×kg-1×min-1) of GLP-1 7-36NH2 in health...

Circulation, Jan 24, 2017

Background -Loss-of-function mutations in hERG (encoding the Kv11.1 voltage-gated potassium chann... more Background -Loss-of-function mutations in hERG (encoding the Kv11.1 voltage-gated potassium channel) cause long QT syndrome (LQT2) due to prolonged cardiac repolarization. However, Kv11.1 is also present in pancreatic α and β cells and intestinal L and K cells, secreting glucagon, insulin, and the incretins glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), respectively. These hormones are crucial for glucose regulation and LQTS may cause disturbed glucose regulation. We measured secretion of these hormones and cardiac repolarization in response to glucose ingestion in LQT2 patients with functional mutations in hERG and matched healthy participants, testing the hypothesis that LQT2 patients have increased incretin and β cell- and decreased α cell function and thus lower glucose levels. Methods -Eleven patients with LQT2 and 22 gender, age- and BMI-matched control participants underwent a 6-hour 75g oral glucose tolerance test (OGTT) with electroc...

International Journal of Obesity, 2016