Publications by authors named "Jens Juul Holst"

275 Publications

GLP-1 and Intestinal Diseases.

Authors:
Jenna Elizabeth Hunt Jens Juul Holst Palle Bekker Jeppesen Hannelouise Kissow

Biomedicines 2021 Apr 5;9(4). Epub 2021 Apr 5.

Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark.

Accumulating evidence implicates glucagon-like peptide-1 (GLP-1) to have, beyond glucose maintenance, a beneficial role in the gastrointestinal tract. Here, we review emerging data investigating GLP-1 as a novel treatment for intestinal diseases, including inflammatory bowel diseases, short-bowel syndrome, intestinal toxicities and coeliac disease. Possible beneficial mechanisms for these diseases include GLP-1's influence on gastric emptying, its anti-inflammatory properties and its intestinotrophic effect. The current knowledge basis derives from the available GLP-1 agonist treatments in experimental animals and small clinical trials. However, new novel strategies including dual GLP-1/GLP-2 agonists are also in development for the treatment of intestinal diseases.
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http://dx.doi.org/10.3390/biomedicines9040383DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8067135PMC
April 2021

Exploring the GLP-1-GLP-1R axis in porcine pancreas and gastrointestinal tract in vivo by ex vivo autoradiography.

Authors:
Elin Manell Emmi Puuvuori Anna Svensson Irina Velikyan Gry Hulsart-Billström Patricia Hedenqvist Jens Juul Holst Marianne Jensen Waern Olof Eriksson

BMJ Open Diabetes Res Care 2021 Apr;9(1)

Science for Life Laboratory, Department of Medicinal Chemistry, Uppsala University, Uppsala, Sweden.

Introduction: Glucagon-like peptide-1 (GLP-1) increases insulin secretion from pancreatic beta-cells and GLP-1 receptor (GLP-1R) agonists are widely used as treatment for type 2 diabetes mellitus. Studying occupancy of the GLP-1R in various tissues is challenging due to lack of quantitative, repeatable assessments of GLP-1R density. The present study aimed to describe the quantitative distribution of GLP-1Rs and occupancy by endogenous GLP-1 during oral glucose tolerance test (OGTT) in pigs, a species that is used in biomedical research to model humans.

Research Design And Methods: GLP-1R distribution and occupancy were measured in pancreas and gastrointestinal tract by ex vivo autoradiography using the GLP-1R-specific radioligand Lu-exendin-4 in two groups of pigs, control or bottle-fed an oral glucose load. Positron emission tomography (PET) data from pigs injected with Ga-exendin-4 in a previous study were used to retrieve data on biodistribution of GLP-1R in the gastrointestinal tract.

Results: High homogenous uptake of Lu-exendin-4 was found in pancreas, and even higher uptake in areas of duodenum. Low uptake of Lu-exendin-4 was found in stomach, jejunum, ileum and colon. During OGTT, there was no increase in plasma GLP-1 concentrations and occupancy of GLP-1Rs was low. The ex vivo autoradiography results were highly consistent with to the biodistribution of Ga-exendin-4 in pigs scanned by PET.

Conclusion: We identified areas with similarities as well as important differences regarding GLP-1R distribution and occupancy in pigs compared with humans. First, there was strong ligand binding in the exocrine pancreas in islets. Second, GLP-1 secretion during OGTT is minimal and GLP-1 might not be an important incretin in pigs under physiological conditions. These findings offer new insights on the relevance of porcine diabetes models.
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http://dx.doi.org/10.1136/bmjdrc-2020-002083DOI Listing
April 2021

The Antiresorptive Effect of GIP, But Not GLP-2, Is Preserved in Patients With Hypoparathyroidism-A Randomized Crossover Study.

Authors:
Kirsa Skov-Jeppesen Nicola Hepp Jannika Oeke Morten Steen Hansen Abbas Jafari Maria Saur Svane Nariman Balenga John A Olson Morten Frost Moustapha Kassem Sten Madsbad Jens-Erik Beck Jensen Jens Juul Holst Mette Marie Rosenkilde Bolette Hartmann

J Bone Miner Res 2021 Apr 14. Epub 2021 Apr 14.

Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark.

Glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-2 (GLP-2) are gut hormones secreted postprandially. In healthy humans, both hormones decrease bone resorption accompanied by a rapid reduction in parathyroid hormone (PTH). The aim of this study was to investigate whether the changes in bone turnover after meal intake and after GIP- and GLP-2 injections, respectively, are mediated via a reduction in PTH secretion. This was tested in female patients with hypoparathyroidism given a standardized liquid mixed-meal test (n = 7) followed by a peptide injection test (n = 4) using a randomized crossover design. We observed that the meal- and GIP- but not the GLP-2-induced changes in bone turnover markers were preserved in the patients with hypoparathyroidism. To understand the underlying mechanisms, we examined the expression of the GIP receptor (GIPR) and the GLP-2 receptor (GLP-2R) in human osteoblasts and osteoclasts as well as in parathyroid tissue. The GIPR was expressed in both human osteoclasts and osteoblasts, whereas the GLP-2R was absent or only weakly expressed in osteoclasts. Furthermore, both GIPR and GLP-2R were expressed in parathyroid tissue. Our findings suggest that the GIP-induced effect on bone turnover may be mediated directly via GIPR expressed in osteoblasts and osteoclasts and that this may occur independent of PTH. In contrast, the effect of GLP-2 on bone turnover seems to depend on changes in PTH and may be mediated through GLP-2R in the parathyroid gland. © 2021 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).
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http://dx.doi.org/10.1002/jbmr.4308DOI Listing
April 2021

Voices: Insulin and beyond.

Authors:
Jesse Roth Frances M Ashcroft Claes B Wollheim Timothy J Kieffer Alan D Cherrington Richard N Bergman Roy Taylor Sonia M Najjar Oluf Pedersen Helga Ellingsgaard Jens Juul Holst Michael A Nauck Takashi Kadowaki Michael P Czech Silvia Corvera Alan R Saltiel Barbara E Corkey Mark A Atkinson

Cell Metab 2021 Apr;33(4):692-699

Marking insulin's centennial, we share stories of researchers and clinicians whose seminal work has advanced our understanding of insulin, islet biology, insulin resistance, and diabetes. The past century of pursuing the "hormone of hormones" and advancing diabetes therapies is replete with stories of collaboration, perseverance, and triumph.
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http://dx.doi.org/10.1016/j.cmet.2021.03.017DOI Listing
April 2021

The role of incretins on insulin function and glucose homeostasis.

Authors:
Jens Juul Holst Lærke Smidt Gasbjerg Mette Marie Rosenkilde

Endocrinology 2021 Mar 30. Epub 2021 Mar 30.

Department of Biomedical Sciences and the NovoNordisk Center for Basic Metabolic Research, Faculty of Health Sciences, University of Copenhagen, The Panum Institute, Copenhagen, Denmark.

The incretin effect - the amplification of insulin secretion after oral versus intravenous administration of glucose as a mean to improve glucose tolerance - was suspected even before insulin was discovered, and today we know that the effect is due to the secretion of two insulinotropic peptides, glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1). But how important is it? Physiological experiments have shown that, because of the incretin effect, we can ingest increasing amounts of amounts of glucose (carbohydrates) without increasing postprandial glucose excursions, which otherwise might have severe consequences. The mechanism behind this is incretin-stimulated insulin secretion. The availability of antagonists for GLP-1 and most recently also for GIP has made it possible to directly estimate the individual contributions to postprandial insulin secretion of a) glucose itself: 26%; b) GIP: 45%; and c) GLP-1: 29%. Thus, in healthy individuals, GIP is the champion. When the action of both incretins is prevented, glucose tolerance is pathologically impaired. Thus, after 100 years of research, we now know that insulinotropic hormones from the gut are indispensable for normal glucose tolerance. The loss of the incretin effect in type 2 diabetes, therefore, contributes greatly to the impaired postprandial glucose control.
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http://dx.doi.org/10.1210/endocr/bqab065DOI Listing
March 2021

Dietary Fiber Is Essential to Maintain Intestinal Size, L-Cell Secretion, and Intestinal Integrity in Mice.

Authors:
Jenna Elizabeth Hunt Bolette Hartmann Kristina Schoonjans Jens Juul Holst Hannelouise Kissow

Front Endocrinol (Lausanne) 2021 26;12:640602. Epub 2021 Feb 26.

Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.

Dietary fiber has been linked to improved gut health, yet the mechanisms behind this association remain poorly understood. One proposed mechanism is through its influence on the secretion of gut hormones, including glucagon-like peptide-1 (GLP-1) and glucagon-like peptide-2 (GLP-2). We aimed to: 1) investigate the impact of a fiber deficient diet on the intestinal morphological homeostasis; 2) evaluate L-cell secretion; and 3) to ascertain the role of GLP-1, GLP-2 and Takeda G protein-receptor-5 (TGR5) signaling in the response using GLP-1 receptor, GLP-2 receptor and TGR5 knockout mice. Female C57BL/6JRj mice (n = 8) either received a standard chow diet or were switched to a crude fiber-deficient diet for a short (21 days) and long (112 days) study period. Subsequent identical experiments were performed in GLP-1 receptor, GLP-2 receptor and TGR5 knockout mice. The removal of fiber from the diet for 21 days resulted in a decrease in small intestinal weight (p < 0.01) and a corresponding decrease in intestinal crypt depth in the duodenum, jejunum and ileum (p < 0.001, p < 0.05, and p < 0.01, respectively). Additionally, colon weight was decreased (p < 0.01). These changes were associated with a decrease in extractable GLP-1, GLP-2 and PYY in the colon (p < 0.05, p < 0.01, and p < 0.01). However, we could not show that the fiber-dependent size decrease was dependent on GLP-1 receptor, GLP-2 receptor or TGR5 signaling. Intestinal permeability was increased following the removal of fiber for 112 days. In conclusion, our study highlights the importance of dietary fiber to maintain intestinal weight, colonic L-cell secretion and intestinal integrity.
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http://dx.doi.org/10.3389/fendo.2021.640602DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7953038PMC
February 2021

In patients with controlled acromegaly, indices of glucose homeostasis correlate with IGF-1 levels rather than with type of treatment.

Authors:
Amelie Decock Charlotte Verroken Frederique Van de Velde Tina Vilsbøll Jens Juul Holst Guy T'Sjoen Bruno Lapauw

Clin Endocrinol (Oxf) 2021 Mar 13. Epub 2021 Mar 13.

Department of Endocrinology, Ghent University Hospital, Ghent, Belgium.

Objective: Acromegaly is accompanied by abnormalities in glucose and lipid metabolism which improve upon treatment. Few studies have investigated whether these improvements differ between treatment modalities. This study aimed to compare glucose homeostasis, lipid profiles and postprandial gut hormone response in patients with controlled acromegaly according to actual treatment.

Design: Cross-sectional study at a tertiary care centre.

Patients: Twenty-one patients with acromegaly under stable control (ie insulin growth factor 1 [IGF1] levels below sex- and age-specific thresholds and a random growth hormone level <1.0 µg/L) after surgery (n = 5), during treatment with long-acting somatostatin analogues (n = 10) or long-acting somatostatin analogues + pegvisomant (n = 6) were included.

Measurements: Glucose, insulin, total cholesterol and high-density lipoprotein-cholesterol were measured in fasting serum samples. Glucose, insulin, triglycerides, glucose-dependent insulinotropic polypeptide and glucagon-like peptide 1 were measured during a mixed meal test. Insulin sensitivity was evaluated by a hyperinsulinaemic-euglycaemic clamp.

Results: There were no significant differences in glucose tolerance, insulin sensitivity or postprandial gut hormone responses between the three groups. Positive correlations between IGF1 levels and HbA1c, fasting glucose and insulin levels and postprandial area under the curve (AUC) of glucose and insulin and also an inverse association between IGF1 and glucose disposal rate were found in the whole cohort (all p < .05, lowest p = .001 for postprandial AUC glucose with r  = 0.660).

Conclusion: In this cross-sectional study in patients with controlled acromegaly, there were no differences in glucose homeostasis or postprandial substrate metabolism according to treatment modality. However, a lower IGF1 level seems associated with a better metabolic profile.
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http://dx.doi.org/10.1111/cen.14461DOI Listing
March 2021

β-Lactoglobulin Is Insulinotropic Compared with Casein and Whey Protein Ingestion during Catabolic Conditions in Men in a Double-Blinded Randomized Crossover Trial.

Authors:
Maike Mose Niels Møller Niels Jessen Ulla Ramer Mikkelsen Britt Christensen Elin Rakvaag Bolette Hartmann Jens Juul Holst Jens Otto Lunde Jørgensen Nikolaj Rittig

J Nutr 2021 Mar 9. Epub 2021 Mar 9.

Department of Endocrinology and Internal Medicine, Aarhus University Hospital, Aarhus, Denmark.

Background: Muscle loss during acute infectious disease is mainly triggered by inflammation, immobilization, and malnutrition.

Objective: The objective was to compare muscle protein kinetics and metabolism following ingestion of the dairy protein supplements β-lactoglobulin (BLG), casein (CAS), and whey (WHE) during controlled catabolic conditions.

Methods: We used a randomized crossover design (registered at clinicaltrials.gov as NCT03319550) to investigate 9 healthy male participants [age: 20-40 y; BMI (in kg/m2) 20-30] who were randomly assigned servings of BLG, CAS, or WHE (0.6 g protein/kg, one-third as bolus and two-thirds as sip every 20 min) on 3 separate occasions separated by ∼6-8 wk. The participants received an infusion of lipopolysaccharide (1 ng/kg) combined with 36 h of fasting and bed rest before each study day, mimicking a clinical catabolic condition. The forearm model and isotopic tracer techniques were used to quantify muscle protein kinetics. Muscle biopsy specimens were obtained and intramyocellular signaling investigated using Western blot.

Results: BLG, CAS, and WHE improved the net balance of phenylalanine (NBphe) from baseline with ∼75% (P < 0.001) with no difference between interventions (primary outcome, P < 0.05). No difference in rates of appearance and disappearance of phenylalanine or in intramyocellular signaling activation was found between interventions (secondary outcomes). The incremental AUC for serum insulin was 62% higher following BLG compared with CAS (P < 0.001) and 30% higher compared with WHE (P = 0.002), as well as 25% higher in WHE compared with CAS (P = 0.006). Following BLG consumption, plasma concentrations of glucose-dependent insulinotropic peptide (GIP) increased 70% compared with CAS (P = 0.001) and increased 34% compared with WHE (P = 0.06). No significant difference was found between WHE and CAS (P = 0.12).

Conclusion: BLG, WHE, and CAS have similar effects on muscle in young male participants during catabolic conditions. BLG showed specific, possibly GIP-dependent, insulinotropic properties, which may have future clinical implications.
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http://dx.doi.org/10.1093/jn/nxab010DOI Listing
March 2021

GIP receptor deletion in mice confers resistance to high-fat diet-induced obesity via alterations in energy expenditure and adipose tissue lipid metabolism.

Authors:
Geke Aline Boer Stacey N Keenan Paula M Miotto Jens Juul Holst Matthew J Watt

Am J Physiol Endocrinol Metab 2021 04 1;320(4):E835-E845. Epub 2021 Mar 1.

Department of Anatomy and Physiology, School of Biomedical Sciences, University of Melbourne, Melbourne, Victoria, Australia.

Glucose-dependent insulinotropic polypeptide (GIP) is best known as an incretin hormone that is secreted from K-cells of the proximal intestine, but evidence also implicates a role for GIP in regulating lipid metabolism and adiposity. It is well-established that GIP receptor knockout (GIPR KO) mice are resistant to diet-induced obesity; however, the factors mediating this effect remain unresolved. Accordingly, we aimed to elucidate the mechanisms leading to adiposity resistance in GIPR KO mice with a focus on whole-body energy balance and lipid metabolism in adipose tissues. Studies were conducted in age-matched male GIPR KO and wild-type (WT) mice fed a high-fat diet for 10 weeks. GIPR KO mice gained less body weight and fat mass compared to WT littermates, and this was associated with increased energy expenditure but no differences in food intake or fecal energy loss. Upon an oral lipid challenge, fatty acid storage in inguinal adipose tissue was significantly increased in GIPR KO compared with WT mice. This was not related to differential expression of lipoprotein lipase in adipose tissue. Adipose tissue lipolysis was increased in GIPR KO compared with WT mice, particularly following β-adrenergic stimulation, and could explain why GIPR KO mice gain less adipose tissue despite increased rates of fatty acid storage in inguinal adipose tissue. Taken together, these results suggest that the GIPR is required for normal maintenance of body weight and adipose tissue mass by regulating energy expenditure and lipolysis. GIPR KO mice fed a high-fat diet have reduced adiposity despite transporting more ingested lipids into adipose tissue. This can be partly explained by accelerated adipose tissue lipolysis and increased energy expenditure in GIPR KO mice. These new insights rationalize targeting the GIPR as part of a weight management strategy in obesity.
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http://dx.doi.org/10.1152/ajpendo.00646.2020DOI Listing
April 2021

Amino acids differ in their capacity to stimulate GLP-1 release from the perfused rat small intestine and stimulate secretion by different sensing mechanisms.

Authors:
Ida Marie Modvig Rune Ehrenreich Kuhre Sara Lind Jepsen Stella Feng Sheng Xu Maja Storm Engelstoft Kristoffer Lihme Egerod Thue Walther Schwartz Cathrine Ørskov Mette Marie Rosenkilde Jens Juul Holst

Am J Physiol Endocrinol Metab 2021 05 1;320(5):E874-E885. Epub 2021 Mar 1.

Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.

The aim of this study was to explore individual amino acid-stimulated GLP-1 responses and the underlying stimulatory mechanisms, as well as to identify the amino acid-sensing receptors involved in amino acid-stimulated GLP-1 release. Experiments were primarily based on isolated perfused rat small intestines, which have intact epithelial polarization allowing discrimination between luminal and basolateral mechanisms as well as quantitative studies of intestinal absorption and hormone secretion. Expression analysis of amino acid sensors on isolated murine GLP-1 secreting L-cells was assessed by qPCR. We found that l-valine powerfully stimulated GLP-1 secretion but only from the luminal side (2.9-fold increase). When administered from the vascular side, l-arginine and the aromatic amino acids stimulated GLP-1 secretion equally (2.6- to 2.9-fold increases). Expression analysis revealed that Casr expression was enriched in murine GLP-1 secreting L-cells, whereas Gpr35, Gprc6a, Gpr142, Gpr93 (Lpar5), and the umami taste receptor subunits Tas1r3 and Tas1r1 were not. Consistently, activation of GPR35, GPR93, GPR142, and the umami taste receptor with specific agonists or allosteric modulators did not increase GLP-1 secretion ( > 0.05 for all experiments), whereas vascular inhibition of CaSR reduced GLP-1 secretion in response to luminal infusion of mixed amino acids. In conclusion, amino acids differ in their capacity to stimulate GLP-1 secretion. Some amino acids stimulated secretion only from the intestinal lumen, whereas other amino acids exclusively stimulated secretion from the vascular side, indicating that amino acid-stimulated GLP-1 secretion involves both apical and basolateral (postabsorptive) sensing mechanisms. Sensing of absorbed amino acids involves CaSR activation as vascular inhibition of CaSR markedly diminished amino acid stimulated GLP-1 release. Using isolated perfused rat small intestines, we show that amino acids differ in their mechanisms and capacity of stimulating GLP-1 release. Furthermore, we demonstrate that sensing by GPR142, GPR35, GPR93, and the umami taste receptor (Tas1R1/Tas1R3) are not involved in amino acid stimulated GLP-1 release. In contrast to previous studies, this experimental model allows discrimination between the luminal and the vascular side of the intestine, which is essential when studying mechanisms of amino acid-stimulated GLP-1 secretion.
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http://dx.doi.org/10.1152/ajpendo.00026.2021DOI Listing
May 2021

Effect of 6 weeks of very low-volume high-intensity interval training on oral glucose-stimulated incretin hormone response.

Authors:
Morten Hindsø Anja Birk Kuhlman Tine Lovsø Dohlmann Michael Taulo Lund Bolette Hartmann Jens Juul Holst Steen Larsen Jørn Wulff Helge

Eur J Sport Sci 2021 Feb 2:1-9. Epub 2021 Feb 2.

Xlab, Department of Biomedical Sciences, University of Copenhagen, Copenhagen N, Denmark.

Decreased fasting and oral glucose-stimulated incretin hormone concentrations following moderate-intensity continuous endurance training interventions have been reported in glucose-tolerant people, however results are conflicting. The effect of more time-efficient, very low-volume, high-intensity interval training (HIT) on circulating incretin hormone levels has never been studied. Ten sedentary and overweight-to-obese participants (4 women and 6 men; age 43 ± 6 years (mean ± SD); BMI 30.2 ± 3.2 kg∙m; HbA1c 35 ± 5.1 mmol∙mol (5.3 ± 0.3%); VOmax 30 ± 5 ml∙min∙kg) from the Copenhagen cohort of the METAPREDICT trial underwent 6 weeks of supervised low-volume HIT (3 sessions per week: 7 × 1 min at ∼100% VOmax separated by 1 min of active recovery). We measured glucose, insulin, C-peptide, glucagon, GLP-1 and GIP concentrations during a frequently sampled 75 g oral glucose tolerance test as well as VOmax and body composition before and after the intervention. Training compliance was 100%. Relative VOmax improved after the intervention (median 2.69 ml∙min∙kg, IQR [0.43; 3.14],  = 0.037) while there were no significant effects on body weight and composition. No significant effects on oral glucose-stimulated glucose and hormone responses or estimates of insulin sensitivity and β-cell function were observed. Low-volume HIT improved aerobic fitness, but neither affected glucose tolerance nor oral glucose-stimulated incretin hormone responses in sedentary and overweight-to-obese people. Ten sedentary, overweight-to-obese, glucose-tolerant participants underwent 6 weeks of supervised, very low-volume HIT. Aerobic fitness improved. Fasting and oral glucose-stimulated incretin hormone concentrations were not affected.
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http://dx.doi.org/10.1080/17461391.2021.1877830DOI Listing
February 2021

Genome-wide association study of circulating levels of glucagon during an oral glucose tolerance test.

Authors:
Anna Jonsson Sara E Stinson Signe S Torekov Tine D Clausen Kristine Færch Louise Kelstrup Niels Grarup Elisabeth R Mathiesen Peter Damm Daniel R Witte Marit E Jørgensen Oluf Pedersen Jens Juul Holst Torben Hansen

BMC Med Genomics 2021 Jan 6;14(1). Epub 2021 Jan 6.

The Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Blegdamsvej 3B, 2200, Copenhagen, Denmark.

Background: In order to explore the pathophysiology underlying type 2 diabetes we examined the impact of gene variants associated with type 2 diabetes on circulating levels of glucagon during an oral glucose tolerance test (OGTT). Furthermore, we performed a genome-wide association study (GWAS) aiming to identify novel genomic loci affecting plasma glucagon levels.

Methods: Plasma levels of glucagon were examined in samples obtained at three time points during an OGTT; 0, 30 and 120 min, in two separate cohorts with a total of up to 1899 individuals. Cross-sectional analyses were performed separately in the two cohorts and the results were combined in a meta-analysis.

Results: A known type 2 diabetes variant in EYA2 was significantly associated with higher plasma glucagon level at 30 min during the OGTT (Beta 0.145, SE 0.038, P = 1.2 × 10) corresponding to a 7.4% increase in plasma glucagon level per effect allele. In the GWAS, we identified a marker in the MARCH1 locus, which was genome-wide significantly associated with reduced suppression of glucagon during the first 30 min of the OGTT (Beta - 0.210, SE 0.037, P = 1.9 × 10), equivalent to 8.2% less suppression per effect allele. Nine additional independent markers, not previously associated with type 2 diabetes, showed suggestive associations with reduced glucagon suppression during the first 30 min of the OGTT (P < 1.0 × 10).

Conclusions: A type 2 diabetes risk variant in the EYA2 locus was associated with higher plasma glucagon levels at 30 min. Ten additional variants were suggestively associated with reduced glucagon suppression without conferring increased type 2 diabetes risk.
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http://dx.doi.org/10.1186/s12920-020-00841-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7788944PMC
January 2021

Incretin Hormones and Type 2 Diabetes-Mechanistic Insights and Therapeutic Approaches.

Authors:
Geke Aline Boer Jens Juul Holst

Biology (Basel) 2020 Dec 16;9(12). Epub 2020 Dec 16.

Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen N, Denmark.

Glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are secreted from the gut upon nutrient stimulation and regulate postprandial metabolism. These hormones are known as classical incretin hormones and are responsible for a major part of postprandial insulin release. The incretin effect is severely reduced in patients with type 2 diabetes, but it was discovered that administration of GLP-1 agonists was capable of normalizing glucose control in these patients. Over the last decades, much research has been focused on the development of incretin-based therapies for type 2 diabetes. These therapies include incretin receptor agonists and inhibitors of the incretin-degrading enzyme dipeptidyl peptidase-4. Especially the development of diverse GLP-1 receptor agonists has shown immense success, whereas studies of GIP monotherapy in patients with type 2 diabetes have consistently been disappointing. Interestingly, both GIP-GLP-1 co-agonists and GIP receptor antagonists administered in combination with GLP-1R agonists appear to be efficient with respect to both weight loss and control of diabetes, although the molecular mechanisms behind these effects remain unknown. This review describes our current knowledge of the two incretin hormones and the development of incretin-based therapies for treatment of type 2 diabetes.
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http://dx.doi.org/10.3390/biology9120473DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7766765PMC
December 2020

The effect of preceding glucose decline rate on low-dose glucagon efficacy in individuals with type 1 diabetes: A randomized crossover trial.

Authors:
Christian Laugesen Signe Schmidt Jens Juul Holst Kirsten Nørgaard Ajenthen G Ranjan

Diabetes Obes Metab 2021 Apr 6;23(4):1057-1062. Epub 2021 Jan 6.

Clinical Research, Steno Diabetes Center Copenhagen, Gentofte, Denmark.

Identifying determinants of low-dose glucagon efficacy is important to optimise its utilization for prevention and treatment of hypoglycaemia in individuals with type 1 diabetes. The study objective was to investigate whether the preceding glucose decline rate affects glucose response to low-dose glucagon administration. Ten adults with insulin pump-treated type 1 diabetes were included in this randomized, single-blind, two-way crossover study. Using a hyperinsulinaemic clamp technique, plasma glucose levels were reduced with either a rapid or slow decline rate while maintaining fixed insulin levels. When the plasma glucose level reached 3.9 mmoL/L, insulin and glucose infusions were discontinued and 150 μg subcutaneous glucagon was administered, followed by 120 minutes of plasma glucose monitoring. The positive incremental area under the glucose curve after administration of low-dose glucagon did not differ between the rapid-decline and slow-decline visits (mean ± SEM: 220 ± 49 vs. 174 ± 31 mmoL/L x min; P = 0.21). Similarly, no differences in total area under the glucose curve, peak plasma glucose, incremental peak plasma glucose, time-to-peak plasma glucose or end plasma glucose were observed. Thus, preceding glucose decline rate did not significantly affect the glucose response to low-dose glucagon.
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http://dx.doi.org/10.1111/dom.14301DOI Listing
April 2021

Pharmacokinetics of exogenous GIP(1-42) in C57Bl/6 mice; Extremely rapid degradation but marked variation between available assays.

Authors:
Geke Aline Boer Bolette Hartmann Jens Juul Holst

Peptides 2021 Feb 24;136:170457. Epub 2020 Nov 24.

NNF Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark; Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark. Electronic address:

Like other peptide hormones, glucose-dependent insulinotropic polypeptide (GIP) is rapidly cleared from the circulation. Dipeptidyl peptidase-4 (DPP-4) is known to be involved. Information on the overall pharmacokinetics of GIP in rodents is, however, lacking. We investigated the pharmacokinetics of exogenous GIP after intravenous, subcutaneous and intraperitoneal injection with and without DPP-4 inhibition in conscious female C57Bl/6 mice. Secondly, we compared total and intact GIP levels measured by an in-house RIA and commercially available ELISA kits to determine the suitability of these methods for in vivo and in vitro measurements. GIP half-life following intravenous injection amounted to 93 ± 2 s, which was extended to 5 ± 0.6 min by inhibition of DPP-4. Intact GIP levels following subcutaneous and intraperitoneal GIP administration were approximately 15 % of total GIP. The area under the curve of intact GIP (GIP exposure) following GIP injection was significantly increased by DPP-4 inhibition, whereas total GIP levels remained unchanged. We found significant variation between measurements of total, but not intact GIP performed with our in-house RIA and ELISAs in samples obtained after in vivo administration of GIP. Different preanalytical sample preparation (EDTA plasma, heparin plasma, assay buffer and PBS) significantly influenced results for all ELISA kits used. Thus, in experiments involving exogenous GIP(1-42) administration in mice, it is important to consider that this will result in a very low ratio of intact:total peptide but co-administration of a DPP-4 inhibitor greatly elevates this ratio. Furthermore, for comparison of GIP levels, it is essential to maintain uniformity concerning assay methodology and sample preparation.
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http://dx.doi.org/10.1016/j.peptides.2020.170457DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7883216PMC
February 2021

Glucose-Dependent Insulinotropic Peptide in the High-Normal Range Is Associated With Increased Carotid Intima-Media Thickness.

Authors:
Amra Jujić Peter M Nilsson Naeimeh Atabaki-Pasdar Anna Dieden Tiinamaija Tuomi Paul W Franks Jens Juul Holst Signe Sørensen Torekov Susana Ravassa Javier Díez Margaretha Persson Emma Ahlqvist Olle Melander Maria F Gomez Leif Groop Martin Magnusson

Diabetes Care 2021 Jan 18;44(1):224-230. Epub 2020 Nov 18.

Department of Clinical Sciences, Lund University, Malmö, Sweden.

Objective: While existing evidence supports beneficial cardiovascular effects of glucagon-like peptide 1 (GLP-1), emerging studies suggest that glucose-dependent insulinotropic peptide (GIP) and/or signaling via the GIP receptor may have untoward cardiovascular effects. Indeed, recent studies show that fasting physiological GIP levels are associated with total mortality and cardiovascular mortality, and it was suggested that GIP plays a role in pathogenesis of coronary artery disease. We investigated the associations between fasting and postchallenge GIP and GLP-1 concentrations and subclinical atherosclerosis as measured by mean intima-media thickness in the common carotid artery (IMTCCA) and maximal intima-media thickness in the carotid bifurcation (IMTBulb).

Research Design And Methods: Participants at reexamination within the Malmö Diet and Cancer-Cardiovascular Cohort study ( = 3,734, mean age 72.5 years, 59.3% women, 10.8% subjects with diabetes, fasting GIP available for 3,342 subjects, fasting GLP-1 available for 3,299 subjects) underwent oral glucose tolerance testing and carotid ultrasound.

Results: In linear regression analyses, each 1-SD increment of fasting GIP was associated with increased (per mm) IMTCCA (β = 0.010, = 0.010) and IMTBulb (β = 0.014; = 0.040) in models adjusted for known risk factors and glucose metabolism. In contrast, each 1-SD increment of fasting GLP-1 was associated with decreased IMTBulb (per mm, β = -0.016, = 0.014). These associations remained significant when subjects with diabetes were excluded from analyses.

Conclusions: In a Swedish elderly population, physiologically elevated levels of fasting GIP are associated with increased IMTCCA, while GLP-1 is associated with decreased IMTBulb, further emphasizing diverging cardiovascular effects of these two incretin hormones.
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http://dx.doi.org/10.2337/dc20-1318DOI Listing
January 2021

Nonalcoholic Fatty Liver Disease Impairs the Liver-Alpha Cell Axis Independent of Hepatic Inflammation and Fibrosis.

Authors:
Julie Steen Pedersen Marte Opseth Rygg Viggo Bjerregaard Kristiansen Beth Hærstedt Olsen Reza Rafiolsadat Serizawa Jens Juul Holst Sten Madsbad Lise Lotte Gluud Flemming Bendtsen Nicolai Jacob Wewer Albrechtsen

Hepatol Commun 2020 Nov 1;4(11):1610-1623. Epub 2020 Sep 1.

Department of Biomedical Sciences Faculty of Health and Medical Sciences University of Copenhagen Copenhagen Denmark.

Nonalcoholic fatty liver disease (NAFLD) is associated with impaired hepatic actions of glucagon and insulin. Glucagon and amino acids are linked in an endocrine feedback circuit, the liver-alpha cell axis, that may be disrupted by NAFLD. We investigated how NAFLD severity affects glucagon and insulin resistance in individuals with obesity and whether bariatric surgery improves these parameters. Plasma and liver biopsies from 33 individuals with obesity (collectively, OBE) were obtained before and 12 months after bariatric surgery (Roux-en-Y gastric bypass [RYGB] or sleeve gastrectomy [SG]). Nine healthy control individuals (collectively, CON) undergoing cholecystectomy were used as a comparison group. The NAFLD activity score (NAS) was used to subdivide study participants into the following groups: OBE-no steatosis, OBE+steatosis, and nonalcoholic steatohepatitis (NASH) and/or grade 2 fibrosis (Fib) (OBE-NASH-Fib). Measurements of amino acids by targeted metabolomics and glucagon were performed. Glucagon, amino acids ( < 0.05), and the glucagon-alanine index, a validated surrogate marker of glucagon resistance, were increased in OBE by 60%, 56%, and 61%, respectively, when compared with CON but irrespective of NAFLD severity. In contrast, markers of hepatic insulin resistance increased concomitantly with NAS. Hyperglucagonemia resolved in OBE-no steatosis and OBE+steatosis but not in OBE-NASH-Fib (median, 7.0; interquartile range, 5.0-9.8 pmol/L), regardless of improvement in insulin resistance and NAS. The type of surgery that participants underwent had no effect on metabolic outcomes. Glucagon resistance to amino acid metabolism exists in individuals with NAFLD independent of NAS severity. Patients with NASH showed persistent hyperglucagonemia 12 months after bariatric surgery, indicating that a disrupted liver-alpha cell may remain in NAFLD despite major improvement in liver histology.
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http://dx.doi.org/10.1002/hep4.1562DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7603528PMC
November 2020

Counterregulatory responses to postprandial hypoglycemia after Roux-en-Y gastric bypass.

Authors:
Caroline C Øhrstrøm Dorte L Hansen Urd Lynge Kielgast Marianne Lerbæk Bergmann Simon Veedfald Jens Juul Holst Dorte Worm

Surg Obes Relat Dis 2021 Jan 4;17(1):55-63. Epub 2020 Sep 4.

Department of Medicine, Amager Hospital, Copenhagen, Denmark.

Background: Postbariatric hypoglycemia (PBH) is a potentially serious complication after Roux-en-Y gastric bypass (RYGB), and impaired counterregulatory hormone responses have been suggested to contribute to the condition.

Objectives: We evaluated counterregulatory responses during postprandial hypoglycemia in individuals with PBH who underwent RYGB.

Setting: University hospital.

Methods: Eleven women with documented PBH who had RYGB underwent a baseline liquid mixed meal test (MMT) followed by 5 MMTs preceded by treatment with (1) acarbose 50 mg, (2) sitagliptin 100 mg, (3) verapamil 120 mg, (4) liraglutide 1.2 mg, and (5) pasireotide 300 μg. Blood was collected at fixed time intervals. Plasma and serum were analyzed for glucose, insulin, glucagon, epinephrine, norepinephrine, pancreatic polypeptide (PP), and cortisol.

Results: During the baseline MMT, participants had nadir blood glucose concentrations of 3.3 ± .2 mmol/L. At the time of nadir glucose, there was a small but significant increase in plasma glucagon. Plasma epinephrine concentrations were not increased at nadir glucose but were significantly elevated by the end of the MMT. There were no changes in norepinephrine, PP, and cortisol concentrations in response to hypoglycemia. After treatment with sitagliptin, 8 individuals had glucose nadirs <3.2 mmol/L (versus 4 individuals at baseline), and significant increases in glucagon, PP, and cortisol responses were observed.

Conclusions: In response to postprandial hypoglycemia, individuals with PBH who underwent RYGB only had minor increases in counterregulatory hormones, while larger hormone responses occurred when glucose levels were lowered during treatment with sitagliptin. The glycemic threshold for counterregulatory activation could be altered in individuals with PBH, possibly explained by recurrent hypoglycemia.
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http://dx.doi.org/10.1016/j.soard.2020.08.037DOI Listing
January 2021

Effects of whey protein and dietary fiber intake on insulin sensitivity, body composition, energy expenditure, blood pressure, and appetite in subjects with abdominal obesity.

Authors:
Rasmus Fuglsang-Nielsen Elin Rakvaag Bente Langdahl Knud Erik Bach Knudsen Bolette Hartmann Jens Juul Holst Kjeld Hermansen Søren Gregersen

Eur J Clin Nutr 2021 Apr 18;75(4):611-619. Epub 2020 Sep 18.

Department of Endocrinology and Internal Medicine, Aarhus University Hospital, Aarhus, Denmark.

Background: Recently, we demonstrated that whey protein (WP) combined with low dietary fiber improved lipemia, a risk factor for cardiovascular disease in subjects with abdominal obesity. In the present study, we investigated the effects of intake of WP and dietary fiber from enzyme-treated wheat bran on other metabolic parameters of the metabolic syndrome.

Methods: The study was a 12-week, double-blind, randomized, controlled, parallel intervention study. We randomized 73 subjects with abdominal obesity to 1 of 4 iso-energetic dietary interventions: 60 g per day of either WP hydrolysate or maltodextrin (MD) combined with high-fiber (HiFi; 30 g dietary fiber/day) or low-fiber (LoFi; 10 g dietary fiber/day) cereal products. We assessed changes in insulin sensitivity, gut hormones (GLP-1, GLP-2, GIP, and peptide YY), body composition, 24-h BP, resting energy expenditure and respiratory exchange ratio (RER), and appetite.

Results: Sixty-five subjects completed the trial. Subjective hunger ratings were lower after 12 weeks of WP compared with MD, independent of fiber content (P = 0.02). We found no effects on ratings of satiety, fullness or prospective food consumption for either of the interventions. Intake of WP combined with LoFi increased the postprandial peptide YY response. There were no effects of WP or fiber on insulin sensitivity, body composition, energy expenditure, incretins, or 24-h BP.

Conclusions: WP consumption for 12 weeks reduced subjective ratings of hunger in subjects with abdominal obesity. Neither WP nor dietary fiber from wheat bran affected insulin sensitivity, 24-h BP, gut hormone responses, body composition, or energy expenditure compared with MD and low dietary fiber.
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http://dx.doi.org/10.1038/s41430-020-00759-4DOI Listing
April 2021

Preserved postprandial suppression of bone turnover markers, despite increased fasting levels, in postmenopausal women.

Authors:
Julie Abildgaard Thorkil Ploug Anette Tønnes Pedersen Pia Eiken Bente Klarlund Pedersen Jens Juul Holst Bolette Hartmann Birgitte Lindegaard

Bone 2021 02 25;143:115612. Epub 2020 Aug 25.

Centre of Inflammation and Metabolism and Centre for Physical Activity Research, Rigshospitalet, University of Copenhagen, Denmark; Department of Pulmonary and Infectious Diseases, Nordsjællands Hospital, Hillerød, Denmark. Electronic address:

Context: Menopause leads to an increased bone turnover associated with a high risk of fractures. Bone turnover is inhibited by meal intake, to some extent mediated by gut hormones, and interventions based on these endocrine changes may have potential in future prevention of osteoporosis.

Objective: To investigate whether postmenopausal women exhibit postprandial suppression of bone turnover markers to the same extent as premenopausal women, despite higher fasting levels. Furthermore, to assess whether menopausal differences in bone turnover markers are related to postmenopausal changes in plasma gut hormone levels.

Methods: A cross-sectional study of 21 premenopausal, 9 perimenopausal, and 24 postmenopausal women between 45 and 60 years of age. Serum/plasma levels of bone turnover markers and gut hormones were investigated during a 120 min oral glucose tolerance test. Bone turnover markers included N-terminal propeptide of type-I procollagen (PINP, bone formation marker) and carboxyterminal collagen I crosslinks (CTX-I, bone resorption marker). Gut hormone secretion was evaluated from responses of glucagon-like peptide-1 (GLP-1), glucagon-like peptide-2 (GLP-2) and glucose-dependent insulinotropic polypeptide (GIP).

Results: Fasting levels of s-CTX-I were increased in peri- and postmenopausal women compared to premenopausal women (p = 0.001). Despite higher fasting levels, the relative postprandial s-CTX-I suppression was comparable across menopausal status (p = 0.14). Fasting levels of s-PINP were also increased in postmenopausal women compared to premenopausal women (p < 0.001) with comparable and modest s-PINP suppression over menopause (p = 0.13). Postprandial plasma GLP-1 (p = 0.006) and GLP-2 (p = 0.01) were significantly increased in postmenopausal women compared to premenopausal women while GIP responses were slightly increased in the perimenopausal group (p = 0.02) but comparable between pre- and postmenopausal women. None of the postprandial gut hormone increases predicted postprandial bone turnover suppression in these women.

Conclusions: Glucose-induced suppression of bone turnover markers is preserved in postmenopausal women, despite significantly higher fasting values, indicating that CTX-I lowering treatments based on these postprandial mechanisms might be a feasible strategy to prevent postmenopausal osteoporosis.
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http://dx.doi.org/10.1016/j.bone.2020.115612DOI Listing
February 2021

Oral D/L-3-Hydroxybutyrate Stimulates Cholecystokinin and Insulin Secretion and Slows Gastric Emptying in Healthy Males.

Authors:
Nikolaj Rittig Mads Svart Henrik Holm Thomsen Esben Thyssen Vestergaard Jens Frederik Rehfeld Bolette Hartmann Jens Juul Holst Mogens Johannsen Niels Møller Niels Jessen

J Clin Endocrinol Metab 2020 10;105(10)

Steno Diabetes Center Aarhus, Aarhus University Hospital, Aarhus N, Denmark.

Background: D-3-hydroxybutyrate (D-3-OHB) is a ketone body that serves as an alternative nutritional fuel but also as an important signaling metabolite. Oral ketone supplements containing D/L-3-OHB are becoming a popular approach to achieve ketosis.

Aim: To explore the gut-derived effects of ketone supplements.

Methods: Eight healthy lean male volunteers were investigated on 2 separate occasions:An acetaminophen test was performed to evaluate gastric emptying and blood samples were obtained consecutively throughout the study period.

Results: We show that oral consumption of D/L-3-OHB stimulates cholecystokinin release (P = 0.02), elevates insulin (P = 0.03) and C-peptide (P < 0.001) concentrations, and slows gastric emptying (P = 0.01) compared with matched intravenous D/L-3-OHB administration. Measures of appetite and plasma concentrations of glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) were unaffected by interventions.

Conclusion: Our findings show that D/L-3-OHB exert incretin effects and indicate luminal sensing in the gut endothelium. This adds to our understanding of ketones as signaling metabolites and displays the important difference between physiological ketosis and oral ketone supplements.
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http://dx.doi.org/10.1210/clinem/dgaa483DOI Listing
October 2020

Secretion of parathyroid hormone may be coupled to insulin secretion in humans.

Authors:
Marie Reeberg Sass Nicolai Jacob Wewer Albrechtsen Jens Pedersen Kristine Juul Hare Nis Borbye-Lorenzen Katalin Kiss Tina Vilsbøll Filip Krag Knop Steen Seier Poulsen Niklas Rye Jørgensen Jens Juul Holst Cathrine Ørskov Bolette Hartmann

Endocr Connect 2020 Jul;9(7):747-754

Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.

Objective: Parathyroid hormone (PTH) is a key hormone in regulation of calcium homeostasis and its secretion is regulated by calcium. Secretion of PTH is attenuated during intake of nutrients, but the underlying mechanism(s) are unknown. We hypothesized that insulin acts as an acute regulator of PTH secretion.

Methods: Intact PTH was measured in plasma from patients with T1D and matched healthy individuals during 4-h oral glucose tolerance tests (OGTT) and isoglycemic i.v. glucose infusions on 2 separate days. In addition, expression of insulin receptors on surgical specimens of parathyroid glands was assessed by immunochemistry (IHC) and quantitative PCR (qPCR).

Results: The inhibition of PTH secretion was more pronounced in healthy individuals compared to patients with T1D during an OGTT (decrementalAUC0-240min: -5256 ± 3954 min × ng/L and -2408 ± 1435 min × ng/L, P = 0.030). Insulin levels correlated significantly and inversely with PTH levels, also after adjusting for levels of several gut hormones and BMI (P = 0.002). Expression of insulin receptors in human parathyroid glands was detected by both IHC and qPCR.

Conclusion: Our study suggests that insulin may act as an acute regulator of PTH secretion in humans.
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http://dx.doi.org/10.1530/EC-20-0092DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7424341PMC
July 2020

GIP as a Therapeutic Target in Diabetes and Obesity: Insight From Incretin Co-agonists.

Authors:
Jens Juul Holst Mette Marie Rosenkilde

J Clin Endocrinol Metab 2020 08;105(8)

Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark.

The 2 hormones responsible for the amplification of insulin secretion after oral as opposed to intravenous nutrient administration are the gut peptides, glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). However, whereas GLP-1 also inhibits appetite and food intake and improves glucose regulation in patients with type 2 diabetes (T2DM), GIP seems to be devoid of these activities, although the 2 hormones as well as their receptors are highly related. In fact, numerous studies have suggested that GIP may promote obesity. However, chimeric peptides, combining elements of both peptides and capable of activating both receptors, have recently been demonstrated to have remarkable weight-losing and glucose-lowering efficacy in obese individuals with T2DM. At the same time, antagonists of the GIP receptor have been reported to reduce weight gain/cause weight loss in experimental animals including nonhuman primates. This suggests that both agonists and antagonist of the GIP receptor should be useful, at least for weight-losing therapy. How is this possible? We here review recent experimental evidence that agonist-induced internalization of the two receptors differs markedly and that modifications of the ligand structures, as in co-agonists, profoundly influence these cellular processes and may explain that an antagonist may activate while an agonist may block receptor signaling.
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http://dx.doi.org/10.1210/clinem/dgaa327DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7308078PMC
August 2020

Effects of a highly controlled carbohydrate-reduced high-protein diet on markers of oxidatively generated nucleic acid modifications and inflammation in weight stable participants with type 2 diabetes; a randomized controlled trial.

Authors:
Mads Juul Skytte Amirsalar Samkani Arne Astrup Thomas Meinert Larsen Jan Frystyk Henrik Enghusen Poulsen Trine Henriksen Jens Juul Holst Ove Andersen Sten Madsbad Steen Bendix Haugaard Thure Krarup Emil List Larsen

Scand J Clin Lab Invest 2020 Sep 6;80(5):401-407. Epub 2020 May 6.

Department of Clinical Pharmacology, Copenhagen University Hospital Bispebjerg, Copenhagen, Denmark.

Carbohydrate-restricted diets are increasingly recognized as options for dietary management of type 2 diabetes mellitus (T2DM). We investigated the effects of a carbohydrate-reduced high-protein (CRHP) and a conventional diabetes (CD) diet on oxidative stress and inflammation in weight stable individuals with T2DM. We hypothesized that the CRHP diet would improve markers of oxidatively generated RNA and DNA modifications as well as inflammatory parameters. Thirty participants with T2DM were randomized to 6 weeks of CRHP or CD dietary treatment (30/50 energy percentage (E%) carbohydrate, 30/17E% protein, 40/33E% fat), followed by a cross-over to the opposite diet for a subsequent 6-week period. All meals were provided during the study and body weight was controlled. Diurnal urine samples were collected after 4 weeks on each diet and oxidatively generated RNA and DNA modifications were measured as 8-oxo-7,8-dihydroguanosine (8-oxoGuo) and 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG), respectively. Fasting concentrations of soluble urokinase plasminogen activator receptor, high-sensitivity C-reactive protein, tumor necrosis factor alpha and interleukin-6 were measured before and after 6 weeks of interventions. Compared with the CD diet, the CRHP diet increased 24-hour urinary excretion of 8-oxoGuo by 9.3% (38.6 ± 12.6 vs. 35.3 ± 11.0 nmol/24 h,  .03), whereas 8-oxodG did not differ between diets (24.0 ± 9.5 vs. 24.8 ± 11.1 nmol/24 h,  = .17). Changes in plasma inflammatory parameters did not differ between CRHP and CD diets, all  .2. The clinical implications of increased RNA oxidation following a CRHP diet as well as long-term effects of carbohydrate-restriction on markers of oxidatively generated nucleic acid modifications should be a field of future study.
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http://dx.doi.org/10.1080/00365513.2020.1759137DOI Listing
September 2020

Predictors of weight loss after bariatric surgery-a cross-disciplinary approach combining physiological, social, and psychological measures.

Authors:
Mette S Nielsen Bodil Just Christensen Julie Berg Schmidt Louise Tækker Lotte Holm Susanne Lunn Christian Ritz Nicolai J Wewer Albrechtsen Jens Juul Holst Theresia M Schnurr Torben Hansen Carel W le Roux Thomas Bøker Lund Andrea Karen Floyd Anders Sjödin

Int J Obes (Lond) 2020 11 23;44(11):2291-2302. Epub 2020 Apr 23.

Department of Nutrition, Exercise and Sports, Faculty of Science, University of Copenhagen, Copenhagen, Denmark.

Background: Bariatric surgery leads to a substantial weight loss (WL), however, a subset of patients undergoing surgery fails to achieve adequate WL. The reason for the individual variation in WL remains unexplained. Using an exploratory cross-disciplinary approach, we aimed to identify preoperative and early postoperative factors explaining the variation in WL after bariatric surgery.

Methods: Sixty-one subjects were recruited. Eighteen subjects did not receive surgery and three subjects dropped out, leaving a total sample of 40 subjects. Physiological, social, and psychological data were collected before and 6 months after surgery. All variables were analyzed in combination using a least absolute shrinkage and selection operator (LASSO) regression to explain the variation in WL 18 months after Roux-en-Y gastric bypass (n = 30) and sleeve gastrectomy (n = 10).

Results: Mean WL was 31% (range: 10-52%). The following preoperative factors predicted 59% of the variation in WL: type of surgery (14%), diabetes status (12%), economic resources (9%), sex (7%), binge eating disorder (7%), degree of depression (5%), household type (3%), and physical activity (1%). Including information on early responses after surgery increased the ability to predict WL to 78% and was explained by early WL (47%), changes in energy density of food consumed from a buffet meal (9%), changes in glicentin (5%), degree of depression (5%), sex (5%), type of surgery (2%), economic resources (2%), and changes in drive for thinness (1%).

Conclusions: Using a cross-disciplinary approach, a substantial part of the individual variation in WL was explained by a combination of basic patient characteristics, psychological profile, and social conditions as well as physiological, psychological and behavioral responses to surgery. These results suggest that patient characteristics collected in a cross-disciplinary approach may help determine predictors for less successful WL after bariatric surgery. If verified in larger cohorts this may form the basis for individualized postoperative support to optimize WL outcome.
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http://dx.doi.org/10.1038/s41366-020-0576-9DOI Listing
November 2020

Pharmacological activation of TGR5 promotes intestinal growth via a GLP-2-dependent pathway in mice.

Authors:
Jenna Elizabeth Hunt Anna Billeschou Johanne Agerlin Windeløv Bolette Hartmann Christoph Ullmer Jens Juul Holst Hannelouise Kissow

Am J Physiol Gastrointest Liver Physiol 2020 05 20;318(5):G980-G987. Epub 2020 Apr 20.

Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.

Glucagon-like peptide (GLP)-1 and -2-secreting L cells have been shown to express the bile acid receptor Takeda G protein-receptor-5 (TGR5) and increase secretion upon receptor activation. Previous studies have explored GLP-1 secretion following acute TGR5 activation, but chronic activation and GLP-2 responses have not been characterized. In this study, we aimed to investigate the consequences of pharmacological TGR5 receptor activation on L cell hormone production in vivo using the specific TGR5 agonist RO5527239 and the GLP-2 receptor knockout mouse. Here, we show that ) TGR5 receptor activation led to increased GLP-1 and GLP-2 content in the colon, which ) was associated with an increased small intestinal weight that ) was GLP-2 dependent. Additionally, we report that TGR5-mediated gallbladder filling occurred independently of GLP-2 signaling. In conclusion, we demonstrate that pharmacological TGR5 receptor activation stimulates L cells, triggering GLP-2-dependent intestinal adaption in mice. Using the specific Takeda G protein-receptor-5 (TGR5) agonist RO5527239 and GLP-2 receptor knockout mice, we show that activation of TGR5 led to the increase in colonic GLP-1 and GLP-2 concomitant with a GLP-2 dependent growth response in the proximal portion of the small intestine.
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http://dx.doi.org/10.1152/ajpgi.00062.2020DOI Listing
May 2020

Changes in the Homeostatic Appetite System After Weight Loss Reflect a Normalization Toward a Lower Body Weight.

Authors:
Julia Nicole DeBenedictis Siren Nymo Karoline Haagensli Ollestad Guro Akersveen Boyesen Jens Frederik Rehfeld Jens Juul Holst Helen Truby Bard Kulseng Catia Martins

J Clin Endocrinol Metab 2020 07;105(7)

Obesity Research Group, Department of Clinical and Molecular Medicine, Faculty of Medicine, Norwegian University of Science and Technology (NTNU), Trondheim, Norway.

Objective: To compare appetite markers in reduced-obese individuals with a nonobese control group.

Methods: A total of 34 adults with obesity who lost 17% body weight at week 13 and maintained this weight loss (WL) at 1 year were compared with 33 nonobese controls matched for body composition. Basal and postprandial subjective appetite ratings and appetite-related hormone concentrations (ghrelin, total peptide YY, peptide YY3-36, total and active glucagon-like peptide 1, and cholecystokinin) were measured in all participants and repeated at week 13 and 1 year in the weight-reduced group.

Results: WL led to a reduction in prospective food consumption and an increase in feelings of hunger, fullness, and ghrelin secretion (basal and postprandial), but these new ratings were no different from those seen in controls. Postprandial concentrations of active glucagon-like peptide 1, total peptide YY, and cholecystokinin were lower in individuals with obesity at all time points compared with controls.

Conclusion: The increased drive to eat (both subjective feelings of hunger and ghrelin concentrations) seen in reduced-obese individuals, both after acute and sustained WL, reflects a normalization toward a lower body weight. Overall, WL does not have a sustained negative impact on satiety peptide secretion, despite a blunted secretion in individuals with obesity compared with nonobese controls.
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http://dx.doi.org/10.1210/clinem/dgaa202DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7250208PMC
July 2020

Proglucagon peptide secretion profiles in type 2 diabetes before and after bariatric surgery: 1-year prospective study.

Authors:
Kleopatra Alexiadou Joyceline Cuenco James Howard Nicolai Jacob Wewer Albrechtsen Ibiyemi Ilesanmi Anna Kamocka George Tharakan Preeshila Behary Paul R Bech Ahmed R Ahmed Sanjay Purkayastha Robert Wheller Matthieu Fleuret Jens Juul Holst Stephen R Bloom Bernard Khoo Tricia M-M Tan

BMJ Open Diabetes Res Care 2020 03;8(1)

Department of Metabolism, Digestion and Reproduction, Imperial College London, London, UK

Introduction: Hyperglucagonemia is a key pathophysiological driver of type 2 diabetes. Although Roux-en-Y gastric bypass (RYGB) is a highly effective treatment for diabetes, it is presently unclear how surgery alters glucagon physiology. The aim of this study was to characterize the behavior of proglucagon-derived peptide (glucagon, glucagon-like peptide-1 (GLP-1), oxyntomodulin, glicentin) secretion after RYGB surgery.

Research Design And Methods: Prospective study of 19 patients with obesity and pre-diabetes/diabetes undergoing RYGB. We assessed the glucose, insulin, GLP-1, glucose-dependent insulinotropic peptide (GIP), oxyntomodulin, glicentin and glucagon responses to a mixed-meal test (MMT) before and 1, 3 and 12 months after surgery. Glucagon was measured using a Mercodia glucagon ELISA using the 'Alternative' improved specificity protocol, which was validated against a reference liquid chromatography combined with mass spectrometry method.

Results: After RYGB, there were early improvements in fasting glucose and glucose tolerance and the insulin response to MMT was accelerated and amplified, in parallel to significant increases in postprandial GLP-1, oxyntomodulin and glicentin secretion. There was a significant decrease in fasting glucagon levels at the later time points of 3 and 12 months after surgery. Glucagon was secreted in response to the MMT preoperatively and postoperatively in all patients and there was no significant change in this postprandial secretion. There was no significant change in GIP secretion.

Conclusions: There is a clear difference in the dynamics of secretion of proglucagon peptides after RYGB. The reduction in fasting glucagon secretion may be one of the mechanisms driving later improvements in glycemia after RYGB.

Trial Registration Number: NCT01945840.
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http://dx.doi.org/10.1136/bmjdrc-2019-001076DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7103850PMC
March 2020

Gain-of-function mutation in the voltage-gated potassium channel gene KCNQ1 and glucose-stimulated hypoinsulinemia - case report.

Authors:
Jinyi Zhang Christian R Juhl Louise Hylten-Cavallius Morten Salling-Olsen Allan Linneberg Jens Juul Holst Torben Hansen Jørgen K Kanters Signe S Torekov

BMC Endocr Disord 2020 Mar 13;20(1):38. Epub 2020 Mar 13.

Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.

Background: The voltage-gated potassium channel Kv7.1 encoded by KCNQ1 is located in both cardiac myocytes and insulin producing beta cells. Loss-of-function mutations in KCNQ1 causes long QT syndrome along with glucose-stimulated hyperinsulinemia, increased C-peptide and postprandial hypoglycemia. The KCNE1 protein modulates Kv7.1 in cardiac myocytes, but is not expressed in beta cells. Gain-of-function mutations in KCNQ1 and KCNE1 shorten the action potential duration in cardiac myocytes, but their effect on beta cells and insulin secretion is unknown.

Case Presentation: Two patients with atrial fibrillation due to gain-of-function mutations in KCNQ1 (R670K) and KCNE1 (G60D) were BMI-, age-, and sex-matched to six control participants and underwent a 6-h oral glucose tolerance test (OGTT). During the OGTT, the KCNQ1 gain-of-function mutation carrier had 86% lower C-peptide response after glucose stimulation compared with matched control participants (iAUC = 34 pmol/l*min VS iAUC = 246 ± 71 pmol/l*min). The KCNE1 gain-of-function mutation carrier had normal C-peptide levels.

Conclusions: This case story presents a patient with a gain-of-function mutation KCNQ1 R670K with low glucose-stimulated C-peptide secretion, additionally suggesting involvement of the voltage-gated potassium channel KCNQ1 in glucose-stimulated insulin regulation.
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http://dx.doi.org/10.1186/s12902-020-0513-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7069191PMC
March 2020

Role of fasting duration and weekday in incretin and glucose regulation.

Authors:
Kim Kb Clemmensen Jonas S Quist Dorte Vistisen Daniel R Witte Anna Jonsson Oluf Pedersen Torben Hansen Jens Juul Holst Torsten Lauritzen Marit Eika Jørgensen Signe Torekov Kristine Færch

Endocr Connect 2020 Mar 1. Epub 2020 Mar 1.

K Færch, Copenhagen, Denmark.

Fasting duration has been associated with lower fasting blood glucose levels, but higher 2-hour post-load levels, and research has indicated an adverse effect of 'weekend behavior' on human metabolism. We investigated associations of fasting duration and weekday of examination with glucose, insulin, glucagon and incretin responses to an oral glucose tolerance test (OGTT). This cross-sectional study is based on data from the ADDITION-PRO study, where 2082 individuals attended a health examination including an OGTT. Linear regression analysis was applied to study the associations of overnight fasting duration and day of the week with glucose, insulin, glucagon, glucose-dependent insulinotropic polypeptide (GIP), and glucagon-like peptide 1 (GLP-1) responses to an OGTT. We found that a one hour longer fasting duration was associated with 1.7% (95%CI:0.8,2.5) higher 2-hour glucose levels, as well as a 3.0% (95%CI:1.3,4.7) higher GIP and 2.3% (95%CI:0.3,4.4) higher GLP-1 response. Fasting insulin levels were 20.6% (95%CI:11.2,30.7) higher on Mondays compared to the other weekdays, with similar fasting glucose levels (1.7%, 95%CI:0.0,3.4). In this study longer overnight fasting duration was associated with a worsening of glucose tolerance and increased incretin response to oral glucose. We found higher fasting insulin levels on Mondays compared to the other days of the week, potentially indicating worsened glucose regulation after the weekend.
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http://dx.doi.org/10.1530/EC-20-0009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7159259PMC
March 2020