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BACKGROUND: Comorbidity with type 2 diabetes (T2D) results in worsening of cancer-specific and overall prognosis in colorectal cancer (CRC) patients. The treatment of CRC per se may be diabetogenic. We assessed the impact of different types of surgical cancer resections and oncological treatment on risk of T2D development in CRC patients.METHODS: We developed a population-based cohort study including all Danish CRC patients, who had undergone CRC surgery between 2001 and 2018. Using nationwide register data, we identified and followed patients from date of surgery and until new onset of T2D, death, or end of follow-up.RESULTS: In total, 46,373 CRC patients were included and divided into six groups according to type of surgical resection: 10,566 Right-No-Chemo (23%), 4645 Right-Chemo (10%), 10,151 Left-No-Chemo (22%), 5257 Left-Chemo (11%), 9618 Rectal-No-Chemo (21%), and 6136 Rectal-Chemo (13%). During 245,466 person-years of follow-up, 2556 patients developed T2D. The incidence rate (IR) of T2D was highest in the Left-Chemo group 11.3 (95% CI: 10.4-12.2) per 1000 person-years and lowest in the Rectal-No-Chemo group 9.6 (95% CI: 8.8-10.4). Between-group unadjusted hazard ratio (HR) of developing T2D was similar and non-significant. In the adjusted analysis, Rectal-No-Chemo was associated with lower T2D risk (HR 0.86 [95% CI 0.75-0.98]) compared to Right-No-Chemo.For all six groups, an increased level of body mass index (BMI) resulted in a nearly twofold increased risk of developing T2D.CONCLUSIONS: This study suggests that postoperative T2D screening should be prioritised in CRC survivors with overweight/obesity regardless of type of CRC treatment applied.FUNDING: The Novo Nordisk Foundation (NNF17SA0031406); TrygFonden (101390; 20045; 125132).

It has been known since 2005 that the secretion of several gut hormones changes radically after gastric bypass operations and, although more moderately, after sleeve gastrectomy but not after gastric banding. It has therefore been speculated that increased secretion of particularly GLP-1 and Peptide YY (PYY), which both inhibit appetite and food intake, may be involved in the weight loss effects of surgery and for improvements in glucose tolerance. Experiments involving inhibition of hormone secretion with somatostatin, blockade of their actions with antagonists, or blockade of hormone formation/activation support this notion. However, differences between results of bypass and sleeve operations indicate that distinct mechanisms may also be involved. Although the reductions in ghrelin secretion after sleeve gastrectomy would seem to provide an obvious explanation, experiments with restoration of ghrelin levels pointed towards effects on insulin secretion and glucose tolerance rather than on food intake. It seems clear that changes in GLP-1 secretion are important for insulin secretion after bypass and appear to be responsible for postbariatric hypoglycemia in glucose-tolerant individuals; however, with time the improvements in insulin sensitivity, which in turn are secondary to the weight loss, may be more important. Changes in bile acid metabolism do not seem to be of particular importance in humans.

An intravenous glucose-infusion of 0.3 g glucose per Kg body weight was administered over 1 min in nine healthy males with simultaneous blood sampling from the hepatic vein, femoral artery and a peripheral vein. Insulin secretion rates (ISR) were determined by the Eaton method and the ISEC method using C-peptide concentrations from arterial and peripheral venous blood. First phase (0–10 min), second phase (10–60 min), and total insulin secretion (0–60 min) were calculated as the incremental areas (iAUC) above baseline. The primary endpoint was first phase insulin response. The first phase insulin response in artery and venous blood did not differ with the Eaton method (p = 0.25), but was significantly greater with the ISEC method in arterial compared with venous blood (p < 0.05). The first phase insulin responses did not differ between methods in artery (p = 0.73) or venous blood (p = 0.73). The first phase responses of insulin and C-peptide were significant higher in the hepatic vein compared with those in the artery (p < 0.05) and peripheral vein (p < 0.05) but did not differ significantly between the artery compared with the peripheral vein for insulin (p = 0.09) or C-peptide (p = 0.26). Prehepatic insulin secretion rates did not differ between the Eaton and ISEC methods, but with the ISEC method the first phase insulin response was significantly greater in arterial compared with venous blood. The first phase insulin response differs when calculated from plasma insulin or C-peptide and depends on sample sites., An intravenous glucose-infusion of 0.3 g glucose per Kg body weight was administered over 1 min in nine healthy males with simultaneous blood sampling from the hepatic vein, femoral artery and a peripheral vein. Insulin secretion rates (ISR) were determined by the Eaton method and the ISEC method using C-peptide concentrations from arterial and peripheral venous blood. First phase (0–10 min), second phase (10–60 min), and total insulin secretion (0–60 min) were calculated as the incremental areas (iAUC) above baseline. The primary endpoint was first phase insulin response. The first phase insulin response in artery and venous blood did not differ with the Eaton method (p = 0.25), but was significantly greater with the ISEC method in arterial compared with venous blood (p < 0.05). The first phase insulin responses did not differ between methods in artery (p = 0.73) or venous blood (p = 0.73). The first phase responses of insulin and C-peptide were significant higher in the hepatic vein compared with those in the artery (p < 0.05) and peripheral vein (p < 0.05) but did not differ significantly between the artery compared with the peripheral vein for insulin (p = 0.09) or C-peptide (p = 0.26). Prehepatic insulin secretion rates did not differ between the Eaton and ISEC methods, but with the ISEC method the first phase insulin response was significantly greater in arterial compared with venous blood. The first phase insulin response differs when calculated from plasma insulin or C-peptide and depends on sample sites.

Follistatin is secreted from the liver and may regulate muscle growth and insulin sensitivity. Protein intake stimulates follistatin secretion, which may be mediated by increased glucagon in the context of low insulin concentrations. We investigated circulating follistatin after mixed-meals in two cohorts of patients who were part of previously published studies and had undergone bariatric surgery with either simultaneous assessment of amino acid absorption or administration of the GLP-1 receptor antagonist exendin-(9-39), which increased glucagon concentrations and impaired insulin secretion. Study 1 comprised obese matched subjects with previous Roux-en-Y gastric bypass (RYGB) or sleeve gastrectomy (SG) surgery and unoperated controls who underwent 6-hour mixed-meal tests with intravenous and oral tracers including intrinsically labelled caseinate in the meal. Study 2 comprised obese subjects with previous RYGB who underwent two 5-hour mixed-meal tests with concomitant exendin-(9-39) or saline infusion. In study 1, the secretion of follistatin as well as the amino acid absorption was accelerated after RYGB compared with SG and controls, but the glucagon-to-C-peptide ratios did not differ between the groups. In study 2, exendin-(9-39) administration increased postprandial glucagon concentrations and lowered insulin secretion, whereas the concentration of follistatin was unchanged. In conclusion, postprandial follistatin secretion is accelerated in patients after RYGB which might be explained by an accelerated protein absorption rate rather than the glucagon-to-insulin ratio.

Background and aims: The metabolic consequences after Roux-en-Y gastric bypass (RYGB) and sleeve gastrectomy (SG) are often studied using a liquid mixed meal. However, liquid meals may not be representative of the patients' everyday diet. We therefore examined postprandial glucose and gut hormone responses using mixed meals differing only with respect to meal texture.Methods: Twelve RYGB-operated, 12 SG-operated, and 12 unoperated individuals (controls) were enrolled in the study. Participants were matched on age, sex, and body mass index. In randomized order, each participant underwent a liquid and a solid 4-h mixed meal test on separate days. The meals were isocaloric (309 kcal), and with identical macronutrient composition (47 E% carbohydrate, 18 E% protein, 32 E% fat, and 3 E% dietary fibers). The liquid meal was blended to create a smooth liquid texture while the other meal retained its solid components.Results: Postprandial glucose concentrations (peak and incremental area under curve, iAUC) did not differ between the two meal textures in any group. In the control group, peak C-peptide was higher after the liquid meal compared with the solid meal (p = 0.04), whereas iAUCs of C-peptide were similar between the two meals in all groups. Peak of glucagon-like peptide-1 (GLP-1) was higher after the liquid meal compared with the solid meal in RYGB- and SG-operated individuals (RYGB p = 0.02; SG p < 0.01), but iAUC of GLP-1 did not differ between meal textures within any group. Peak of glucose-dependent insulin tropic polypeptide (GIP) was higher after the liquid meal in the SG and control groups (SG p = 0.02; controls p < 0.01), but iAUCs of GIP were equal between meals. There were no differences in total AUC of ghrelin between the liquid and solid meals within any of the groups.Conclusion: A liquid and a solid meal with identical macronutrient composition result in similar postprandial glucose responses, both in operated and unoperated

The intestinal hormones glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-2 (GLP-2) are key regulators of postprandial bone turnover in humans. We hypothesized that GIP and GLP-2 co-administration would provide stronger effect on bone turnover than administration of the hormones separately, and tested this using subcutaneous injections of GIP and GLP-2 alone or in combination in humans. Guided by these findings, we designed series of GIPR-GLP-2R co-agonists as template for new osteoporosis treatment. The clinical experiment was a randomized cross-over design including 10 healthy men administered subcutaneous injections of GIP and GLP-2 alone or in combination. The GIPR-GLP-2R co-agonists were characterized in terms of binding and activation profiles on human and rodent GIP and GLP-2 receptors, and their pharmacokinetic (PK) profiles were improved by dipeptidyl peptidase-4 protection and site-directed lipidation. Co-administration of GIP and GLP-2 in humans resulted in an additive reduction in bone resorption superior to each hormone individually. The GIPR-GLP-2R co-agonists, designed by combining regions of importance for cognate receptor activation, obtained similar efficacies as the two native hormones and nanomolar potencies on both human receptors. The PK-improved co-agonists maintained receptor activity along with their prolonged half-lives. Finally, we found that the GIPR-GLP-2R co-agonists optimized toward the human receptors for bone remodeling are not feasible for use in rodent models. The successful development of potent and efficacious GIPR-GLP-2R co-agonists, combined with the improved effect on bone metabolism in humans by co-administration, support these co-agonists as a future osteoporosis treatment.

OBJECTIVE: Neurotensin (NT) is released from enteroendocrine cells and lowers food intake in rodents. We evaluated postprandial NT secretion in humans after surgeries associated with accelerated small intestinal nutrient delivery, and after Roux-en-Y gastric bypass (RYGB) when glucagon-like peptide-1 (GLP-1) signalling and dipeptidyl peptidase 4 (DPP-4) were inhibited, and during pharmacological treatments influencing entero-pancreatic functions.METHODS: We measured NT concentrations in plasma from meal studies: (I) after truncal vagotomy with pyloroplasty (TVP), cardia resection +TVP (CTVP), and matched controls (n = 10); (II) after RYGB, sleeve gastrectomy (SG), and in matched controls (n = 12); (III) after RYGB (n = 11) with antagonism of GLP-1 signalling using exendin(9-39) and DPP-4 inhibition using sitagliptin; (IV) after RYGB (n = 11) during a run-in period and subsequent treatment with, sitagliptin, liraglutide (GLP-1 receptor agonist), verapamil (calcium antagonist), acarbose (alpha glucosidase inhibitor), and pasireotide (somatostatin analogue), respectively.RESULTS: (I) NT secretion was similar after TVP/CTVP (p = 0.9), but increased vs. controls (p < 0.0001). (II) NT secretion was increased after RYGB vs. SG and controls (p < 0.0001). NT responses were similar in SG and controls (p = 0.3), but early postprandial NT concentrations were higher after SG (p < 0.05). (III) Exendin (9-39) and sitagliptin did not change NT responses vs placebo (p > 0.2), but responses were lower during sitagliptin vs. exendin(9-39) (p = 0.03). (IV) Pasireotide suppressed NT secretion (p = 0.004). Sitagliptin tended to lower NT secretion (p = 0.08). Liraglutide, verapamil, and acarbose had no effect (p > 0.9).CONCLUSION: Neurotensin secretion is increased after surgeries associated with accelerated gastric emptying and lowered by pasireotide.

Growth differentiating factor 15 (GDF15) is expressed in the intestine and is one of the most recently identified satiety peptides. The mechanisms controlling its secretion are unclear. The present study investigated whether plasma GDF15 concentrations are meal-related and if potential responses depend on macronutrient type or are affected by previous bariatric surgery. The study included: (1) volunteers ingesting rapidly vs. slowly digested carbohydrates (sucrose vs. isomaltose) (n=10), (2) volunteers who had undergone Roux-en-Y Gastric bypass (RYGB) or sleeve gastrectomy (SG) surgery and unoperated matched controls ingesting a liquid mixed meal (n=9-10 in each group), and (3) individuals with previous RYGB compared with unoperated controls ingesting isocaloric glucose, fat or protein (n=6 in each group). Plasma was collected after an overnight fast and up to 6 h after ingestion (≥12 timepoints). In cohort 1, fasting GDF15 concentrations were ~480 pg/ml. Concentrations after sucrose or isomaltose intake did not differ from baseline (P=0.26-P>0.99) and total area-under-the-curves (tAUCs were similar between groups (P=0.77). In cohort 2, fasting GDF15 concentrations were (pg/ml): RYGB=540±41.4, SG=477±36.4, and controls=590±41.8, with no between-group differences (P=0.73). Concentrations did not increase at any postprandial time point (over all time factor: P=0.10) and tAUCs were similar between groups (P=0.73). In cohort 3, fasting plasma GDF15 was similar among the groups (P>0.99) and neither glucose, fat or protein intake consistently increased the concentrations. In conclusion, we find that plasma GDF15 was not stimulated by meal intake, and that fasting concentrations did not differ between RYGB, SG and BMI-matched controls when investigated during the weight stable phase after RYGB and SG.

BackgroundAltered bile acid (BA) turnover has been suggested to be involved in the improved glucose regulation after Roux-en-Y gastric bypass (RYGB), possibly via stimulation of GLP-1 secretion. We investigated the role of exogenous as well as endogenous BAs for GLP-1 secretion after RYGB by administering chenodeoxycholic acid (CDCA) and the BA sequestrant colesevelam (COL) both in the presence and the absence of a meal stimulus.MethodsTwo single-blinded randomized cross-over studies were performed. In study 1, eight RYGB operated participants ingested 200 ml water with 1) CDCA 1.25 g or 2) CDCA 1.25 g + colesevelam 3.75 g on separate days. In study 2, twelve RYGB participants ingested on separate days a mixed meal with addition of 1) CDCA 1.25 g, 2) COL 3.75 g or 3) COL 3.75 g x 2, or 4) no additions.ResultsIn study 1, oral intake of CDCA increased circulating BAs, GLP-1, C-peptide, glucagon, and neurotensin. Addition of colesevelam reduced all responses. In study 2, addition of CDCA enhanced meal-induced increases in plasma GLP-1, glucagon and FGF-19 and lowered plasma glucose and C-peptide concentrations, while adding colesevelam lowered circulating BAs but did not affect meal-induced changes in plasma glucose or measured gastrointestinal hormones.ConclusionIn RYGB-operated persons, exogenous CDCA enhanced meal-stimulated GLP-1 and glucagon secretion but not insulin secretion, while the BA sequestrant colesevelam decreased CDCA-stimulated GLP-1 secretion but did not affect meal-stimulated GLP-1, C-peptide or glucagon secretion, or glucose tolerance. These findings suggest a limited role for endogenous bile acids in the acute regulation of postprandial gut hormone secretion or glucose metabolism after RYGB.

Weight Loss Maintenance with Exercise and LiraglutideIn this trial, adults with obesity without diabetes were randomly assigned, after an 8-week low-calorie diet, to 1 year of placebo, an exercise program, liraglutide, or exercise plus liraglutide. Combined treatment with exercise and liraglutide improved healthy weight loss maintenance more than either treatment alone.BackgroundWeight regain after weight loss is a major problem in the treatment of persons with obesity.MethodsIn a randomized, head-to-head, placebo-controlled trial, we enrolled adults with obesity (body-mass index [the weight in kilograms divided by the square of the height in meters], 32 to 43) who did not have diabetes. After an 8-week low-calorie diet, participants were randomly assigned for 1 year to one of four strategies: a moderate-to-vigorous-intensity exercise program plus placebo (exercise group); treatment with liraglutide (3.0 mg per day) plus usual activity (liraglutide group); exercise program plus liraglutide therapy (combination group); or placebo plus usual activity (placebo group). End points with prespecified hypotheses were the change in body weight (primary end point) and the change in body-fat percentage (secondary end point) from randomization to the end of the treatment period in the intention-to-treat population. Prespecified metabolic health-related end points and safety were also assessed.ResultsAfter the 8-week low-calorie diet, 195 participants had a mean decrease in body weight of 13.1 kg. At 1 year, all the active-treatment strategies led to greater weight loss than placebo: difference in the exercise group, -4.1 kg (95% confidence interval [CI], -7.8 to -0.4; P=0.03); in the liraglutide group, -6.8 kg (95% CI, -10.4 to -3.1; PConclusionsA strategy combining exercise and liraglutide therapy improved healthy weight loss maintenance more than either treatment alone. (Funde

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.

Follistatin is secreted from the liver and is involved in the regulation of muscle mass and insulin sensitivity via inhibition of activin A in humans. The secretion of follistatin seems to be stimulated by glucagon and inhibited by insulin, but only limited knowledge on the postprandial regulation of follistatin exists. Moreover, results on postoperative changes after Roux-en-Y gastric bypass (RYGB) are conflicting with reports of increased, unaltered and lowered fasting concentrations of follistatin. In this study, we investigated postprandial follistatin and activin A concentrations after intake of isocaloric amounts of protein, fat or glucose in obese subjects with and without previous RYGB to explore the regulation of follistatin by the individual macronutrients. Protein intake enhanced follistatin concentrations similarly in the two groups, while glucose and fat ingestion did not change postprandial follistatin concentrations. Concentrations of activin A were lower after protein intake compared with glucose intake in RYGB. Glucagon concentrations were also particularly enhanced by protein intake and tended to correlate with follistatin in RYGB. In conclusion, we demonstrated that protein intake, but not glucose or fat, is a strong stimulus for follistatin secretion in obese subjects and that this regulation is maintained after RYGB surgery.