The impact of surgery and oncological treatment on risk of type 2 diabetes onset in patients with colorectal cancer: nationwide cohort study in Denmark.

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).

Change in abdominal obesity after colon cancer surgery - effects of left-sided and right-sided colonic resection.

BACKGROUND: Excess abdominal visceral adipose tissue (VAT) is associated with metabolic diseases and poor survival in colon cancer (CC). We assessed the impact of different types of CC surgery on changes in abdominal fat depots. MATERIAL AND METHODS: Computed tomography (CT)-scans performed preoperative and 3 years after CC surgery were analyzed at L3-level for VAT, subcutaneous adipose tissue (SAT) and total adipose tissue (TAT) areas. We assessed changes in VAT, SAT, TAT and VAT/SAT ratio after 3 years and compared the changes between patients who had undergone left-sided and right-sided colonic resection in the total population and in men and women separately. RESULTS: A total of 134 patients with stage I-III CC undergoing cancer surgery were included. Patients who had undergone left-sided colonic resection had after 3 years follow-up a 5% (95% CI: 2-9%, p < 0.01) increase in abdominal VAT, a 4% (95% CI: 2-6%, p < 0.001) increase in SAT and a 5% increase (95% CI: 2-7%, p < 0.01) in TAT. Patients who had undergone right-sided colonic resection had no change in VAT, but a 6% (95% CI: 4-9%, p < 0.001) increase in SAT and a 4% (95% CI: 1-7%, p < 0.01) increase in TAT after 3 years. Stratified by sex, only males undergoing left-sided colonic resection had a significant VAT increase of 6% (95% CI: 2-10%, p < 0.01) after 3 years. CONCLUSION: After 3 years follow-up survivors of CC accumulated abdominal adipose tissue. Notably, those who underwent left-sided colonic resection had increased VAT and SAT, whereas those who underwent right-sided colonic resection demonstrated solely increased SAT.

GIP and GLP-2 together improve bone turnover in humans supporting GIPR-GLP-2R co-agonists as future osteoporosis treatment.

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.

Plasma GDF15 levels are similar between subjects after bariatric surgery and matched controls and are unaffected by meals.

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 time points). In cohort 1, fasting GDF15 concentrations were ∼480 pg/mL. Concentrations after sucrose or isomaltose intake did not differ from baseline (P = 0.26 to P > 0.99) and total area under the curves (tAUCs were similar between groups (P = 0.77). In cohort 2, fasting GDF15 concentrations were as follows (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, nor 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 body mass index (BMI)-matched controls when investigated during the weight stable phase after RYGB and SG.NEW & NOTEWORTHY Our combined data show that GDF15 does not increase in response to a liquid meal. Moreover, we show for the first time that ingestion of sucrose, isomaltose, glucose, fat, or protein also does not increase plasma GDF15 concentrations, questioning the role of GDF15 in regulation of food source preference. Finally, we find that neither fasting nor postprandial plasma GDF15 concentrations are increased in individuals with previous bariatric surgery compared with unoperated body mass index (BMI)-matched controls.

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

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).

[Multidisciplinary treatment of acute iron poisoning due to suicide attempt].

Intentional iron overdoses have an insidious and potentially fatal clinical course. This is a case report of a young woman, who deliberately ingested 300 tablets ferrous fumarate 330 mg, i.e. 400 mg elementary iron per kg body weight. Plain abdominal radiographs showed a conglomerate of iron tablets in the ventricle. Treatment consisted of endoscopic removal of tablets, deferoxamine antidote treatment, and whole bowel irrigation with macrogol laxatives. Toxicological risk evaluation of intentional iron overdoses is necessary to timely effectuate life-saving multidisciplinary empiric treatments.

Gut Hormones and Their Effect on Bone Metabolism. Potential Drug Therapies in Future Osteoporosis Treatment.

Bone homeostasis displays a circadian rhythm with increased resorption during the night time as compared to day time, a difference that seems-at least partly-to be caused by food intake during the day. Thus, ingestion of a meal results in a decrease in bone resorption, but people suffering from short bowel syndrome lack this response. Gut hormones, released in response to a meal, contribute to this link between the gut and bone metabolism. The responsible hormones appear to include glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1), known as incretin hormones due to their role in regulating glucose homeostasis by enhancing insulin release in response to food intake. They interact with their cognate receptors (GIPR and GLP-1R), which are both members of the class B G protein-coupled receptors (GPCRs), and already recognized as targets for treatment of metabolic diseases, such as type 2 diabetes mellitus (T2DM) and obesity. Glucagon-like peptide-2 (GLP-2), secreted concomitantly with GLP-1, acting via another class B receptor (GLP-2R), is also part of this gut-bone axis. Several studies, including human studies, have indicated that these three hormones inhibit bone resorption and, moreover, that GIP increases bone formation. Another hormone, peptide YY (PYY), is also secreted from the enteroendocrine L-cells (together with GLP-1 and GLP-2), and acts mainly via interaction with the class A GPCR NPY-R2. PYY is best known for its effect on appetite regulation, but recent studies have also shown an effect of PYY on bone metabolism. The aim of this review is to summarize the current knowledge of the actions of GIP, GLP-1, GLP-2, and PYY on bone metabolism, and to discuss future therapies targeting these receptors for the treatment of osteoporosis.

Augmented GLP-1 Secretion as Seen After Gastric Bypass May Be Obtained by Delaying Carbohydrate Digestion.

CONTEXT: Exaggerated postprandial glucagon-like peptide-1 (GLP-1) secretion seems important for weight loss and diabetes remission after Roux-en-Y gastric bypass (RYGB) and may result from carbohydrate absorption in the distal small intestine. OBJECTIVE: To investigate distal [GLP-1; peptide YY (PYY)] and proximal [glucose-dependent insulinotropic polypeptide (GIP)] gut hormone secretion in response to carbohydrates hydrolyzed at different rates. We hypothesized that slow digestion restricts proximal absorption, facilitating distal delivery of carbohydrates and thereby enhanced GLP-1 secretion in unoperated individuals, whereas this may not apply after RYGB. DESIGN: Single-blinded, randomized, crossover study. SETTING: Hvidovre Hospital, Hvidovre, Denmark. PARTICIPANTS: Ten RYGB-operated patients and 10 unoperated matched subjects. INTERVENTIONS: Four separate days with ingestion of different carbohydrate loads, either rapidly/proximally digested (glucose plus fructose; sucrose) or slowly/distally digested (isomaltulose; sucrose plus acarbose). MAIN OUTCOME MEASURES: GLP-1 secretion (area under the curve above baseline). Secondary outcomes included PYY and GIP. RESULTS: Isomaltulose enhanced secretion of GLP-1 nearly threefold (P = 0.02) and PYY ninefold (P = 0.08) compared with sucrose in unoperated subjects but had a modest effect after RYGB. Acarbose failed to increase sucrose induced GLP-1 secretion in unoperated subjects and diminished the responses by 50% after RYGB (P = 0.03). In both groups, GIP secretion was reduced by isomaltulose and even more so by sucrose plus acarbose when compared with sucrose intake. CONCLUSIONS: GLP-1 secretion depends on the rate of carbohydrate digestion, but in a different manner after RYGB. Enhanced GLP-1 secretion is central after RYGB, but it may also be obtained in unoperated individuals by delaying hydrolysis of carbohydrates, pushing their digestion and absorption distally in the small intestine.

Mechanisms of action of a carbohydrate-reduced, high-protein diet in reducing the risk of postprandial hypoglycemia after Roux-en-Y gastric bypass surgery.

BACKGROUND: Postprandial hypoglycemia is a risk after Roux-en-Y gastric bypass (RYGB). OBJECTIVES: We speculated that a carbohydrate-reduced, high-protein (CRHP) diet might reduce the risk of hypoglycemia and therefore compared the acute effects of a conventionally recommended (CR) diet and CRHP diet [55/30 energy percent (E%) carbohydrate and 15/30 E% protein, respectively] in RYGB patients. METHODS: Ten individuals (2 males, 8 females, mean ± SD age 47 ± 7 y; stable body mass index 31 ± 6 kg/m2; 6 ± 3 y post-RYGB) with recurrent postprandial hypoglycemia documented by plasma glucose (PG) ≤3.4 mmol/L were examined on 2 d with isoenergetic CRHP or CR diets comprising a breakfast and subsequent lunch meal. RESULTS: Peak PG was significantly reduced on the CRHP diet after breakfast and lunch by 11% and 31% compared with the CR diet. Nadir PG increased significantly on CRHP (by 13% and 9%). Insulin secretion was reduced, and glucagon secretion increased on the CRHP diet after both meals. Glucagon-like peptide 1 and glucose-dependent insulinotropic polypeptide secretion were lower after lunch but unaltered after breakfast on CRHP; ß-cell function and insulin clearance were unchanged. CONCLUSIONS: The CRHP diet lowered glucose excursions and reduced insulin secretion and incretin hormone responses, but enhanced glucagon responses compared with the CR diet. Taken together, the results may explain the decreased glucose variability and lower risk of postprandial hypoglycemia. This study was registered at clinicaltrials.gov as NCT02665715.

Mechanisms in bariatric surgery: Gut hormones, diabetes resolution, and weight loss.

Gastric bypass surgery leads to profound changes in the secretion of gut hormones with effects on metabolism, appetite, and food intake. Here, we discuss their contributions to the improvement in glucose tolerance and the weight loss that results from the operations. We find that the improved glucose tolerance is due the following events: a negative energy balance and resulting weight loss, which improve first hepatic and later peripheral insulin sensitivity, in combination with increased postprandial insulin secretion elicited particularly by exaggerated glucagon-like peptide-1 responses. The weight loss is due to loss of appetite resulting in reduced energy intake, and we find it probable that this process is driven by exaggerated secretion of appetite-regulating gut hormones including, but probably not limited to, glucagon-like peptide-1 and peptide-YY. The increased secretion is due to an accelerated exposure to and absorption of nutrients in the small intestine. This places the weight loss and the gut hormones in key positions with respect to the metabolic improvements after bypass surgery.

Emerging drugs for the treatment of obesity.

INTRODUCTION: The increasing prevalence of obesity represents a huge threat to public health and the current pharmacological treatment options are limited. Bariatric surgery is by far the most effective treatment for severe obesity, highlighting the urgent need for new and improved drug therapies. Areas covered: Based on the physiological regulation of energy homeostasis, pharmacological strategies to treat obesity are evaluated with focus on drugs in phase 2 and 3 clinical development. The potential impact of these drugs on current treatment standards and the barriers for development are discussed and set in a historical perspective of previous antiobesity medications. Expert opinion: The radical effects of bariatric surgery have extended our understanding of the mechanisms controlling appetite and boosted the search for new drug targets in obesity treatment. Accordingly, several compounds targeting the central nervous system and/or periphery are in pipeline for obesity. These drugs should be evaluated over a wide array of end-points; in particular, long-term safety monitoring is necessary as serious adverse events may appear. Combination therapy targeting more than one pathway controlling energy balance might be necessary to achieve substantial weight loss while minimising side effects.

[Medical therapy versus bariatric surgery of obese patients with Type 2 diabetes].

Bariatric surgery induces large and sustainable weight loss in obese patients and improves glycaemic control in patients with Type 2 diabetes. Eleven randomized controlled trials have shown superior glycaemic outcomes after bariatric procedures vs. medical therapy/intensive lifestyle interventions in obese patients with Type 2 diabetes. Furthermore, many patients experience remission of Type 2 diabetes after surgery but relapse may occur during follow-up. Data from observational studies show reduced incidence of micro- and macrovascular complications in addition to reduced cardiovascular and total mortality after surgery.

Updates in weight loss surgery and gastrointestinal peptides.

PURPOSE OF REVIEW: Roux-en-Y gastric bypass (RYGB) and sleeve gastrectomy are referred to as 'metabolic surgery' due to hormonal shifts with impacts on diabetes remission and weight loss. The purpose of this review is to summarize recent findings in mechanisms underlying beneficial effects of weight loss surgery. RECENT FINDINGS: Importantly, gut hormone secretion is altered after RYGB and sleeve gastrectomy due to accelerated transit of nutrients to distal parts of the small intestine, leading to excessive release of L-cell peptide hormones [e.g. glucagon-like peptide-1 (GLP-1), peptide YY].Improved glucose metabolism after RYGB and sleeve gastrectomy involves several mechanisms: early increased hepatic insulin sensitivity, resulting from reduced liver fat content in response to the postoperative caloric restriction, improved beta-cell function mediated by exaggerated postprandial GLP-1 secretion; as demonstrated by relapse of impaired glucose tolerance in studies blocking the GLP-1 receptor by exendin 9-39, and later after major weight loss increased peripheral insulin sensitivity. Gut hormone secretion changes towards a more anorectic profile and is likely important for less caloric intake and weight loss. SUMMARY: Changes in gut hormone secretion after RYGB and sleeve gastrectomy surgery induce the beneficial effects on weight and glycemic control through the influence on appetite regulation and insulin secretion.

Bariatric surgery - effects on obesity and related co-morbidities.

Laparoscopic adjustable gastric banding (LAGB), laparoscopic Roux-en-Y gastric bypass (RYGB) and laparoscopic sleeve gastrectomy (SG) are the three most commonly performed bariatric procedures. Obesity responds well to bariatric surgery, with major long-lasting weight loss that is most pronounced after RYGB and SG, where the mean weight loss is about 40 kg or 15 body mass index (BMI) units. Some of the benefits after RYGB and SG are independent of weight loss, and the remission of type 2 diabetes is observed a few days after the operation; this depends on changes in insulin sensitivity and gut hormone responses, especially a 10-fold increase in glucagon-like peptide-1 (GLP-1), which improves insulin secretion. After gastric banding, the remission of diabetes depends more on weight loss. Bariatric surgery reduces cardiovascular risk factors including hypertension, lipid disturbances, non-alcoholic fatty liver, musculoskeletal pain and reduces mortality of diabetes, cardiovascular diseases and cancers. Bariatric surgery also improves quality of life. The acute complications of surgery are infection, bleeding and anastomotic leak. Long-term complications are nutritional deficiencies, including vitamins and minerals, and anemia. Some patients have dumping after meals, and a few patients will develop postprandial hypoglycemia after RYGB. About 25% of patients require plastic surgery to provide relief from excessive skin tissue.