Diet and Gastrointestinal Bypass–Induced Weight Loss: The Roles of Ghrelin and Peptide YY

OBJECTIVE-Bariatric surgery causes durable weight loss. Gut hormones are implicated in obesity pathogenesis, dietary failure, and mediating gastrointestinal bypass (GIBP) surgery weight loss. In mice, we determined the effects of diet-induced obesity (DIO), subsequent dieting, and GIBP surgery on ghrelin, peptide YY (PYY), and glucagon-like peptide-1 (GLP-1). To evaluate PYY's role in mediating weight loss post-GIBP, we undertook GIBP surgery in PyyKO mice.RESEARCH DESIGN AND METHODS-Male C57BL/6 mice randomized to a high-fat diet or control diet were killed at 4-week intervals. DIO mice underwent switch to ad libitum low-fat diet (DIO-switch) or caloric restriction (CR) for 4 weeks before being killed. PyyKO mice and their DIO wild-type (WT) littermates underwent GIBP or sham surgery and were culled 10 days post-operatively. Fasting acyl-ghrelin, total PYY, active GLP-1 concentrations, stomach ghrelin expression, and colonic Pyy and glucagon expression were determined. Fasting and postprandial PYY and GLP-1 concentrations were assessed 30 days postsurgery in GIBP and sham pair-fed (sham.PF) groups.RESULTS-DIO progressively reduced circulating fasting acyl-ghrelin, PYY, and GLP-1 levels. CR and DIO-switch caused weight loss but failed to restore circulating PYY to weight-appropriate levels. After GIBP, WT mice lost weight and exhibited increased circulating fasting PYY and colonic Pyy and glucagon expression. In contrast, the acute effects of GIBP on body weight were lost in PyyKO mice. Fasting PYY and postprandial PYY and GLP-1 levels were increased in GIBP mice compared with sham.PF mice.CONCLUSIONS-PYY plays a key role in mediating the early weight loss observed post-GIBP, whereas relative PYY deficiency during dieting may compromise weight-loss attempts. Diabetes 60:810-818, 201

Insulin degludec/liraglutide (IDegLira) was effective across a range of dysglycaemia and body mass index categories in the DUAL V randomized trial

This study assessed the efficacy of insulin degludec/liraglutide (IDegLira) vs insulin glargine U100 (IGlar) across categories of baseline glycated haemoglobin (HbA1c; ≤7.5%, >7.5% to ≤8.5% and >8.5%), body mass index (BMI; <30, ≥30 to <35 and ≥35 kg/m2 ) and fasting plasma glucose (FPG; <7.2 and ≥7.2 mmol/L) in patients with type 2 diabetes (T2D) uncontrolled on basal insulin, using post hoc analyses of the DUAL V 26-week trial. With IDegLira, mean HbA1c was reduced across all baseline HbA1c (1.0%-2.5%), FPG (1.5%-1.9%) and BMI categories (1.8%-1.9%), with significantly greater reductions compared with IGlar U100. For all HbA1c, FPG and BMI categories, IDegLira resulted in weight loss and IGlar U100 in weight gain; hypoglycaemia rates were lower for IDegLira vs IGlar U100. More patients achieved HbA1c <7% with IDegLira than IGlar U100 across all HbA1c (59%-87% vs 31%-66%), FPG (71%-74% vs 40%-51%) and BMI categories (71%-73% vs 40%-54%). IDegLira improved glycaemic control and induced weight loss in patients with T2D previously uncontrolled on basal insulin, across the categories of baseline HbA1c, FPG or BMI that were tested.Sin financiación6.133 JCR (2018) Q1, 16/145 Endocrinology & Metabolism2.777 SJR (2018) Q1, 9/137 Endocrinology, 11/245 Endocrinology, Diabetes and Metabolism, 8/141 Internal MedicineNo data IDR 2018UE

IDegLira is efficacious across baseline HbA1c categories in subjects with Type 2 diabetes uncontrolled on sulphonylurea, glucagon-like peptide-1 receptor agonist or insulin glargine U100: analyses from completed phase 3b trials

Aims: Previous analyses of phase 3a trials (DUAL I extension;DUAL II) showed IDegLira (insulin degludec/liraglutide combina-tion) is efficacious irrespective of baseline HbA1c. This analysisaimed to confirm this observation in additional populations withType 2 diabetes uncontrolled on (i) a glucagon-like peptide-1receptor agonist (GLP-1RA) (DUAL III: IDegLira vs unchangedGLP-1RA), (ii) sulphonylurea metformin (DUAL IV: IDegLiravs placebo) or (iii) insulin glargine (IGlar U100) (DUAL V:IDegLira vs continued IGlar U100 titration). Methods: DUAL III–V were 26 week, randomised trials. IDe-gLira starting dose was 10 dose steps (1 dose step = 1 unit IDeg +0.036mg Lira) in DUAL IV and 16 dose steps in DUAL III and V;maximum IDegLira dose: 50 dose steps. This post hoc analysisgrouped subjects by baseline HbA1c; ≤7.5, > 7.5–≤8.5and > 8.5%.Results: In all trials a higher baseline HbA1c resulted in greaterHbA1c reductions. The change in HbA1c was significantly greater(p 7.5–≤8.5 and > 8.5%: -0.74, -1.13, -1.18; -0.91, -1.00, -1.36; -0.48, -0.55, -0.68 for DUAL III, IV and V,respectively). In all trials for all baseline HbA1c groups, IDegLiradecreased mean HbA1c to 9% (median 9.5%),HbA1c was reduced to 6.9% with IDegLira vs 7.8% with IGlarU100. Conclusions: Significant HbA1c reductions occur with IDegLiraregardless of baseline HbA1c group or study population.Sin financiaciónNo data (2017)UE

Subject standardization, acclimatization, and sample processing affect gut hormone levels and appetite in humans

Background & Aims: Gut hormones represent attractive therapeutic targets for the treatment of obesity and type 2 diabetes. However, controversy surrounds the effects that adiposity, dietary manipulations, and bariatric surgery have on their circulating concentrations. We sought to determine whether these discrepancies are due to methodologic differences. Methods: Ten normal-weight males participated in a 4-way crossover study investigating whether fasting appetite scores, plasma acyl-ghrelin, active glucagon-like peptide-1 (GLP-1), and peptide YY3–36 (PYY3–36) levels are altered by study-induced stress, prior food consumption, and sample processing. Results: Study visit order affected anxiety, plasma cortisol, and temporal profiles of appetite and plasma PYY3–36, with increased anxiety and cortisol concentrations on the first study day. Plasma cortisol area under the curve (AUC) correlated positively with plasma PYY3–36 AUC. Despite a 14-hour fast, baseline hunger, PYY3–36 concentrations, temporal appetite profiles, PYY3–36 AUC, and active GLP-1 were affected by the previous evening's meal. Sample processing studies revealed that sample acidification and esterase inhibition are required when measuring acyl-ghrelin and dipeptidyl-peptidase IV inhibitor addition for active GLP-1. However, plasma PYY3–36 concentrations were unaffected by addition of dipeptidyl-peptidase IV. Conclusions: Accurate assessment of appetite, feeding behavior, and gut hormone concentrations requires standardization of prior food consumption and subject acclimatization to the study protocol. Moreover, because of the labile nature of acyl-ghrelin and active GLP-1, specialized sample processing needs to be undertaken

Peripheral activation of the Y2-receptor promotes secretion of GLP-1 and improves glucose tolerance

International audienceThe effect of peptide tyrosine–tyrosine (PYY) on feeding is well established but currently its role in glucose homeostasis is poorly defined. Here we show in mice, that intraperitoneal (ip) injection of PYY3-36 or Y2R agonist improves nutrient-stimulated glucose tolerance and enhances insulin secretion; an effect blocked by peripheral, but not central, Y2R antagonist administration. Studies on isolated mouse islets revealed no direct effect of PYY3-36 on insulin secretion. Bariatric surgery in mice, enterogastric anastomosis (EGA), improved glucose tolerance in wild-type mice and increased circulating PYY and active GLP-1. In contrast, in Pyy-null mice, post-operative glucose tolerance and active GLP-1 levels were similar in EGA and sham-operated groups. PYY3-36 ip increased hepato-portal active GLP-1 plasma levels, an effect blocked by ip Y2R antagonist. Collectively, these data suggest that PYY3-36 therefore acting via peripheral Y2R increases hepato-portal active GLP-1 plasma levels and improves nutrient-stimulated glucose tolerance

Changes in body-weight, leptin and gut hormones after surgery.

<p>GBP = modified gastric bypass surgery; data presented as Mean (Standard Error of Mean) or P value (<i>t</i> test).</p

Isoform-specific <i>Nnat</i> expression in the hypothalamus after surgery in relation to weight-loss and circulating leptin.

<p>A–B) <i>Nnat</i>-α expression in the hypothalamus did not correlate with either change in body-weight or with circulating leptin after surgery; C–D) by contrast <i>Nnat</i>-β expression showed positive correlation with change in body-weight and weak positive correlation with circulating leptin after surgery; <i>key – Nnat-α expression shown with open squares, Nnat-β with filled circles, AU = arbitrary units where Nnat expression was standardised using ubiquitin (Ubc) as a reference gene</i>.</p

Change in body weight and leptin after chronic dietary switches.

<p>Control = standard dietary chow maintained, Control-HF = standard dietary chow switch to high-fat diet, Control-CR = standard dietary chow switch to caloric restriction; HF-Control = high-fat diet switch to standard dietary chow, HF = high-fat diet maintained, HF-CR = high-fat diet switch to caloric restriction; data presented as P value (post-hoc ANOVA).</p

Hypothalamic and brainstem <i>Nnat</i> expression after modified gastric bypass <i>versus</i> sham surgery.

<p>A) <i>Nnat</i>-β showed a significant reduction in the hypothalamus (**P = 0.003) after modified gastric bypass (n = 8) compared to sham surgery (n = 7) whilst <i>Nnat</i>-α did not reduce significantly, consistent with a bypass-specific effect on <i>Nnat</i>-β expression; B) expression of <i>Nnat</i>-α and <i>Nnat</i>-β did not differ in the brainstem after modified gastric bypass (n = 8) compared to sham surgery (n = 7); <i>key – GBP = modified gastric bypass surgery, Sham = sham surgery, AU = arbitrary units where Nnat expression was standardised using an endogenous reference gene (ubiquitin (Ubc) for hypothalamus, hypoxanthine guanine phosphoriboribosyl transferase (Hprt) for brainstem).</i></p

Expression of <i>Nnat</i> isoforms in response to fasting versus <i>ad-libitum</i> feeding.

<p>A) Hypothalamic <i>Nnat</i>-α and -β showed a non-significant reduction in response to overnight fasting (n = 10) when compared to <i>ad-libitum</i> fed counterparts (n = 10); B) but a significant reduction after 24-h fasting (n = 10) compared to feeding (n = 11), equivalent for both isoforms (**<i>Nnat</i>-α P = 0.005, **<i>Nnat</i>-β P = 0.007); C–D) <i>Nnat</i> isoforms did not show a consistent or significant change after overnight fasting in the stomach or duodenum (n = 10 fasted, n = 10 <i>ad-libitum</i> fed in both tissues); <i>key – AU = arbitrary units where Nnat expression was standardised using ubiquitin (Ubc) as a reference gene</i>.</p