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The gut motility and gastrointestinal hormones in relation to type 2 diabetesBackground and aimsGastric emptying is a major determinant of postprandial glycaemia in both health and type 2 diabetes mellitus(T2DM);the potential impact of ethnicity on gastric emptying is unclear.The incretin hormones,glucagon-like peptide-1(GLP-1)and glucose-dependent insulinotropic polypeptide(GIP),are gut-derived peptides released predominantly after meals.Together,these hormones are capable of regulating glucose homeostasis via pleiotropic actions within and outside of the endocrine pancreas.The secretory patterns of GLP-1 and GIP induced by ingested nutrients,however,have been poorly characterized,due largely to wide inter-individual variations in the rate of gastric emptying(i.e.1-4 kcal/min).We therefore evaluated i)the GLP-1 and GIP responses to intraduodenal(ID)infusions of glucose and protein at different rates,spanning the physiological range of gastric emptying,in both healthy and T2 DM subjects,ii)the rate of gastric emptying of a standardised meal and the associated glycaemic response in Han Chinese and Caucasian patients with T2 DM.Methods:?)We derived GLP-1 and GIP data from previously studies conducted in our center,which employed ID administration of glucose at rates of 0,1,2,3,4 kcal/min or whey protein at rates of 0,0.5,1.5 and 3 kcal/min,for a minimum of 60 min.Incremental area under the curves(iAUCs)for plasma GLP-1 and GIP were calculated to as a surrogate of the incretin responses to ID infusions.A maximum likelihood mixed effects model was used to estimate the relationship between the ID infusion rate and the iAUCs for plasma GLP-1 and GIP.?)14 Han Chinese and 14 Caucasian T2 DM patients,managed by diet and/or metformin monotherapy,underwent concurrent measurements of gastric emptying and blood glucose for 240 min after a 99 m Tc-calcium phytate-labelled mashed potato meal.Results?)GIP secretion was effectively stimulated by the infusion of glucose or protein at a low rate,while only when the infusion rate of glucose or protein reached1.5-2kcal/min could stimulate the GLP-1 secretion effectively.GIP started to release when the nutrients were given at lower rates,while The dose-response relationship for GLP-1,but not for GIP,differs significantly between glucose and protein.Compared with glucose,protein was more effective at stimulating GLP-1 secretion at the rate between 1-2 kcal/min,but showed similar,maximum effect on GLP-1 secretion at the rate higher than 3 kcal/min(GLP-1: Likelihood ratio = 8.68,degrees of freedom = 3,p-value = 0.0339;GIP: Likelihood ratio = 1.56,degrees of freedom = 3,p-value =0.6691).There were no differences in either GLP-1 or GIP secretions in response to different rates of ID glucose infusion in healthy and T2 DM subjects.?)Han Chinese patients were slightly younger(P<0.05),and had a lower BMI(P<0.05),than Caucasians.There were no differences in either Hb A1 c or fasting blood glucose between them.Gastric half-emptying time(T50)was shorter(P<0.05)and the postprandial blood glucose increment greater(P<0.05)in Han Chinese than Caucasian patients.Both the increment in blood glucose from baseline at 60 min and peak blood glucose were related inversely to T50(P<0.05 each).Conclusions?)The secretion of GIP and GLP-1 in response to intestinal nutrient stimulation does not follow a linear pattern,and patients with T2 DM do not seem to exhibit a deficit.Relative to glucose,protein is more effective at stimulating GLP-1 when delivered at low rates.Both glucose and protein induce a similar,and maximum,secretion of GLP-1 and GIP at higher ID infusion rates.?)Han Chinese with relatively well-controlled T2 DM have more rapid gastric emptying compared to Caucasians,which is associated with a greater postprandial glycaemic excursion.These differences may inform the choice of management,e.g.Han Chinese may particularly benefit from therapies that slow gastric emptying.Prat ? Gastrointestinal hormones and postprandial blood glucose regulated by gastrointestinal bitter taste receptors and bile acidsBackground and aims The small intestine detects the presence of intraluminal contents through activation of an array of specifically tuned “taste” receptors.In rodents,stimulation of intestinal bitter taste receptors(BTRs;i.e.the type 2 receptor family of taste specific G-protein-coupled receptors(T2Rs))modulates gastrointestinal hormone secretion,leading to reductions in blood glucose and energy intake,but these actions have not been tested in humans.Bile acids(BAs)are recently recognised as important signalling molecules participating in glucose metabolism.It is uncertain whether the postprandial serum BA response is altered in type 2 diabetes(T2D)and,if so,how this relates to postprandial glycaemic excursions.We have,therefore,evaluated i)the distribution and co-location of T2 Rs with enteroendocrine L-cells along the human intestine in health and T2 DM,and the effect of T2 R agonism on gut hormone release from cultured intestinal mucosa of mice,ii)the effects of the BTR agonist,denatonium benzoate(DB),on glucagon-like peptide-1(GLP-1),peptide YY(PYY),ghrelin,blood glucose,insulin and energy intake in response to ID glucose infusion in healthy humans,iii)the effects of the non-nutritive bitter taste flavouring,denatonium benzoate(DB),on gastrointestinal hormone secretion and energy intake in healthy subjects – regional differences in small intestinal exposure and iv)serum BA and plasma glucose concentrations before and after an oral glucose load in health and T2 DM.Methods ?)Thirty five healthy subjects provided biopsies from the duodenum(n=7),ileum(n=10),right colon(n=9)and rectum(n=9)while 11 patients with T2 DM provided duodenal biopsies,all with consent,under approved protocols.T2 R expression was determined in biopsies by q RT-PCR,while selected T2 R proteins were immuno-localised to GLP-1 expressing L-cells within the duodenum in healthy subjects(n=6).Isolated jejunum and ileum from C57BL/6 mice were used in ex vivo experiments to assess dose-and T2R-dependent GLP-1 release in response to the bitter agent,denatonium benzoate(0.1,1 and 10 m M,n=8).?)Sixteen healthy subjects were studied on three days,after an overnight fast.An intraduodenal catheter was positioned for infusion of a 250 mL aqueous solution containing either DB(10mg or 30mg)or water only(control)between t =0-150 min,with a concurrent intraduodenal glucose infusion at 2kcal/min between t=60-150 min.Energy intake was then assessed at a standardised ad libitum meal.“Arterialised” blood was sampled at frequent intervals for measurements of plasma glucose and gastrointestinal hormones.?)Sixteen healthy subjects were studied on three days,after an overnight fast.An intraluminal catheter was positioned following one of the 3 treatments:(i)duodenal + ileal water(150 mL)(i.e.control);(ii)duodenal DB(30 mg dissolved in water to 150 mL)+ ileal water(i.e.duodenal DB),and(iii)duodenal water + ileal DB(30 mg dissolved in water to 150 mL)for 60 minutes.Energy intake was then assessed at a standardised ad libitum meal.“Arterialised” blood was sampled at frequent intervals for measurements of plasma glucose and gastrointestinal hormones.?)40 Chinese healthy subjects and 40 treatment-na(?)ve Chinese T2 D subjects underwent a 75 g oral glucose tolerance test(OGTT)following an overnight fast.Plasma glucose and serum BA profiles(including CA,CDCA,DCA,GCA,GCDCA,GDCA,TCA,TCDCA and TDCA,analysed by liquid chromatography-mass spectrometry)were evaluated immediately before and 2h after OGTT.Total BA concentrations were calculated as the sum of individual BAs,and subsequently transformed to their natural logarithms to normalise their distribution for statistical analysis.Fasting serum cholesterol,triglycerides,LDL and HDL,were also measured.Results ?)T2R expression was evident across all intestinal regions with peak T2R3,4,5 and 14 expression in ileum in health.Duodenal T2 R expression was preserved in T2 DM.T2Rs were highly co-localised to GLP-1 expressing duodenal L-cells with T2R3 the most co-expressed target(66% T2R3-L-cells).DB triggered dose-dependent GLP-1 release from the mouse duodenum(5-fold over basal,P < 0.001)and jejunum(7-fold,P < 0.001).?)All subjects tolerated the studies well without nausea.DB increased the incremental area under the curve(iAUC)for plasma total GLP-1(control 39.0±169.6 pmol/L*min vs 10 mg DB 95.3±110.7 pmol/L*min vs 30 mg DB 442.7±133.4 pmol/L*min,P<0.05)and reduced the iAUC for total ghrelin(control 13.6±157.8 pg/mL*min vs 10 mg DB-283.9±91.34 pg/mL*min vs 30 mg DB-719.1±169.8 pg/mL *min,P<0.05)and energy intake(control 4969±270.5 KJ vs 10 mg DB 4677±281.3 KJ vs 30 mg DB 3979±315.4 KJ,P<0.05),with significant differences between 30 mg DB and control(P<0.05 each).Plasma glucose,insulin,glucagon,or PYY did not differ between the treatments.?)All subjects tolerated the studies well without nausea.The glucose concentrations(iAUC0-90min,control 35.7±7.3 mmol/L*min vs intraduodenal DB 31.1 ± 5.7 mmol/L*min vs intraileal DB 29.8 ± 7.4 mmol/L*min),GLP-1 levels(iAUC0-90min,control 308.8±61.7 pmol/L*min vs intraduodenal DB 253.6±64.5 pmol/L*min vs intraileal DB 319.7±68.8 pmol/L*min),PYY levels(iAUC0-90min,control 119.5±42.0 pmol/L*min vs intraduodenal DB 88.0±34.0 pmol/L*min vs intraileal DB 150.1±40.7 pmol/L*min)and the energy intake(control 4854±463.3 KJ vs intraduodenal DB 5040±492.1 KJ vs intraileal DB 4740±438.3 KJ)did not differ between the three treatments.?)Hb A1 c and plasma glucose levels(both fasting and 2h after OGTT)were predictably higher in the T2 D group(P < 0.05 each).Fasting and 2h post-OGTT serum insulin levels were higher in T2 DM than healthy subjects(P=0.001 and 0.004,respectively).Serum total GLP-1 levels did not differ between the two groups at fasting(healthy 28.74(13.41,46.67)pmol/L vs T2 DM 27.97(22.45,32.51)pmol/L),however,the magnitude of the increase at 2h post-OGTT was less in T2 DM than healthy subjects(healthy 60.93(55.57,68.42)pmol/L vs T2 DM 45.11(31.73,61.18)pmol/L,P=0.012).FGF19 levels were similar between the two groups at baseline and 2h post-OGTT.Total BA levels at 2h post-OGTT increased in healthy subjects(fasting 605.7(362.4,887.4)ng/mL vs OGTT-2h 757.0(442.9,1376.9)ng/mL),but decreased slightly in T2 DM patients(fasting 717.0(408.6,1304.8)ng/mL vs OGTT-2h 749.1(451.2,900.0)ng/mL).In the healthy subjects,serum total BA levels at 2h post-OGTT was related inversely to 2h-PPG(r =-0.42,P = 0.0063)and serum triglycerides(r =-0.40,P = 0.0114),and directly to serum FGF19(r = 0.42,P = 0.0057)and HDL(r = 0.50,P = 0.0009).Conclusions ?)T2Rs are highly expressed in L-cells in the human intestine and their expression is preserved in patients with T2 DM.This,combined with evidence of T2R-evoked GLP-1 release in the mouse small intestine,adds support that bitter agents have the potential to serve as novel anti-diabetic agents in humans.?)In healthy subjects,intraduodenal DB stimulates GLP-1 and suppresses ghrelin and energy intake,without affecting the PYY,glucose,insulin or glucagon responses to intraduodenal glucose.These observations support further investigation of the potential for stimulation of intestinal BTRs to be useful in the management of obesity and type 2 diabetes.?)In healthy subjects,intraduodenal or intraileal DB alone had no effects on glucose,gut hormones or energy intake,indicating that the metabolic effects of intestinal bitter receptors may be potentiated by intraluminal nutrients.?)T2D is associated with an impaired bile acid response to oral glucose.In health,the glycaemia in response to oral glucose is inversely,but the FGF19 levels and the HDL levels are positively,related to serum BA levels,indicating the changes of bile acid files after OGTT may be a potential predict factor for the incidence of T2 D. |
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