Investigation of gut hormone physiology in the regulation of appetite

Peptide tyrosine tyrosine (PYY) and glucagon like peptide-1 (GLP-1) are endogenous, anorectic gut hormones released from entero-endocrine L cells. The aims of this thesis were to: investigate the breakdown of PYY using peptide analogues in vitro and in vivo, determine the stimuli for release of PYY and GLP-1 from L cells in vitro and finally to attempt to stimulate the endogenous secretion of PYY and GLP-1 and so suppress appetite in man. The breakdown of PYY was studied using specially designed PYY analogues with changes to known enzyme cleavage sites. Degradation of the analogues was studied by incubation with proteolytic enzymes. Receptor binding assays were carried out to confirm that changes to the PYY structure had not altered binding to the endogenous PYY receptors. In vivo studies in rodents previously confirmed an extended pharmacological profile of these analogues. In order to study the various stimulants for PYY and GLP-1 release, a primary L cell model was developed. This was used to study the effect of various nutrients: glucose, amino acids and short chain fatty acids (SCFA) on PYY and GLP-1 release. In mouse and human primary L cell cultures the SCFA propionate increased PYY release significantly compared to basal levels, indicating that propionate is a potent stimulus of PYY release. To further investigate the results of the in vitro work, a randomised, double blind, crossover study was carried out in human volunteers to evaluate the effect of propionate on appetite. Administration of propionate ester over six days reduced energy intake at a buffet meal by 18.8% compared to control (P < 0.05, n = 20). However, there was no significant change in plasma GLP-1 or PYY levels between the groups, possibly suggesting an alternative explanation for the reduction in appetite seen. This may provide an interesting avenue for future studies. These studies of the physiological mechanisms underlying release and degradation of PYY and GLP-1 may contribute towards the development of an anti-obesity therapy based around L cell stimulation

Clinicopathological spectrum of operated thyroid lesions in a tertiary care centre : a cross sectional study

Background: Thyroid diseases are one of the most common endocrine disorders affecting the general population worldwide.They comprise a spectrum of entities causing systemic disease (Grave’s disease) or a localised abnormality in the thyroid gland such as nodular enlargement (goitre) or a tumour mass.The prevalence and pattern of these disorders depend on various factors including sex, age, ethnic and geographical patterns.Aim: To study the clinicopathological spectrum of thyroid lesions and the treatment outcome among the operated cases of thyroid. Variables in the spectrum includes age and sex distribution, mode of presentation, pre-operative&nbsp; thyroid function, evaluation by&nbsp; ultrasound, FNAC and final histopathology, postoperative complications and duration of hospital stay.Materials and Methods:This was a cross sectional study which included all patients who underwent surgery for&nbsp; thyroid pathologies in the department of general surgery, at our teaching hospital from January 2016 to December 2017.150 patients were included in the study. Patients who underwent thyroid surgery but whose records were not complete for thyroid function tests, USG findings and FNA findings were excluded from the study. Results:The highest incidences (38.6%) of thyroid lesionswere found in age group of 46-60 years with female predominance (87.3%). Out of total 150 cases, 30 were malignant and 120 were benign lesions. Thyroid function test was carried out for all cases and out of them 84 were euthyroid. Most common clinical symptom was swelling in the neck which was present in all cases. Multinodular goitre was the most common radiological finding seen in 76.7% cases. Benign follicular nodule was the most common diagnosis in FNAC (80%).The most common surgery performed was Total thyroidectomy (71%).Papillary carcinoma was the most common malignant lesion in this study (29 cases) and it was associated with MNG in 55% of cases. The incidence of clinical hypocalcemia was 10.6% and RLN injury was 5%.The mean duration of hospital stay was 4 days.Conclusions: Multinodulargoitre was found to be the most common thyroid lesion in this study. Thyroid diseases showed definite female predominance, with most of them occurring in an age group of 36 - 60 years. Papillary carcinoma was the most common malignant lesion in this study.In our study USG neck showed a moderate agreement with final histopathology compared to FNAC in diagnosing malignant lesions preoperatively. USG guided FNAC may improve the diagnostic accuracy. Combined approach based on history, clinical examination, FNAC and ultrasound is required to make an accurate diagnosis

Inflammatory stress exacerbates ectopic lipid deposition in C57BL/6J mice

<p>Abstract</p> <p>Background</p> <p>Chronic systemic inflammation and abnormal free fatty acid metabolism are closely related to ectopic lipid deposition. In this study, we investigate if inflammation tissue-specifically disrupts lipogenesis and lipolysis in nonadipose tissues and adipose tissue, resulting in ectopic lipid deposition in C57BL/6J mice.</p> <p>Methods</p> <p>We used casein injection in C57BL/6J mice to induce a chronic systemic inflammatory stress in vivo. Serum was analyzed for free fatty acid and cytokines. Insulin sensitivities were evaluated by glucose and insulin tolerance tests. Liver, muscle, adipose tissues were taken for lipid analysis. Real-time polymerase chain reaction and western blotting were used to examine the gene and protein expression of molecules involved in adipogenesis and lipolysis in tissues.</p> <p>Results</p> <p>Casein injection elevated serum levels of IL-6 and SAA in mice, which are associated with increased lipid accumulation in liver and muscle, suggesting that chronic systemic inflammation induces ectopic lipid deposition in nonadipose tissues. The inflammatory stress upregulated mRNA and protein expression of sterol regulatory element binding protein 1, fatty acid synthase, and acetyl CoA carboxylase alpha, while inhibited these molecules expression in adipose. Interestingly, in the same experimental setting, inflammation increased triglyceride lipase and hormone-sensitive lipase expression in white adipose tissue. Inflammation also induced insulin resistance and increased serum free fatty acid levels in C57BL/6J mice.</p> <p>Conclusions</p> <p>Chronic systemic inflammation increased lipogenesis in nonadipose tissues and lipolysis in white adipose tissue, resulting in ectopic lipid deposition in nonadipose tissues. This disturbed free fatty acid homeostasis and caused insulin resistance in C57BL/6J mice.</p

Management of Hypertension in Patients With Diabetic Kidney Disease: Summary of the Joint Association of British Clinical Diabetologists and UK Kidney Association (ABCD-UKKA) Guideline 2021.

Diabetic kidney disease (DKD) accounts for >40% cases of chronic kidney disease (CKD) globally. Hypertension is a major risk factor for progression of DKD and the high incidence of cardiovascular disease and mortality in these people. Meticulous management of hypertension is therefore crucial to slow down the progression of DKD and reduce cardiovascular risk. Randomized controlled trial evidence differs in type 1 and type 2 diabetes and in different stages of DKD in terms of target blood pressure (BP). Renin-angiotensin blocking agents reduce progression of DKD and cardiovascular events in both type 1 and type 2 diabetes, albeit differently according to the stage of CKD. There is emerging evidence for the benefit of sodium glucose cotransporter 2, nonsteroidal selective mineralocorticoid antagonists, and endothelin-A receptor antagonists in slowing progression and reducing cardiovascular events in DKD. This UK guideline, developed jointly by diabetologists and nephrologists, has reviewed all available current evidence regarding the management of hypertension in DKD to produce a set of comprehensive individualized recommendations for BP control and the use of antihypertensive agents according to age, type of diabetes, and stage of CKD (https://ukkidney.org/sites/renal.org/files/Management-of-hypertension-and-RAAS-blockade-in-adults-with-DKD.pdf). A succinct summary of the guideline, including an infographic, is presented here

Randomised clinical study: inulin short-chain fatty acid esters for targeted delivery of short-chain fatty acids to the human colon

SUMMARY Background Short-chain fatty acids (SCFA) produced through fermentation of nondigestible carbohydrates by the gut microbiota are associated with positive metabolic effects. However, well-controlled trials are limited in humans

INNODIA Master Protocol for the evaluation of investigational medicinal products in children, adolescents and adults with newly diagnosed type 1 diabetes

Background The INNODIA consortium has established a pan-European infrastructure using validated centres to prospectively evaluate clinical data from individuals with newly diagnosed type 1 diabetes combined with centralised collection of clinical samples to determine rates of decline in beta-cell function and identify novel biomarkers, which could be used for future stratification of phase 2 clinical trials. Methods In this context, we have developed a Master Protocol, based on the “backbone” of the INNODIA natural history study, which we believe could improve the delivery of phase 2 studies exploring the use of single or combinations of Investigational Medicinal Products (IMPs), designed to prevent or reverse declines in beta-cell function in individuals with newly diagnosed type 1 diabetes. Although many IMPs have demonstrated potential efficacy in phase 2 studies, few subsequent phase 3 studies have confirmed these benefits. Currently, phase 2 drug development for this indication is limited by poor evaluation of drug dosage and lack of mechanistic data to understand variable responses to the IMPs. Identification of biomarkers which might permit more robust stratification of participants at baseline has been slow. Discussion The Master Protocol provides (1) standardised assessment of efficacy and safety, (2) comparable collection of mechanistic data, (3) the opportunity to include adaptive designs and the use of shared control groups in the evaluation of combination therapies, and (4) benefits of greater understanding of endpoint variation to ensure more robust sample size calculations and future baseline stratification using existing and novel biomarkers

Investigation of gut hormone physiology in the regulation of appetite

Peptide tyrosine tyrosine (PYY) and glucagon like peptide-1 (GLP-1) are endogenous, anorectic gut hormones released from entero-endocrine L cells. The aims of this thesis were to: investigate the breakdown of PYY using peptide analogues in vitro and in vivo, determine the stimuli for release of PYY and GLP-1 from L cells in vitro and finally to attempt to stimulate the endogenous secretion of PYY and GLP-1 and so suppress appetite in man. The breakdown of PYY was studied using specially designed PYY analogues with changes to known enzyme cleavage sites. Degradation of the analogues was studied by incubation with proteolytic enzymes. Receptor binding assays were carried out to confirm that changes to the PYY structure had not altered binding to the endogenous PYY receptors. In vivo studies in rodents previously confirmed an extended pharmacological profile of these analogues. In order to study the various stimulants for PYY and GLP-1 release, a primary L cell model was developed. This was used to study the effect of various nutrients: glucose, amino acids and short chain fatty acids (SCFA) on PYY and GLP-1 release. In mouse and human primary L cell cultures the SCFA propionate increased PYY release significantly compared to basal levels, indicating that propionate is a potent stimulus of PYY release. To further investigate the results of the in vitro work, a randomised, double blind, crossover study was carried out in human volunteers to evaluate the effect of propionate on appetite. Administration of propionate ester over six days reduced energy intake at a buffet meal by 18.8% compared to control (P < 0.05, n = 20). However, there was no significant change in plasma GLP-1 or PYY levels between the groups, possibly suggesting an alternative explanation for the reduction in appetite seen. This may provide an interesting avenue for future studies. These studies of the physiological mechanisms underlying release and degradation of PYY and GLP-1 may contribute towards the development of an anti-obesity therapy based around L cell stimulation.EThOS - Electronic Theses Online ServiceWellcome TrustGBUnited Kingdo