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OBJECTIVES: Co-agonists at the glucagon-like peptide-1 and glucagon receptors (GLP1R/GCGR) show promise as treatments for metabolic dysfunction-associated steatotic liver disease (MASLD). Although most co-agonists to date have been heavily GLP1R-biased, glucagon directly acts on the liver to reduce fat content. The aims of this study were to investigate a GCGR-biased co-agonist as treatment for hepatic steatosis in mice. METHODS: Mice with diet-induced obesity (DIO) were treated with Dicretin, a GLP1/GCGR co-agonist with high potency at the GCGR, Semaglutide (GLP1R monoagonist) or food restriction over 24 days, such that their weight loss was matched. Hepatic steatosis, glucose tolerance, hepatic transcriptomics, metabolomics and lipidomics at the end of the study were compared with Vehicle-treated mice. RESULTS: Dicretin lead to superior reduction of hepatic lipid content when compared to Semaglutide or equivalent weight loss by calorie restriction. Markers of glucose tolerance and insulin resistance improved in all treatment groups. Hepatic transcriptomic and metabolomic profiling demonstrated many changes that were unique to Dicretin-treated mice. These include some known targets of glucagon signaling and others with as yet unclear physiological significance. CONCLUSIONS: Our study supports the development of GCGR-biased GLP1/GCGR co-agonists for treatment of MASLD and related conditions.
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Hígado Graso , Péptido 1 Similar al Glucagón , Ratones Endogámicos C57BL , Obesidad , Receptores de Glucagón , Pérdida de Peso , Animales , Obesidad/tratamiento farmacológico , Obesidad/metabolismo , Pérdida de Peso/efectos de los fármacos , Receptores de Glucagón/agonistas , Receptores de Glucagón/metabolismo , Masculino , Hígado Graso/tratamiento farmacológico , Hígado Graso/metabolismo , Ratones , Péptido 1 Similar al Glucagón/metabolismo , Dieta Alta en Grasa/efectos adversos , Hígado/metabolismo , Hígado/efectos de los fármacos , Receptor del Péptido 1 Similar al Glucagón/agonistas , Receptor del Péptido 1 Similar al Glucagón/metabolismo , Resistencia a la Insulina , Péptidos Similares al Glucagón/farmacologíaRESUMEN
Obesity and type 2 diabetes mellitus (T2DM) are widespread, non-communicable diseases that are responsible for considerable levels of morbidity and mortality globally, primarily in the form of cardiovascular disease (CVD). Changes to lifestyle and behaviour have insufficient long-term efficacy in most patients with these diseases; metabolic surgery, although effective, is not practically deliverable on the scale that is required. Over the past two decades, therapies based on incretin hormones, spearheaded by glucagon-like peptide 1 (GLP1) receptor agonists (GLP1RAs), have become the treatment of choice for obesity and T2DM, and clinical evidence now suggests that these agents have benefits for CVD. We review the latest advances in incretin-based pharmacotherapy. These include 'GLP1 plus' agents, which combine the known advantages of GLP1RAs with the activity of additional hormones, such as glucose-dependent insulinotropic peptide, glucagon and amylin, to achieve desired therapeutic goals. Second-generation non-peptidic oral GLP1RAs promise to extend the benefits of GLP1 therapy to those who do not want, or cannot have, subcutaneous injection therapy. We conclude with a discussion of the knowledge gaps that must be addressed before incretin-based therapies can be properly deployed for maximum benefit in the treatment of obesity and T2DM.
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Diabetes Mellitus Tipo 2 , Receptor del Péptido 1 Similar al Glucagón , Incretinas , Obesidad , Humanos , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Diabetes Mellitus Tipo 2/metabolismo , Incretinas/uso terapéutico , Incretinas/metabolismo , Obesidad/tratamiento farmacológico , Obesidad/metabolismo , Receptor del Péptido 1 Similar al Glucagón/agonistas , Péptido 1 Similar al Glucagón/metabolismo , Animales , Hipoglucemiantes/uso terapéuticoRESUMEN
Post bariatric hypoglycaemia (PBH) is typically a post-prandial hypoglycaemia occurring about 2-4 hours after eating in people who have undergone bariatric surgery. PBH develops relatively late after surgery and often after discharge from post-surgical follow-up by bariatric teams, leading to variability in diagnosis and management in non-specialist centres. AIM: to improve and standardise clinical practice in the diagnosis and management of PBH. OBJECTIVES: (1) to undertake an up-to-date review of the current literature; (2) to formulate practical and evidence-based guidance with regards on the diagnosis and treatment of PBH; (3) to recommend future avenues for research in this condition. METHOD: A scoping review was undertaken after an extensive literature search. A consensus on the guidance and confidence in the recommendations was reached by the steering group authors prior to review by key stakeholders. OUTCOME: We make pragmatic recommendations for the practical diagnosis and management of PBH including criteria for diagnosis and recognition, as well as recommendations for research areas that should be explored.
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AIMS: To determine whether a continuous infusion of a glucagon-like peptide receptor (GLP-1R)/glucagon receptor (GCGR) co-agonist, G3215 is safe and well tolerated in adults with overweight or obesity. METHODS: A phase 1 randomized, double blind, placebo-controlled trial of G3215 in overweight or obese participants, with or without type 2 diabetes. RESULTS: Twenty-six participants were recruited and randomized with 23 completing a 14-day subcutaneous infusion of G3215 or placebo. The most common adverse events were nausea or vomiting, which were mild in most cases and mitigated by real-time adjustment of drug infusion. There were no cardiovascular concerns with G3215 infusion. The pharmacokinetic characteristics were in keeping with a continuous infusion over 14 days. A least-squares mean body weight loss of 2.39 kg was achieved with a 14-day infusion of G3215, compared with 0.84 kg with placebo infusion (p < .05). A reduction in food consumption was also observed in participants receiving G3215 and there was no deterioration in glycaemia. An improved lipid profile was seen in G3215-treated participants and consistent with GCGR activation, a broad reduction in circulating amino acids was seen during the infusion period. CONCLUSION: An adaptive continuous infusion of the GLP-1/GCGR co-agonist, G3215, is safe and well tolerated offering a unique strategy to control drug exposure. By allowing rapid, response-directed titration, this strategy may allow for mitigation of adverse effects and afford significant weight loss within shorter time horizons than is presently possible with weekly GLP-1R and multi-agonists. These results support ongoing development of G3215 for the treatment of obesity and metabolic disease.
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Diabetes Mellitus Tipo 2 , Sobrepeso , Adulto , Humanos , Sobrepeso/complicaciones , Sobrepeso/tratamiento farmacológico , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Diabetes Mellitus Tipo 2/metabolismo , Receptores de Glucagón , Obesidad/complicaciones , Obesidad/tratamiento farmacológico , Péptido 1 Similar al Glucagón/uso terapéutico , Receptor del Péptido 1 Similar al Glucagón/uso terapéuticoRESUMEN
INTRODUCTION: Bariatric surgery is associated with adverse pregnancy outcomes such as reduced birth weight and premature birth. One possible mechanism for this is increased glycemic variability (GV) which occurs after bariatric surgery. The objective of this study was to compare the effect of Roux-en-Y gastric bypass (RYGB) versus vertical sleeve gastrectomy (SG) on GV during pregnancy and to investigate the relationships of GV, type of bariatric surgery and maternal and neonatal outcomes. RESEARCH DESIGN AND METHODS: Fourteen pregnant women after RYGB and 14 after SG were investigated with continuous glucose monitoring in their second or third trimester in this observational study carried out as part of routine clinical care. RESULTS: Pregnant women with RYGB had similar mean interstitial glucose values but significantly increased indices of GV and a lower %time in range 3.9-7.8 mmol/L (70-140 mg/dL), compared with SG. CONCLUSIONS: Pregnant women who have undergone RYGB have greater GV during pregnancy compared with those who have undergone SG. Further research is needed to establish the relationship between GV and pregnancy outcomes to determine the preferred bariatric operation in women of reproductive age, and whether interventions to reduce GV might improve outcomes.
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Derivación Gástrica , Recién Nacido , Humanos , Femenino , Embarazo , Derivación Gástrica/efectos adversos , Mujeres Embarazadas , Automonitorización de la Glucosa Sanguínea , Glucemia , Resultado del Embarazo/epidemiología , Gastrectomía/efectos adversosRESUMEN
PURPOSE: Adrenal vein sampling (AVS) is used to lateralise and differentiate unilateral from bilateral aldosterone production in primary aldosteronism. The adrenal venous samples are standardised to a peripheral or low inferior vena cava (IVC) sample and compared. It is unknown whether the location of the non-adrenal sample affects the results. This study compares AVS results standardised to the low IVC and right external iliac vein (REIV). METHODS: Patients who underwent AVS between March 2021 and May 2023 were included. All procedures were undertaken by a single operator (AA). Demographic data and AVS results were collected from patients' electronic records. Catheterisation success and lateralisation were assessed using both low IVC and REIV samples. Equivalence test was used to compare the cortisol and aldosterone levels. RESULTS: Eighty-one patients, (M: F = 38:43), aged between 29 and 74 were included. Bilateral successful adrenal vein cannulation was achieved in 79/81 (97.5%) cases. The mean cortisol levels from the REIV were statistically equivalent although there was a small and not biologically significant difference from the low IVC (respective geometric means 183 nmol/l vs. 185 nmol/l, p = 0.015). This small difference in cortisol may be due to accessory adrenal venous drainage into the IVC. The aldosterone and aldosterone/cortisol ratios were statistically equivalent. There was no discordance in selectivity or lateralisation when the IVC or REIV measurements were used. CONCLUSION: The IVC and REIV samples may be used interchangeably during AVS.
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Aldosterona , Hiperaldosteronismo , Humanos , Adulto , Persona de Mediana Edad , Anciano , Hiperaldosteronismo/diagnóstico , Hidrocortisona , Estudios Retrospectivos , Glándulas Suprarrenales/irrigación sanguíneaRESUMEN
BACKGROUND AND AIMS: Sleeve gastrectomy (VSG) leads to improvement in hepatic steatosis, associated with weight loss. The aims of this study were to investigate whether VSG leads to weight-loss independent improvements in liver steatosis in mice with diet-induced obesity (DIO); and to metabolically and transcriptomically profile hepatic changes in mice undergoing VSG. METHODS: Mice with DIO were treated with VSG, sham surgery with subsequent food restriction to weight-match to the VSG group (Sham-WM), or sham surgery with return to unrestricted diet (Sham-Ad lib). Hepatic steatosis, glucose tolerance, insulin and glucagon resistance, and hepatic transcriptomics were investigated at the end of the study period and treatment groups were compared with mice undergoing sham surgery only (Sham-Ad lib). RESULTS: VSG led to much greater improvement in liver steatosis than Sham-WM (liver triglyceride mg/mg 2.5 ± 0.1, 2.1 ± 0.2, 1.6 ± 0.1 for Sham-AL, Sham-WM and VSG respectively; p = 0.003). Homeostatic model assessment of insulin resistance was improved following VSG only (51.2 ± 8.8, 36.3 ± 5.3, 22.3 ± 6.1 for Sham-AL, Sham-WM and VSG respectively; p = 0.03). The glucagon-alanine index, a measure of glucagon resistance, fell with VSG but was significantly increased in Sham-WM (9.8 ± 1.7, 25.8 ± 4.6 and 5.2 ± 1.2 in Sham Ad-lib, Sham-WM and VSG respectively; p = 0.0003). Genes downstream of glucagon receptor signalling which govern fatty acid synthesis (Acaca, Acacb, Me1, Acly, Fasn and Elovl6) were downregulated following VSG but upregulated in Sham-WM. CONCLUSIONS: Changes in glucagon sensitivity may contribute to weight-loss independent improvements in hepatic steatosis following VSG.
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Hígado Graso , Glucagón , Ratones , Animales , Glucemia , Pérdida de Peso , Obesidad/complicaciones , Obesidad/cirugía , Hígado Graso/complicaciones , Gastrectomía/efectos adversosRESUMEN
OBJECTIVES: Peptide tyrosine tyrosine (PYY) exists as two species, PYY1-36 and PYY3-36 , with distinct effects on insulin secretion and appetite regulation. The detailed effects of bariatric surgery on PYY1-36 and PYY3-36 secretion are not known as previous studies have used nonspecific immunoassays to measure total PYY. Our objective was to characterize the effect of sleeve gastrectomy (SG) and Roux-en-Y gastric bypass (RYGB) on fasting and postprandial PYY1-36 and PYY3-36 secretion using a newly developed liquid chromatography-tandem mass spectrometry (LC-MS/MS) assay. DESIGN AND SUBJECTS: Observational study in 10 healthy nonobese volunteers and 30 participants with obesity who underwent RYGB (n = 24) or SG (n = 6) at the Imperial Weight Centre [NCT01945840]. Participants were studied using a standardized mixed meal test (MMT) before and 1 year after surgery. The outcome measures were PYY1-36 and PYY3-36 concentrations. RESULTS: Presurgery, the fasting and postprandial levels of PYY1-36 and PYY3-36 were low, with minimal responses to the MMT, and these did not differ from healthy nonobese volunteers. The postprandial secretion of both PYY1-36 and PYY3-36 at 1 year was amplified after RYGB, but not SG, with the response being significantly higher in RYGB compared with SG. CONCLUSIONS: There appears to be no difference in PYY secretion between nonobese and obese volunteers at baseline. At 1 year after surgery, RYGB, but not SG, is associated with increased postprandial secretion of PYY1-36 and PYY3-36 , which may account for long-term differences in efficacy and adverse effects between the two types of surgery.
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Derivación Gástrica , Humanos , Derivación Gástrica/métodos , Péptido YY , Cromatografía Liquida , Glucemia , Espectrometría de Masas en Tándem , Obesidad/cirugía , Gastrectomía , TirosinaRESUMEN
Acromegaly due to ectopic secretion of growth hormone-releasing hormone (GHRH) is rare. Treatment consists of surgical removal of the primary tumor, cytostatic therapy, "cold" or radioactive somatostatin analogue treatment, and medical therapy for acromegaly, if needed. A 53 year-old female had an ocular lesion noted on a routine optician visit, originally considered to be an ocular melanoma. She had a bronchial carcinoid successfully removed 22 years previously. She had acromegalic features with an enlarged pituitary gland on magnetic resonance imaging and, additionally, metastatic lesions in her bones, liver, and thyroid gland. Elevated GHRH levels (>250× upper limit of normal) suggested a metastatic lung neuroendocrine tumor secreting GHRH. Cold and radioactive somatostatin analogue therapy reduced both GHRH and insulin-like growth factor 1 (IGF-1) levels, but normalization of the biochemical markers of acromegaly was only achieved after pegvisomant was introduced. Complete control of IGF-1 was achieved, and this may have hindered the growth of the metastatic lesions as well, as the patient remains well 13 years after the diagnosis of metastatic disease and 35 years after the original lung operation. A gradual rise in prolactin levels over last 4 years was noted, which is likely due to the prolonged effect of GHRH on prolactin-secreting cells. The diagnosis of this case applied the law of parsimony from the Ockham's razor principle. We consider that breaking the vicious circle of IGF-1 feeding the metastatic tumor was key for the long-term outcome of this case.
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Objective: The insulin tolerance test (ITT) is the gold standard endocrine test used to assess the integrity of the growth hormone (GH) and cortisol axes. The ITT has potential risks, and severe hypoglycaemia may necessitate intravenous glucose rescue. There is no clear consensus as to the optimal insulin dose for the ITT. Therefore, we sought to compare the standard dose (0.15 U/kg) and a low-dose ITT (0.1 U/kg). Design: Single-centre audit of ITT data (2012-2021). Patients and Measurements. Patients who underwent an ITT to assess possible GH deficiency/adrenal insufficiency were included. Glucose, GH, and cortisol were measured at baseline and 30, 45, 60, 90, and 120 minutes following I.V. insulin bolus (0.15 U/kg or 0.10 U/kg). Results: Of the ITTs performed, only 3/177 (1.7%) did not achieve adequate hypoglycaemia (≤2.2 mmol/L) with a single insulin dose. In total, 174 patients (43.5 ± 12.1 yrs, mean ± standard deviation) were included for analysis (0.15 U/kg: n = 113, 0.10 U/kg: n = 61). All 174 subjects had adequate hypoglycaemia regardless of baseline fasting blood glucose level or insulin dose. Neither nadir glucose nor glucose delta (i.e., baseline minus nadir) differed between insulin doses. Trends in both cortisol and GH responses over time were similar between groups, and a greater proportion of patients receiving the standard dose had an adequate cortisol response (77/106 (72.6%) vs. 32/60 (53.3%), p=0.01). The rates of glucose rescue did not differ in a subset of 79 patients, with on-demand glucose rescue in 4/35 (11%) for the standard dose and 2/44 (5%) for the low dose (p=0.25). Conclusions: Our results suggest that the low-dose ITT produces comparable glucose, cortisol, and GH responses to the higher dose. Given the risks associated with hypoglycaemia, the low dose appears to be preferable to the standard dose ITT in most circumstances.
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Diabetes Mellitus Tipo 2/tratamiento farmacológico , Polipéptido Inhibidor Gástrico/uso terapéutico , Hipoglucemiantes/uso terapéutico , Insulina Glargina/uso terapéutico , Glucemia/efectos de los fármacos , Femenino , Receptor del Péptido 1 Similar al Glucagón/uso terapéutico , Hemoglobina Glucada/efectos de los fármacos , Humanos , Inyecciones , Insulina Glargina/efectos adversos , Masculino , Persona de Mediana EdadRESUMEN
CONTEXT: Metastatic medullary thyroid cancer (MTC) is a rare malignancy with minimal treatment options. Many, but not all, MTCs express somatostatin receptors. OBJECTIVE: Our aim was to explore the role of 68Ga-DOTA-somatostatin analogue (SSA) positron emission tomography (PET)/computed tomography (CT) in patients with metastatic MTC and to determine their eligibility for peptide receptor radionuclide therapy (PRRT). METHODS: We retrospectively identified patients with metastatic MTC who had 68Ga-DOTA-SSA PET/CT at 5 centers. We collected characteristics on contrast-enhanced CT, 68Ga-DOTA-SSA and 18F-FDG PET/CT. The efficacy of PRRT was explored in a subgroup of patients. Kaplan-Meier analysis was used to estimate time to treatment failure (TTF) and overall survival (OS). RESULTS: Seventy-one patients were included (10 local recurrence, 61 distant disease). Of the patients with distant disease, 16 (26%) had ≥50% of disease sites with tracer avidity greater than background liver, including 10 (10/61, 16%) with >90%. In 19 patients with contemporaneous contrast-enhanced CT, no disease regions were independently identified on 68Ga-DOTA-SSA PET/CT. Thirty-five patients had an 18F-FDG PET/CT, with 18F-FDG positive/68Ga-DOTA-SSA negative metastases identified in 15 (43%). Twenty-one patients had PRRT with a median TTF of 14 months (95% CI 8-25) and a median OS of 63 months (95% CI 21-not reached). Of the entire cohort, the median OS was 323 months (95% CI 152-not reached). Predictors of poorer OS included a short calcitonin doubling-time (≤24 months), strong 18F-FDG avidity, and age ≥60 years. CONCLUSIONS: The prevalence of high tumor avidity on 68Ga-DOTA-SSA PET/CT is low in the setting of metastatic MTC; nevertheless, PRRT may still be a viable treatment option in select patients.