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Metabolic-associated steatotic liver disease (MASLD) is closely associated with obesity. MASLD affects over 1 billion adults globally but there are few treatment options available. Glucagon is a key metabolic regulator, and its actions include the reduction of liver fat through direct and indirect means. Chronic glucagon signalling deficiency is associated with hyperaminoacidaemia, hyperglucagonaemia and increased circulating levels of glucagon-like peptide 1 (GLP-1) and fibroblast growth factor 21 (FGF-21). Reduction in glucagon activity decreases hepatic amino acid and triglyceride catabolism; metabolic effects include improved glucose tolerance, increased plasma cholesterol and increased liver fat. Conversely, glucagon infusion in healthy volunteers leads to increased hepatic glucose output, decreased levels of plasma amino acids and increased urea production, decreased plasma cholesterol and increased energy expenditure. Patients with MASLD share many hormonal and metabolic characteristics with models of glucagon signalling deficiency, suggesting that they could be resistant to glucagon. Although there are few studies of the effects of glucagon infusion in patients with obesity and/or MASLD, there is some evidence that the expected effect of glucagon on amino acid catabolism may be attenuated. Taken together, this evidence supports the notion that glucagon resistance exists in patients with MASLD and may contribute to the pathogenesis of MASLD. Further studies are warranted to investigate the direct effects of glucagon on metabolism in patients with MASLD. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Objective: Weight loss achieved with very-low-calorie diets (VLCDs) can produce remission of type 2 diabetes (T2D), but weight regain very often occurs with reintroduction of higher calorie intakes. In contrast, bariatric surgery produces clinically significant and durable weight loss, with diabetes remission that translates into reductions in mortality. We hypothesized that in patients living with obesity and prediabetes/T2D, longitudinal changes in brain activity in response to food cues as measured using functional MRI would explain this difference.Research Design and Methods: Sixteen participants underwent gastric bypass surgery, and 19 matched participants undertook a VLCD (meal replacement) for 4 weeks. Brain responses to food cues and resting-state functional connectivity were assessed with functional MRI pre- and postintervention and compared across groups.Results: We show that Roux-en-Y gastric bypass surgery (RYGB) results in three divergent brain responses compared with VLCD-induced weight loss: 1) VLCD resulted in increased brain reward center food cue responsiveness, whereas in RYGB, this was reduced; 2) VLCD resulted in higher neural activation of cognitive control regions in response to food cues associated with exercising increased cognitive restraint over eating, whereas RYGB did not; and 3) a homeostatic appetitive system (centered on the hypothalamus) is better engaged following RYGB-induced weight loss than VLCD.Conclusions: Taken together, these findings point to divergent brain responses to different methods of weight loss in patients with diabetes, which may explain weight regain after a short-term VLCD in contrast to enduring weight loss after RYGB. [ABSTRACT FROM AUTHOR]

Objective: Roux-en-Y gastric bypass (RYGB) is an established treatment for type 2 diabetes and obesity. The study objective was to establish RYGB's effects on glycemic variability (GV) and hypoglycemia.Research Design and Methods: This was a prospective observational study of 10 participants with obesity and prediabetes or type 2 diabetes who underwent RYGB. Patients were studied before RYGB (Pre) and 1 month, 1 year, and 2 years postsurgery with continuous glucose measurement (CGM). A mixed-meal test (MMT) was conducted at Pre, 1 month, and 1 year.Results: After RYGB, mean CGM decreased (at 1 month, 1 year, and 2 years), and GV increased (at 1 year and 2 years). Five of the 10 participants had a percent time in range (%TIR) <3.0 mmol/L (54 mg/dL) greater than the international consensus target of 1% at 1 or 2 years. Peak glucagon-like peptide-1 (GLP-1) and glucagon area under the curve during MMT were positively and negatively associated, respectively, with contemporaneous %TIR <3.0 mmol/L.Conclusions: Patients undergoing RYGB are at risk for development of postbariatric hypoglycemia due to a combination of reduced mean glucose, increased GV, and increased GLP-1 response. [ABSTRACT FROM AUTHOR]

We describe the case of a patient who presented with a right-sided glomus jugulare tumor and bilateral glomus vagale tumors. These proved to be nonmalignant paragangliomas on histopathological analysis. Genetic analysis revealed a germline heterozygous missense mutation (Pro81Leu) in the succinate dehydrogenase subunit D (SDHD) gene. We discuss the clinical presentations of the familial paraganglioma syndrome type 1, which is caused by mutations in SDHD, and the implications for the clinical diagnosis and care of such patients. [ABSTRACT FROM AUTHOR]

A caption is presented to photographs of a case study of the damage done to a young woman by a weight-loss cream containing toxic elements.

Objectives: Peptide tyrosine tyrosine (PYY) exists as two species, PYY 1-36 and PYY 3-36 , with distinct effects on insulin secretion and appetite regulation. The detailed effects of bariatric surgery on PYY 1-36 and PYY 3-36 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 PYY 1-36 and PYY 3-36 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 PYY 1-36 and PYY 3-36 concentrations., Results: Presurgery, the fasting and postprandial levels of PYY 1-36 and PYY 3-36 were low, with minimal responses to the MMT, and these did not differ from healthy nonobese volunteers. The postprandial secretion of both PYY 1-36 and PYY 3-36 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 PYY 1-36 and PYY 3-36 , which may account for long-term differences in efficacy and adverse effects between the two types of surgery., (© 2022 The Authors. Clinical Endocrinology published by John Wiley & Sons Ltd.)

Introduction: With obesity rates growing globally, there is a paramount need for new obesity pharmacotherapies to tackle this pandemic., Areas Covered: This review focuses on the design of therapeutics that target the glucose-dependent insulinotropic polypeptide receptor (GIPR) to aid weight loss. The authors highlight the paradoxical observation that both GIPR agonism and antagonism appear to provide metabolic benefits when combined with glucagon-like peptide-1 receptor (GLP-1 R) agonism. The therapeutic potential of compounds that target the GIPR alongside the GLP-1 R and the glucagon receptor are discussed, and the impressive clinical findings of such compounds are reviewed., Expert Opinion: In this area, the translation of pre-clinical findings to clinical studies appears to be particularly difficult. Well-designed physiological studies in man are required to answer the paradox highlighted above, and to support the safe future development of a combination of GLP-1 R/GIPR targeting therapies.

Glucagon analogs show promise as components of next-generation, multi-target, anti-obesity therapeutics. The biology of chronic glucagon treatment, in particular, its ability to induce energy expenditure and weight loss, remains poorly understood. Using a long-acting glucagon analog, G108, we demonstrate that glucagon-mediated body weight loss is intrinsically linked to the hypoaminoacidemia associated with its known amino acid catabolic action. Mechanistic studies reveal an energy-consuming response to low plasma amino acids in G108-treated mice, prevented by dietary amino acid supplementation and mimicked by a rationally designed low amino acid diet. Therefore, low plasma amino acids are a pre-requisite for G108-mediated energy expenditure and weight loss. However, preventing hypoaminoacidemia with additional dietary protein does not affect the ability of G108 to improve glycemia or hepatic steatosis in obese mice. These studies provide a mechanism for glucagon-mediated weight loss and confirm the hepatic glucagon receptor as an attractive molecular target for metabolic disease therapeutics., Competing Interests: Declaration of interests J.S.M., T.M.M.T., and S.R.B. are employees and/or shareholders in Zihipp, Ltd., which is developing gut hormone analogs for treatment of metabolic disease. T.A.L. has a collaboration with Novo Nordisk that is unrelated to the work presented here., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

Bile acids (BA) regulate postprandial metabolism directly and indirectly by affecting the secretion of gut hormones like glucagon-like peptide-1 (GLP-1). The postprandial effects of BA on the secretion of other metabolically active hormones are not well understood. The objective of this study was to investigate the effects of oral ursodeoxycholic acid (UDCA) and chenodeoxycholic acid (CDCA) on postprandial secretion of GLP-1, oxyntomodulin (OXM), peptide YY (PYY), glucose-dependent insulinotropic peptide (GIP), glucagon, and ghrelin. Twelve healthy volunteers underwent a mixed meal test 60 min after ingestion of UDCA (12-16 mg/kg), CDCA (13-16 mg/kg), or no BA in a randomized crossover study. Glucose, insulin, GLP-1, OXM, PYY, GIP, glucagon, ghrelin, and fibroblast growth factor 19 were measured prior to BA administration at -60 and 0 min (just prior to mixed meal) and 15, 30, 60, 120, 180, and 240 min after the meal. UDCA and CDCA provoked differential gut hormone responses; UDCA did not have any significant effects, but CDCA provoked significant increases in GLP-1 and OXM and a profound reduction in GIP. CDCA increased fasting GLP-1 and OXM secretion in parallel with an increase in insulin. On the other hand, CDCA reduced postprandial secretion of GIP, with an associated reduction in postprandial insulin secretion. Exogenous CDCA can exert multiple salutary effects on the secretion of gut hormones; if these effects are confirmed in obesity and type 2 diabetes, CDCA may be a potential therapy for these conditions. NEW & NOTEWORTHY Oral CDCA and UDCA have different effects on gut and pancreatic hormone secretion. A single dose of CDCA increased fasting secretion of the hormones GLP-1 and OXM with an accompanying increase in insulin secretion. CDCA also reduced postprandial GIP secretion, which was associated with reduced insulin. In contrast, UDCA did not change gut hormone secretion fasting or postprandially. Oral CDCA could be beneficial to patients with obesity and diabetes.

Obesity, defined by a body mass index greater than 30kg/m(2), claims an increasing number of lives every year, underscoring a dire need for effective therapeutic interventions. The origins of the obesity epidemic are complex, but commonly cited factors include the large quantities of calorie-rich food that are readily accessible in modern society; eating habits adapted to fast-paced lifestyles; low levels of physical activity; and genetic programs that have evolved, especially in populations prone to famine, to favor the storage of excess calories (i.e., the thrifty-gene theory). It is estimated that more than thirty percent of adults, and about fifteen percent of juveniles, are obese. These high rates have led to dramatic increases in diseases such as type 2 diabetes, cardiovascular and respiratory diseases, depression, and some forms of cancer.

Vitamin D deficiency and insufficiency may further increase fracture risk in patients with decreased bone mineral density. We audited serum 25-hydroxyvitamin D (25OHD) concentrations in patients with osteopenia or osteoporosis attending endocrine osteoporosis clinics in North London between January 1998 and September 2001. The total number of patients analyzed was 448 (age range 17-89 years), with 191 patients being < 50 years old (42.6%). The following cut-off points for serum 25OHD were used: levels < or = 30 nmol/L for deficiency, > 30-50 nmol/L for insufficiency, and > 50 nmol/L for sufficiency. The overall prevalence of vitamin D deficiency was 30.5% and of vitamin D insufficiency was 35.9%. Vitamin D deficiency was as prevalent in young patients as in older ones: the prevalence of serum 25OHD < or = 30 nmol/L in those < 50 years of age was 33.0% (n = 63 of 191), compared with 31.1% (n = 80 of 257) in patients aged > or = 50 years. Our results indicate that vitamin D deficiency and insufficiency is a common problem in patients with osteopenia or osteoporosis. This situation persists despite dietary advice and prescription of vitamin D3 supplementation. Vitamin D deficiency affects all age groups, not merely the elderly.