Metformin is the most commonly used treatment to increase insulin sensitivity in insulin-resistant (IR) conditions such as diabetes, prediabetes, polycystic ovary syndrome, and obesity. There is a ...well-documented correlation between glucose transporter 4 (GLUT4) expression and the level of IR. Therefore, the observed increase in peripheral glucose utilization after metformin treatment most likely comes from the induction of GLUT4 expression and its increased translocation to the plasma membrane. However, the mechanisms behind this effect and the critical metformin targets are still largely undefined. The present review explores the evidence for the crucial role of changes in the expression and activation of insulin signaling pathway mediators, AMPK, several GLUT4 translocation mediators, and the effect of posttranscriptional modifications based on previously published preclinical and clinical models of metformin's mode of action in animal and human studies. Our aim is to provide a comprehensive review of the studies in this field in order to shed some light on the complex interactions between metformin action, GLUT4 expression, GLUT4 translocation, and the observed increase in peripheral insulin sensitivity.
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Polycystic ovary syndrome (PCOS) is the most common endocrine and metabolic disorder in women of reproductive age. Its heterogeneous clinical presentation is characterized by hyperandrogenemia, ...reproductive changes, polycystic ovary morphology, and insulin resistance (IR). The primary pathophysiological process in its multifactorial etiology has not yet been identified. However, the two most proposed core etiologies are the disruption of insulin metabolism and hyperandrogenemia, both of which begin to intertwine and propagate each other in the later stages of the disease. Insulin metabolism can be viewed as the interconnectedness of beta cell function, IR or insulin sensitivity, and insulin clearance. Previous studies of insulin metabolism in PCOS patients have yielded conflicting results, and literature reviews have focused mainly on the molecular mechanisms and clinical implications of IR. In this narrative review, we comprehensively explored the role of insulin secretion, clearance, and decreased sensitivity in target cells as a potential primary insult in PCOS pathogenesis, along with the molecular mechanism behind IR in PCOS.
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Obesity, primarily characterized by excessive fat accumulation, is a multifactorial chronic disease with an increasing global prevalence. Despite the well-documented epidemiology and significant ...advances in understanding its pathophysiology and clinical implications, the impact of sex is typically overlooked in obesity research. Worldwide, women have a higher likelihood to become obese compared to men. Although women are offered weight loss interventions more often and at earlier stages than men, they are more vulnerable to psychopathology. Men, on the other hand, are less likely to pursue weight loss intervention and are more susceptible to the metabolic implications of obesity. In this narrative review, we comprehensively explored sex- and gender-specific differences in the development of obesity, focusing on a variety of biological variables, such as body composition, fat distribution and energy partitioning, the impact of sex steroid hormones and gut microbiota diversity, chromosomal and genetic variables, and behavioural and sociocultural variables influencing obesity development in men and women. Sex differences in obesity-related comorbidities and varying effectiveness of different weight loss interventions are also extensively discussed.
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Preclinical studies provided some important insights into the action of glucagon-like peptide 1 (GLP-1) in taste perception. This review examines the literature to uncover some molecular mechanisms ...and connections between GLP-1 and the gustatory coding. Local GLP-1 production in the taste bud cells, the expression of GLP-1 receptor on the adjacent nerves, a functional continuum in the perception of sweet chemicals from the gut to the tongue and an identification of GLP-1 induced signaling pathways in peripheral and central gustatory coding all strongly suggest that GLP-1 is involved in the taste perception, especially sweet. However, the impact of GLP-1 based therapies on gustatory coding in humans remains largely unaddressed. Based on the molecular background we encourage further exploration of the tongue as a new treatment target for GLP-1 receptor agonists in clinical studies. Given that pharmacological manipulation of gustatory coding may represent a new potential strategy against obesity and diabetes, the topic is of utmost clinical relevance.
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Adipose tissue can be divided into white adipose tissue (WAT), brown adipose tissue (BAT), and beige adipose tissue, according to the differences in morphology. WAT acts as a buffer for increased ...energy intake and decreased energy expenditure during the development of obesity, resulting in visceral and ectopic WAT accumulation. These WAT depots are strongly associated with chronic systemic inflammation, insulin resistance, and cardiometabolic risk related to obesity. They represent a primary weight loss target in anti-obesity management. Second-generation anti-obesity medications glucagon-like peptide-1 receptor agonists (GLP-1RAs) cause weight loss and improve body composition by reducing visceral and ectopic fat depots of WAT, resulting in improved cardiometabolic health. Recently, the understanding of the physiological significance of BAT beyond its primary function in generating heat through non-shivering thermogenesis has been expanded. This has raised scientific and pharmaceutical interest in the manipulation of BAT to further enhance weight reduction and body weight maintenance. This narrative review focuses on the potential impact of GLP-1 receptor agonism on BAT, particularly in human clinical studies. It provides an overview of the role of BAT in weight management and highlights the need for further research to elucidate the mechanisms by which GLP-1RAs affect energy metabolism and weight loss. Despite encouraging preclinical data, limited clinical evidence supports the notion that GLP-1RAs contribute to BAT activation.
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Withdrawal of semaglutide is frequently followed by weight regain due to compensatory biological changes that prevent the maintenance of long-term weight loss. There are some studies implying that ...metformin might attenuate weight regain. The weight trajectory after discontinuation of short-term semaglutide treatment in obese women with PCOS who continued metformin treatment has not yet been evaluated.
We explored changes in body weight, cardiometabolic and endocrine parameters in obese women with PCOS who continued treatment with metformin 2 years after discontinuation of short-term intervention with semaglutide.
25 women with PCOS and obesity, aged 33.7 ± 5.3 years (mean ± SD), were treated with once-weekly subcutaneous semaglutide 1.0 mg as an adjunct to metformin 2000 mg/day and lifestyle intervention for 16 weeks. At week 16, semaglutide was discontinued. Treatment with metformin 2000 mg/day and promotion of lifestyle intervention were continued during the 2-year follow-up period. Weight change, cardiometabolic, and endocrine parameters were assessed 2 years after semaglutide discontinuation.
During semaglutide treatment phase, weight decreased from 101 (90-106.8) kg to 92 (83.3-100.8) kg. Two years after semaglutide withdrawal, weight was 95 (77-104) kg. The net weight loss 2 years after discontinuation of semaglutide remained significant when compared to baseline (p=0.003). At the end of the study, 21 out of 25 subjects had lower body weight compared to baseline. Improvements in cardiometabolic parameters including decrease in total and LDL cholesterol, fasting glucose, and glucose after OGTT that had been seen during semaglutide-treatment phase reverted towards baseline two years after semaglutide cessation. Free testosterone levels significantly decreased during semaglutide treatment from 6.16 (4.07-9.71) to 4.12 (2.98-6.93) nmol/l, (p= 0.012) and did not significantly deteriorate after semaglutide discontinuation.
Two years after semaglutide withdrawal, women with PCOS who continued with metformin regained about one-third of the semaglutide-induced weight loss. At the end of the follow up, 84% of women had a lower body weight than at baseline.
ObjectiveThe effect of metformin on weight reduction in polycystic ovary syndrome (PCOS) is often unsatisfactory. In this study, we investigated the potential add-on effect of treatment with the ...glucagon-like peptide-1 receptor agonist liraglutide on weight loss in obese nondiabetic women with PCOS who had lost <5% body weight during pretreatment with metformin.MethodsA total of 40 obese women with PCOS, who had been pretreated with metformin for at least 6 months, participated in a 12-week open-label, prospective study. They were randomized to one of three treatment arms: metformin (MET) arm 1000 mg BID, liraglutide (LIRA) arm 1.2 mg QD s.c., or combined MET 1000 mg BID and LIRA (COMBI) 1.2 mg QD s.c. Lifestyle intervention was not actively promoted. The primary outcome was change in body weight.ResultsThirty six patients (aged 31.3±7.1 years, BMI 37.1±4.6 kg/m2) completed the study: 14 on MET, 11 on LIRA, and 11 on combined treatment. COMBI therapy was superior to LIRA and MET monotherapy in reducing weight, BMI, and waist circumference. Subjects treated with COMBI lost on average 6.5±2.8 kg compared with a 3.8±3.7 kg loss in the LIRA group and a 1.2±1.4 kg loss in the MET group (P<0.001). The extent of weight loss was stratified: a total of 38% of subjects were high responders who lost ≥5% body weight, 22% of them in the COMBI arm compared with 16 and 0% in the LIRA and MET arm respectively. BMI decreased by 2.4±1.0 in the COMBI arm compared with 1.3±1.3 in LIRA and 0.5±0.5 in the MET arm (P<0.001). Waist circumference also decreased by 5.5±3.8 cm in the COMBI arm compared with 3.2±2.9 cm in LIRA and 1.6±2.9 cm in the MET arm (P=0.029). Subjects treated with liraglutide experienced more nausea than those treated with metformin, but severity of nausea decreased over time and did not correlate with weight loss.ConclusionsShort-term combined treatment with liraglutide and metformin was associated with significant weight loss and decrease in waist circumference in obese women with PCOS who had previously been poor responders regarding weight reduction on metformin monotherapy.
Abstract Background The escalating prevalence of adrenal incidentaloma (AI) has been associated with the improvement of radiologic techniques and widespread imaging in aging population. It is ...currently unclear whether patients with obesity more likely develop AI and the current rise in the prevalence of AI could be at least partly associated with the respective rise in obesity. We compared the prevalence and characteristics of non-functional (NF) and autonomous cortisol secreting (ACS) adrenal incidentalomas (AIs) after the study population was stratified by different body mass indexes (BMI) and age groups. Methods Retrospective cross-sectional study comprising of 432 patients (40.6% male, 59.4% female) with NFAI ( N = 290) and ACS ( N = 142), of median age 63.4 (54.0–71.6) years and median BMI 28.6 (25.5–31.7) kg/m 2 . The data collection contained 11.132 points including demographic, anthropometric, radiologic, hormonal and metabolic parameters. Results We observed 68–87% higher prevalence of AI across different age groups in NFAI and ACS in obese/overweight compared to normal weight subjects. Patients with ACS were older ( P = 0.008), with higher basal cortisol ( P < 0.001), lower basal DHEAS ( P = 0.001), lower suppression DHEAS ( P = 0.027) and higher aldosterone ( P = 0.039). AIs with ACS were larger than NFAI ( P < 0.001). Interestingly, ACS group had lower body mass ( P = 0.023) and did not differ in BMI, blood pressure, heart rate, lipid profile, fasting glucose and presence of diabetes mellitus type 2 when compared to NFAI., By contrast to the similarity of metabolic profiles in ACS and NFAI, some components of adverse metabolic traits were rather associated with higher BMI and older age, in particular in NFAI. Conclusion The prevalence of NFAI and ACS were significantly higher in overweight/obese subgroup across the age distribution. Stratification by age and BMI displayed significant differences in some metabolic traits, in particular in NFAI.
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