Pharmacological Management of Obesity: A Century of Expert Opinions in Cecil Textbook of Medicine.

BACKGROUND: Innovations in drug therapy for obesity have had a limited impact on the body mass index, prevalence of medical complications, quality of life, and work potential of a substantial majority of affected persons. STUDY QUESTION: What are the milestones of the changes in the expert approach to the pharmacological management of obesity in the past century? STUDY DESIGN: To determine the changes in the experts' approach to the management of obesity, as presented in a widely used textbook in the United States. DATA SOURCES: The primary sources were chapters describing the management of obesity in the 26 editions of Cecil Textbook of Medicine published from 1927 through 2020. Secondary sources were publications retrieved from Medline that clarified technical issues related to the development, regulatory approval, and use of the drugs mentioned in the Cecil Textbook of Medicine. RESULTS: Pharmacological interventions aimed at increasing caloric expenditures through thermogenesis were recommended from 1927 through 1943. Thyroid extracts were prescribed even in the absence of demonstrated hypothyroidism or decreased basal metabolic rate throughout this period. Dinitrophenol was mentioned in 1937, but was banned soon thereafter. Appetite suppression with amphetamine was considered useful from 1943 through 1988, after which the drug was replaced with other centrally acting molecules, such as fenfluramine in 1988, sibutramine in 2000, and rimonabant in 2008, which were in turn withdrawn because of major adverse effects. In the past decade, obesity has been treated with the appetite suppressants phentermine-topiramate, bupropion-naltrexone, lorcaserin, and liraglutide, and with orlistat, a drug promoting fat malabsorption. The change in weight produced by these drugs is generally modest and transient. CONCLUSIONS: The pharmacological management of obesity has remained frustratingly inefficient. The reasons for the relative lack of success may reside in the ever-growing access to dense, palatable, and relatively inexpensive food, coupled with the decrease in energy expenditure created by a sedentary lifestyle.

Involvement of Ceramides in Non-Alcoholic Fatty Liver Disease (NAFLD) Atherosclerosis (ATS) Development: Mechanisms and Therapeutic Targets.

Non-alcoholic fatty liver disease (NAFLD) and atherosclerosis (ATS) are worldwide known diseases with increased incidence and prevalence. These two are driven and are interconnected by multiple oxidative and metabolic functions such as lipotoxicity. A gamut of evidence suggests that sphingolipids (SL), such as ceramides, account for much of the tissue damage. Although in humans they are proving to be accurate biomarkers of adverse cardiovascular disease outcomes and NAFLD progression, in rodents, pharmacological inhibition or depletion of enzymes driving de novo ceramide synthesis prevents the development of metabolic driven diseases such as diabetes, ATS, and hepatic steatosis. In this narrative review, we discuss the pathways which generate the ceramide synthesis, the potential use of circulating ceramides as novel biomarkers in the development and progression of ATS and related diseases, and their potential use as therapeutic targets in NAFDL-ATS development which can further provide new clues in this field.

Role of Gut Microbiota on Onset and Progression of Microvascular Complications of Type 2 Diabetes (T2DM).

Type 2 diabetes mellitus (T2DM) remains one of the most problematic and economic consumer disorders worldwide, with growing prevalence and incidence. Over the last years, substantial research has highlighted the intricate relationship among gut microbiota, dysbiosis and metabolic syndromes development. Changes in the gut microbiome composition lead to an imbalanced gastrointestinal habitat which promotes abnormal production of metabolites, inflammatory status, glucose metabolism alteration and even insulin resistance (IR). Short-chain fatty acids (SCFAs), trimethylamine N-oxide (TMAO), lipopolysaccharide, aromatic amino acids and their affiliated metabolites, contribute to T2DM via different metabolic and immunologic pathways. In this narrative review, we discuss the immunopathogenic mechanism behind gut dysbiosis, T2DM development and the major known diabetic microvascular complications (retinopathy, neuropathy and nephropathy), the beneficial use of pre- and pro-biotics and fecal microbiota transplantation in T2DM management and new findings and future perspectives in this field.

The Intricate Relationship between Type 2 Diabetes Mellitus (T2DM), Insulin Resistance (IR), and Nonalcoholic Fatty Liver Disease (NAFLD).

Nonalcoholic fatty liver disease (NAFLD) and type 2 diabetes mellitus (T2DM) remain as one of the most global problematic metabolic diseases with rapidly increasing prevalence and incidence. Epidemiological studies noted that T2DM patients have by two-fold increase to develop NAFLD, and vice versa. This complex and intricate association is supported and mediated by insulin resistance (IR). In this review, we discuss the NAFLD immunopathogenesis, connection with IR and T2DM, the role of screening and noninvasive tools, and mostly the impact of the current antidiabetic drugs on steatosis liver and new potential therapeutic targets.

The Predictive Role of the Biomarker Kidney Molecule-1 (KIM-1) in Acute Kidney Injury (AKI) Cisplatin-Induced Nephrotoxicity.

Acute kidney injury (AKI) following platinum-based chemotherapeutics is a frequently reported serious side-effect. However, there are no approved biomarkers that can properly identify proximal tubular injury while routine assessments such as serum creatinine lack sensitivity. Kidney-injury-molecule 1 (KIM-1) is showing promise in identifying cisplatin-induced renal injury both in vitro and in vivo studies. In this review, we focus on describing the mechanisms of renal tubular cells cisplatin-induced apoptosis, the associated inflammatory response and oxidative stress and the role of KIM-1 as a possible biomarker used to predict cisplatin associated AKI.

Left Ventricular Diastolic Dysfunction in Type 2 Diabetes-Progress and Perspectives.

In-depth understanding of early cardiovascular manifestations in diabetes is high on international research and prevention agendas given that cardiovascular events are the leading cause of death for diabetic patients. Our aim was to review recent developments in the echocardiographic assessment of left ventricular diastolic dysfunction (LVDD) as a telltale pre-clinical disturbance preceding diabetic cardiomyopathy. We analyzed papers in which patients had been comprehensively assessed echocardiographically according to the latest LVDD guidelines (2016), and those affording comparisons with previous, widely used recommendations (2009). We found that the updated algorithm for LVDD is more effective in predicting adverse cardiovascular events in patients with established LVDD, and less specific in grading other patients (labelled "indeterminate"). This may prove instrumental for recruiting "indeterminate" LVDD cases among patients with type 2 diabetes mellitus (T2DM) in future screening programs. As an interesting consideration, the elevated values of the index E/e' can point to early diastolic impairment, foretelling diabetic cardiomyopathy. Identifying subclinical signs early makes clinical sense, but the complex nature of T2DM calls for further research. Specifically, longitudinal studies on rigorously selected cohorts of diabetic patients are needed to better understand and predict the subtle, slow onset of cardiac manifestations with T2DM as a complicating backdrop.

Pathological aspects underlying pancreatogenous hyperinsulinemic hypoglycemia--report of three cases.

Pancreatogenous hyperinsulinemic hypoglycemia (PHH) is a rare disorder determined by an abnormally high secretion of insulin in the pancreas, in the absence of other medical or pharmacological factors. Either ß-cell tumors (insulinomas) or ß-cell hyperplasia (nesidioblastosis) can determine this pathology. Most publications on insulinomas or nesidioblastosis approached these subjects from a clinical point of view. This paper aims to analyze pathological aspects underlying pancreatogenous hyperinsulinemic hypoglycemia. We present two cases of insulinomas with unusual pancreatic localization and size, one of them showing amyloid deposits in the stroma. In both cases, immunohistochemistry confirmed the clinical and imagistic supposition. The third reported case refers to a 57-year-old patient with nesidioblastosis with isolated disposition of endocrine cells and areas of focal organization, both morphological aspects being extremely rare in adults. Although clinical and laboratory data are usually identical in the two forms of PHH, histopathological and immunohistochemical diagnosis is essential in differentiating insulinomas from nesidioblastosis, as the surgical management is different: enucleation for insulinomas and total or subtotal pancreatectomy for nesidioblastosis.

Insulin resistance and adipokine levels correlate with early atherosclerosis - a study in prediabetic patients.

Cardiovascular risk of prediabetes is still subject to controversies. We analyzed the associations between insulin resistance, adipokines and incipient atherosclerosis estimated by intima-media thickness (IMT) in a cross-sectional study on 122 prediabetic subjects without clinical signs of atherosclerotic disease. Homeostasis model assessment of insulin resistance (HOMA-IR, calculated as fasting insulin × fasting plasma glucose / 22.5), adiponectin, leptin, leptin-to-adiponectin ratio, carotid and femoral IMT were evaluated. We also assessed other parameters related to insulin resistance and adipokines (HbA1c, anthropometric and lipid parameters), as they may also influence atherosclerosis. Carotid IMT was correlated to adiponectin and leptin-to-adiponectin ratio (all p < 0.05), but not with HOMA-IR or leptin, while femoral IMT showed no relationship with these factors. After adjusting for leptin, leptin-to-adiponectin ratio, triglycerides, HDL-cholesterol, cholesterol-to-HDL ratio, triglycerides-to-HDL ratio and HbA1c, IMT values became correlated with HOMA-IR. Adjustment for HOMA-IR induced the appearance of new correlations between adipokines and both IMT values. In conclusion, insulin resistance and adipokines seem related to IMT in prediabetic subjects without clinical signs of arterial obstruction.