Glucagon-like peptide 1 (GLP-1).

BACKGROUND: The glucagon-like peptide-1 (GLP-1) is a multifaceted hormone with broad pharmacological potential. Among the numerous metabolic effects of GLP-1 are the glucose-dependent stimulation of insulin secretion, decrease of gastric emptying, inhibition of food intake, increase of natriuresis and diuresis, and modulation of rodent ß-cell proliferation. GLP-1 also has cardio- and neuroprotective effects, decreases inflammation and apoptosis, and has implications for learning and memory, reward behavior, and palatability. Biochemically modified for enhanced potency and sustained action, GLP-1 receptor agonists are successfully in clinical use for the treatment of type-2 diabetes, and several GLP-1-based pharmacotherapies are in clinical evaluation for the treatment of obesity. SCOPE OF REVIEW: In this review, we provide a detailed overview on the multifaceted nature of GLP-1 and its pharmacology and discuss its therapeutic implications on various diseases. MAJOR CONCLUSIONS: Since its discovery, GLP-1 has emerged as a pleiotropic hormone with a myriad of metabolic functions that go well beyond its classical identification as an incretin hormone. The numerous beneficial effects of GLP-1 render this hormone an interesting candidate for the development of pharmacotherapies to treat obesity, diabetes, and neurodegenerative disorders.

Anti-Obesity Therapy: from Rainbow Pills to Polyagonists.

With their ever-growing prevalence, obesity and diabetes represent major health threats of our society. Based on estimations by the World Health Organization, approximately 300 million people will be obese in 2035. In 2015 alone there were more than 1.6 million fatalities attributable to hyperglycemia and diabetes. In addition, treatment of these diseases places an enormous burden on our health care system. As a result, the development of pharmacotherapies to tackle this life-threatening pandemic is of utmost importance. Since the beginning of the 19th century, a variety of drugs have been evaluated for their ability to decrease body weight and/or to improve deranged glycemic control. The list of evaluated drugs includes, among many others, sheep-derived thyroid extracts, mitochondrial uncouplers, amphetamines, serotonergics, lipase inhibitors, and a variety of hormones produced and secreted by the gastrointestinal tract or adipose tissue. Unfortunately, when used as a single hormone therapy, most of these drugs are underwhelming in their efficacy or safety, and placebo-subtracted weight loss attributed to such therapy is typically not more than 10%. In 2009, the generation of a single molecule with agonism at the receptors for glucagon and the glucagon-like peptide 1 broke new ground in obesity pharmacology. This molecule combined the beneficial anorectic and glycemic effects of glucagon-like peptide 1 with the thermogenic effect of glucagon into a single molecule with enhanced potency and sustained action. Several other unimolecular dual agonists have subsequently been developed, and, based on their preclinical success, these molecules illuminate the path to a new and more fruitful era in obesity pharmacology. In this review, we focus on the historical pharmacological approaches to treat obesity and glucose intolerance and describe how the knowledge obtained by these studies led to the discovery of unimolecular polypharmacology.

The New Biology and Pharmacology of Glucagon.

In the last two decades we have witnessed sizable progress in defining the role of gastrointestinal signals in the control of glucose and energy homeostasis. Specifically, the molecular basis of the huge metabolic benefits in bariatric surgery is emerging while novel incretin-based medicines based on endogenous hormones such as glucagon-like peptide 1 and pancreas-derived amylin are improving diabetes management. These and related developments have fostered the discovery of novel insights into endocrine control of systemic metabolism, and in particular a deeper understanding of the importance of communication across vital organs, and specifically the gut-brain-pancreas-liver network. Paradoxically, the pancreatic peptide glucagon has reemerged in this period among a plethora of newly identified metabolic macromolecules, and new data complement and challenge its historical position as a gut hormone involved in metabolic control. The synthesis of glucagon analogs that are biophysically stable and soluble in aqueous solutions has promoted biological study that has enriched our understanding of glucagon biology and ironically recruited glucagon agonism as a central element to lower body weight in the treatment of metabolic disease. This review summarizes the extensive historical record and the more recent provocative direction that integrates the prominent role of glucagon in glucose elevation with its under-acknowledged effects on lipids, body weight, and vascular health that have implications for the pathophysiology of metabolic diseases, and the emergence of precision medicines to treat metabolic diseases.

Dietary triglycerides act on mesolimbic structures to regulate the rewarding and motivational aspects of feeding.

Circulating triglycerides (TGs) normally increase after a meal but are altered in pathophysiological conditions, such as obesity. Although TG metabolism in the brain remains poorly understood, several brain structures express enzymes that process TG-enriched particles, including mesolimbic structures. For this reason, and because consumption of high-fat diet alters dopamine signaling, we tested the hypothesis that TG might directly target mesolimbic reward circuits to control reward-seeking behaviors. We found that the delivery of small amounts of TG to the brain through the carotid artery rapidly reduced both spontaneous and amphetamine-induced locomotion, abolished preference for palatable food and reduced the motivation to engage in food-seeking behavior. Conversely, targeted disruption of the TG-hydrolyzing enzyme lipoprotein lipase specifically in the nucleus accumbens increased palatable food preference and food-seeking behavior. Finally, prolonged TG perfusion resulted in a return to normal palatable food preference despite continued locomotor suppression, suggesting that adaptive mechanisms occur. These findings reveal new mechanisms by which dietary fat may alter mesolimbic circuit function and reward seeking.

Estrogen, astrocytes and the neuroendocrine control of metabolism.

Obesity, and its associated comorbidities such as type 2 diabetes, cardiovascular diseases, and certain cancers, represent major health challenges. Importantly, there is a sexual dimorphism with respect to the prevalence of obesity and its associated metabolic diseases, implicating a role for gonadal hormones. Specifically, estrogens have been demonstrated to regulate metabolism perhaps by acting as a leptin mimetic in the central nervous system (CNS). CNS estrogen receptors (ERs) include ER alpha (ERα) and ER beta (ERß), which are found in nuclear, cytoplasmic and membrane sites throughout the brain. Additionally, estrogens can bind to and activate a G protein-coupled estrogen receptor (GPER), which is a membrane-associated ER. ERs are expressed on neurons as well as glia, which are known to play a major role in providing nutrient supply for neurons and have recently received increasing attention for their potentially important involvement in the CNS regulation of systemic metabolism and energy balance. This brief overview summarizes data focusing on the potential role of astrocytic estrogen action as a key component of estrogenic modulation responsible for mediating the sexual dimorphism in body weight regulation and obesity.

Continence following nerve-sparing radical prostatectomy.

Urinary incontinence after radical prostatectomy is a difficult postoperative problem and often is a major consideration in the selection of therapy for clinically localized disease. The occurrence of incontinence is unpredictable and the relationship of incontinence to operative technique is unclear. We compared urinary continence in 68 consecutive patients undergoing radical prostatectomy. In 34 patients nonnerve-sparing radical prostatectomy was performed and in 34 subsequent patients a nerve-sparing operation was done. Patient age, Gleason score and stage of the tumor, and operative time were not significantly different between the groups. In the nonnerve-sparing operated group there were 4 patients (12%) with total and 6 (18%) with stress incontinence requiring absorbent pads, compared to 0 and 2 (6%), respectively, in the nerve-sparing group. The postoperative functional urethral length in the nonnerve-sparing group was 1.9 +/- 0.6 cm. (standard deviation) and in the nerve-sparing group it was 2.3 +/- 0.5 cm., which was significantly different (p less than 0.05). The peak resting urethral pressure of the nonnerve-sparing group was 35.4 +/- 14.2 cm. water and in the nerve-sparing group it was 46.5 +/- 12.3 cm. water, which also was significantly different (p less than 0.05). The study indicates that preservation of the pelvic nerves during radical prostatectomy has a major role in the functional preservation of urinary continence.

Modified open renal biopsy. An experience with fifty consecutive cases.

Fifty consecutive patients underwent a modified open renal biopsy using bronchial forceps under general anesthesia. A small incision (2-3 cm) was made, and several small pieces of renal tissue (5-7) were excised in each case. Adequate tissue for diagnosis was obtained in 100% of the biopsies. Morbidity was minimal, and no deaths occurred as a result of biopsy. Traditionally, the open renal biopsy consists of a large incision (7-10 cm) with a deep wedge excision. It is significant that the modified technique provided a high tissue yield (the average number of glomeruli was 80) with few complications. This tissue yield was significantly higher than that usually seen with percutaneous needle biopsy.

Giant ectopic ureter presenting as abdominal mass in infant.

A case is presented of an abdominal mass created by massive ureteral dilation in an infant with VATER association. Curiously, only the terminal portion of the ureter was dilated.

Incidence of serum acid phosphatase elevation after transurethral prostatectomy.

Serum acid phosphatase levels were measured in 402 patients after transurethral resection of the prostate for benign adenoma. All patients had normal preoperative serum acid phosphatase levels (less than 0.8 IU/L) and the tissue specimen was histologically benign in all patients. Ninety-three patients (23%) showed normal postoperative serum acid phosphatase levels, while 309 (77%) showed postoperative elevation of serum acid phosphatase. One hundred forty-eight patients (37%) had postoperative levels higher than 5 IU/L. Significant elevation of serum acid phosphatase may follow transurethral prostate resection in patients having no evidence of malignancy.

Electrocardiograph voltage in fit young men.

Several criteria exist for the diagnosis for left ventricular hypertrophy as shown by high voltage on the electrocardiograph. This study of 200 healthy young recruits to the Royal Artillery with normal blood pressure and normal left ventricular wall thickness as measured by echocardiography [corrected] shows that no matter which criteria are used the false positive rate is approximately 25%. High voltage is a normal phenomenon in young men and its use as a predictor of left ventricular hypertrophy is likely to be misleading in this age group.

Neonatal genital trauma.

A neonate with severe scrotal ecchymosis resulting from a breech delivery is presented. The incidence, potential complications, and management are discussed.

Intraluminal antibiotic regimen for patients undergoing transrectal needle biopsy of prostate.

Twenty-five consecutive patients who had an abnormal prostate examination were subjected to transrectal biopsy of the prostate gland. The day prior to biopsy the patients were started on a modification of the Nichols-Condon bowel preparation utilizing only neomycin and erythromycin base. Although none of the patients became febrile, 3 patients had a positive post-biopsy blood culture (2 anaerobic and 1 aerobic). None of the 24 patients with a negative pre-biopsy urine culture had a positive post-biopsy culture. This regimen effectively reduces the reported incidence of both fever (95% confidence limit of 0 to 13.7% for the true proportion) and bacteremia (95% confidence limit of 2.6 to 31.2% for the true proportion).