Liraglutide in the treatment of type 2 diabetes mellitus: clinical utility and patient perspectives

Type 2 diabetes mellitus (T2DM) is a progressive disease associated with significant morbidity and mortality. There is good evidence that intensive glycemic control reduces the development and progression of complications in patients with diabetes. In order to achieve glycemic targets, patients often require a combination of oral therapy and/or insulin in addition to lifestyle modification. Unfortunately many currently available therapies for T2DM are associated with weight gain and hypoglycemia resulting in poor compliance and subsequent worsening glycemic control. Glucagon like peptide-1 (GLP-1) is an incretin hormone secreted from the small intestine that lowers fasting and postprandial glucose through multiple mechanisms including glucose-dependent insulin secretion, reduction of glucagon secretion, delaying gastric emptying and increased satiety. Liraglutide is a long acting GLP-1 mimetic that is administered once a day by subcutaneous injection and is now licensed for the treatment of T2DM. Phase 3 clinical trials have demonstrated beneficial effects on glycemic control and weight with liraglutide therapy. Within this article, we provide an overview of pharmacology, efficacy, safety and patient experience on liraglutide in the management of T2DM

The Adaptive Nature of Impulsivity

An old joke circulates among animal behavior instructors. One can, the joke goes, divide the topics of animal behavior into four Fs: fighting, fleeing, feeding, and reproduction. This somewhat tired joke carries considerable truth. Animals behaving in nature surely must make decisions about conflicts, predator avoidance, feeding, and mating. Male crickets, for example, are notoriously combative. Studies have shown, however, that they escalate fights in some situations and retreat to fight another day in others (Beaugrand, 1997; Parker, 1974; Parker & Rubenstein, 1981). Squirrels, like many small animals, respond to the presence or absence of protective cover; for example, they will carry large food items into the safety of the bushes to consume them but eat small items immediately (Lima, Valone, & Caraco, 1985). Female widow birds prefer males with long tails, and evolutionary theorists have argued that tail length correlates with male quality (Andersson, 1982, 1994). So a female confronted with a short-tailed male faces a dilemma: mate now or keep looking. Notice that in all of these choice situations, time complicates the animal’s problem: Risk injury by fighting now or retreat to fight later; stay exposed to possible predation or invest time in moving to a safer place; settle for the short-tailed male or keep looking. Each of these situations, and indeed virtually any naturally occurring choice situation one can imagine, is an intertemporal choice problem. We define these as choice situations in which an animal’s alternatives vary in the time at which the animal realizes consequences and in the quality of those consequences once the animal secures them. Although intertemporal choice applies to many domains (and all four Fs), we need to focus on a specific situation to make scientific headway, and for virtually all behavioral ecologists interested in intertemporal choice that focal situation is foraging. We can observe animal foraging choices easily (e.g., animals eat more often than they reproduce), and we can manipulate the time and magnitude of foraging options much more easily than we can manipulate mate quality or predation risk. Moreover, we have a large base of theoretical and empirical results that help us frame the intertemporal choice problem in the context of animal foraging behavior. Foraging is not only a convenient topic but also a fundamentally important one; actively seeking food is a basic part of animal existence that deserves our attention. In the first part of this chapter, we focus on adaptive aspects of intertemporal choice in animal foraging behavior, and especially on the problem of impulsivity, which we see as a central problem in intertemporal choice. In the second part of this chapter, we take a broader perspective, including domains other than food and extending beyond impulsivity to a more encompassing view of intertemporal choice. Within this general view, we explore the adaptive nature of impulsivity

Discounting and Reciprocity in an Iterated Prisoner’s Dilemma

The Iterated Prisoner’s Dilemma (IPD) is a central paradigm in the study of animal cooperation. According to the IPD framework, repeated play (repetition) and reciprocity combine to maintain a cooperative equilibrium. However, experimental studies with animals suggest that cooperative behavior in IPDs is unstable, and some have suggested that strong preferences for immediate benefits (that is, temporal discounting) might explain the fragility of cooperative equilibria. We studied the effects of discounting and strategic reciprocity on cooperation in captive blue jays. Our results demonstrate an interaction between discounting and reciprocity. Blue jays show high stable levels of cooperation in treatments with reduced discounting when their opponent reciprocates, but their levels of cooperation decline in all other treatment combinations. This suggests that stable cooperation requires both reduced discounting and reciprocity, and it offers an explanation of earlier failures to find cooperation in controlled payoff games

Bariatric surgery is accompanied by changes in extracellular vesicle-associated and plasma Fatty Acid Binding Protein 4

BACKGROUND: Bariatric surgery markedly reduces fat mass with beneficial effects on cardiometabolic health but the mechanisms involved are not fully understood. Extracellular vesicles (EVs) are secreted by a variety of cells, including adipocytes, and may mediate some of these benefits. However, the effects of bariatric surgery on circulating EVs are unclear. METHODS: Concentration of plasma EVs isolated by ultracentrifugation at baseline, 1 and 6 months post-bariatric surgery (n = 20) was established using Nanoparticle Tracking Analysis. EV origin (CD9: exosome; CD41: platelet; CD235a: erythrocyte; CD11b: leukocyte; CD144: endothelial), cytokine (interferon γ, interleukin-6, TNF-α) and adipocyte marker (adiponectin, FABP4, PPARγ) expression was measured by time-resolved fluorescence immunoassay. RESULTS: EV concentration and cell-of-origin markers (CD41, CD235a, CD11b, CD144) did not alter in response to surgery, neither did EV-expressed interferon γ, IL-6, TNF-α, adiponectin, PPARγ or CD9. EV-derived fatty acid binding protein 4 (FABP4) increased at 1 month (+ 49%) before returning to baseline by 6 months (- 51%, p < 0.05), corresponding to similar changes in circulating plasma FABP4 (+ 22 and - 24% at 1 and 6 months, respectively; p < 0.001). Patients who underwent biliopancreatic diversion had lower FABP4-expressing EVs at 6 months compared to those who underwent sleeve gastrectomy/gastric banding (p < 0.05), despite similar percentage weight reduction (- 19 vs - 20%, respectively). CD9 expression correlated with EV-expressed FABP4, adiponectin, TNF-α and interferon γ (r = 0.5, r = 0.59, r = 0.53, r = 0.41, respectively, p < 0.005), suggesting transport by an EV population of exosomal rather than microvesicular origin. CONCLUSIONS: Bariatric surgery leads to a transient change in circulating EV- and plasma-derived FABP4, reflecting alterations in adipose tissue homeostasis

Complete Genome Sequences of Four Escherichia coli ST95 Isolates from Bloodstream Infections

Finished genome sequences are presented for four Escherichia coli strains isolated from bloodstream infections at San Francisco General Hospital. These strains provide reference sequences for four major fimH-identified sublineages within the multilocus sequence type (MLST) ST95 group, and provide insights into pathogenicity and differential antimicrobial susceptibility within this group

Genetic Susceptibility for Coronary Heart Disease and Type 2 Diabetes Complications

Type II diabetes (T2D) 3 represents a major public health challenge, with the WHO having estimated a current prevalence of 346 million worldwide. Cardiovascular disease, including coronary heart disease (CHD), stroke, and peripheral vascular disease, is one of the major complications of T2D, and the development of new strategies to tackle this problem is undoubtedly necessary. Although the association between diabetes and cardiovascular risk is well established, the pathologic basis of CHD in patients with T2D may differ from that in the general population. Whether this relationship has a genetic component is not fully understood. With regard to understanding the genetic basis of complex diseases, genomewide association studies (GWASs) have led to an unprecedented number of well-validated variants associated with complex diseases. There is now considerable interest in understanding both the mechanism by which these variants confer risk and whether the variants identified will be useful for predicting complex disease phenotypes. A recent report by Qi et al. (1 ) addressed 2 questions in this regard: (a) Are single-nucleotide polymorphisms (SNPs) identified by GWASs of CHD associated with the risk of CHD in T2D, and (b) can these variants be combined in a score that will aid prediction of CHD risk in T2D? In investigating these questions, Qi and coworkers genotyped 12 CHD susceptibility loci in 3 nested case-control studies of CHD in T2D: the Nurses&apos; Health Study, the Health Professional Follow-Up Study, and the Joslin Heart Study. As expected, the chromosome 9p21 CHD risk locus showed a strong association with CHD risk, whereas 4 other loci [PHACTR1 4 (phosphatase and ac- None of the other variants tested showed associations with CHD below the significance threshold (P ϭ 0.05), although the authors noted that 2 of the loci examined [MRAS (muscle RAS oncogene homolog) and KCNE2 (potassium voltage-gated channel, Isk-related family, member 2)] had summary effect sizes in the direction opposite to that described in previous reports. Although it may be tempting to speculate on the reasons for this result, the 95% CI for the summary odds ratios crosses the line of null effect, and the study had limited power to detect overall effects. Therefore, these results should be interpreted with caution. The authors then constructed a simple unweighted genetic risk score (GRS) based on the number of risk alleles carried (each individual will carry 0, 1, or 2 risk alleles at each locus) and assessed the performance of the GRS in predicting CHD. In common with other reports of studies that used a similar methodology, the discriminative performance of the GRS was modest (area under the ROC curve, 0.5782). Addition of the GRS to a panel of clinical risk factors did lead to a modest improvement in both the area under the ROC curve and the net reclassification index. Two important features that could have aided in discrimination but were not included in the clinical parameters are the duration of diabetes in patients who developed CHD and the age of diabetes diagnosis

Associations between metabolic syndrome components and markers of inflammation in Welsh school children

We investigated the multivariate dimensionality and strength of the relationship between metabolic syndrome (MetS) and inflammation in children. Caucasian school children (N = 229; 12-14 yr) from Wales were tested on several health indicators including measures of body composition, inflammation, fasting glucose regulation, blood pressure and lipids. The multivariate associationbetween MetS and inflammation was investigated via canonical correlation analysis. Data were corrected for non-normality by log transformation, and sex-specific z-scores computed for variables where there was a significant sex difference. Structure r’s were interpreted to determine the dimensions of MetS and inflammation responsible for significant canonical variates. The overallmultivariate association between MetS and inflammation was significant (Wilks’ Lambda = 0.54, p < 0.001). The relationship was explained primarily by the waist circumference dimension of MetS (CC = 0.87) and inflammatory markers of fibrinogen (CC = 0.52) and C-reactive protein (CC = 0.50). The pattern of results was similar regardless of whether variables were adjusted for sex differences.Conclusions: Central adiposity is the strongest predictor of the inflammatory aspect of cardiovascular disease risk in Caucasian adolescents. Future research into MetS and cardiometabolic risk should consider multivariate statistical approaches, in order to identify the separate contributions of each dimension in interrelationships and to identify which dimensions are influenced by preventive interventions