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Obesity treatment: novel peripheral targets
British Journal of Clinical Pharmacology
Abstract
Our knowledge of the complex mechanisms underlying energy homeostasis has expanded enormously in recent years. Food intake and body weight are tightly regulated by the hypothalamus, brainstem and reward circuits, on the basis both of cognitive inputs and of diverse humoral and neuronal signals of nutritional status. Several gut hormones, including cholecystokinin, glucagon-like peptide-1, peptide YY, oxyntomodulin, amylin, pancreatic polypeptide and ghrelin, have been shown to play an important role in regulating short-term food intake. These hormones therefore represent potential targets in the development of novel anti-obesity drugs. This review focuses on the role of gut hormones in short- and long-term regulation of food intake, and on the current state of development of gut hormone-based obesity therapies.
... Treatments for obesity are limited due to the complexity of the disease. Diet and physical activity are effective but adherence is needed 26 . Behavioral therapy, physical activity, stress management, stimulus control, problem solving, cognitive restructuring, contingency management, and social support are effective too. ...
... We evaluated 131 patients (78 non-diabetic patients and 53 diabetic), 37 patients BMI ≤ 35 (3 BMI < 25, 18 9,[16][17][18][19][20][21][22][23][24][25][26][27][28][29][30][31][32][33][34]9) and 94 patients BMI ≥ 35 (81 BMI 35-49,9 and 13 BMI ≥ 50). We analyzed BMI, gender, presence of diabetes and its time of evolution. ...
... Tailored BAGUA 18,31 consisted in the construction of a gastric pouch from the gastroesophageal junction to the end of the minor gastric curvature at the lower level of the cisura angularis. The stapler line of the gastric pouch was fixed approximately 12 cm to the intestinal loop (first layer of the anti-reflux mechanism of BAGUA), and it was anastomosed in a laterolateral position to the mesenteric border of a small bowel loop 100 cm (BMI [23][24][25][26][27][28][29], 120 cm (BMI 30-32), 150 cm (BMI 33-34), 200 cm (BMI 35-40), 250 cm (BMI 40-45), and 280 cm distal (BMI 45-50) to the treitz ligament. The anti-reflux mechanism is completed fixing the afferent loop to the gastric remnant and the efferent loop to the antrum. ...
Introduction:
Obesity and diabetes are diseases with high prevalence worldwide. There is currently no effective medical treatment for combat the weight gain. It is precursor of diseases such as diabetes or metabolic syndrome. It is necessary to know if weight gain has cumulative effects on the glycemic and lipid metabolism as precursors of complications or comorbidities.
Patients and methods:
We studied 131 patients (78 nondiabetic and 53 diabetic), 37 BMI ≤35 (3 BMI < 25, 18 BMI 25-29.9, 16 BMI 30-34.9) and 94 BMI ≥35 (81 BMI 35-49.9 and 13 BMI ≥50).We analyzed BMI, gender, diabetes and the time of evolution. Lipid profile, glucose, HbA1c and C-peptide evaluated after 12-hour fasting.
Results:
Diabetic and diabese patients showed high triglycerides. Non-diabetics have impaired glucose (58% BMI < 35 and 36% BMI > 35). The 20% of non-diabetics BMI < 35 had high C-peptide, and 19% of BMI > 35 had high levels. The 5% of diabetics BMI < 35 had low Cpeptide and 36% of BMI > 35 had high levels. HbA1c was higher in 40% of non-diabetic patients BMI < 35 compared to 13% BMI > 35.
Conclusions:
Glucose and triglycerides increase with age and years of development of T2DM. Age of 51 and more, and men are more affected. The weight increase has cumulative effect by altering the metabolism favoring the onset of diabetes and comorbidities. Despite having intensive control treatment of diabetes, it continues its deleterious effects on patients through the years.
... Four fatty acids were selected to study the effects of saturation, cis and trans configurations C18:1,cis-9 and C18:1,trans-9, and chain lengths C18:0 and C16:0. The following acylaminoethanolamides were synthesized and purified: oleoyl-L-valinolamide (1), oleoyl-D-valinolamide (2), elaidoyl-L-valinolamide (3), elaidoyl-D-valinolamide (4), stearoyl-L-valinolamide (5), and palmitoyl-L-valinolamide (6). These compounds were tested for their effects on food consumption, body weight, activity, cognitive function, neurological score, glucose levels, liver enzymes, histopathology, and survival. ...
... Following solvent evaporation the resultant mixtures were applied to silica column chromatography (dichloromethane/ethyl acetate, 1:1, v/v). The products obtained ranged from a viscous oily state in the case of oleoyl-L-valinolamide (1) to solid in the case of stearoyl-L-valinolamide (6) in yields of 65−90%. ...
... To evaluate the effect of the tested compounds on orexigenic and anorexigenic pathways in the hypothalamus, real time PCR experiments were performed. The results demonstrated that among the four weight reducing compounds oleoyl-L-valinolamide (1), oleoyl-D-valinolamide (2), stearoyl-L-valinolamide (5), and palmitoyl-L-valinolamide (6), only the actions of 1 (p < 0.01), 2, and 5 (p < 0.05) are probably mediated through the POMC cascade (Table 6) and partially by the CART pathway (compounds 1 and 2 (Table 6), p < 0.05). Down-regulation of NPY mRNA ( Table 6) was initiated by compounds 1, 5, and 6, probably impairing the ghrelin signaling pathway of starvation. ...
ABSTRACT Newly synthesized acylethanolamide derivatives: oleoyl-L-valinolamide (1), oleoyl-D-valinolamide (2), elaidoyl-L-valinolamide (3), elaidoyl-D-valinolamide (4) stearoyl-L-valinolamide (5) and palmitoyl-L-valinolamide (6) were investigated in mice as anti-obesity compounds. Compounds 1, 2, 5, 6 significantly decreased body weight by c6.57% following 8 injections of 1mg/kg i.p. during 39 days, while 3 and 4 showed no such activity. Receptor binding indicated that no compound activated CB1, CB2, PPARα or TRPV1 receptors. Hypothalamic RT-PCR showed that mRNA expression of the anorexigenic genes POMC and CART were upregulated by 1, 2, 5 and 1, 2 respectively, while those of the orexigenic genes: NPY and CaMKK2 were downregulated by the respective compounds 1, 5, 6 and 1, 2, 5. Oleoyl-L-valinolamide (1) enhances anorectic pathways and lead to decreased glucose levels, enhanced locomotor activity and improved cognition. Effects of oleoyl-L-valinolamide (1) on weight were dose-dependent and it could be given orally. 1, 2, 4, 5 down regulated FAAH mRNA expression.
... Apart from ghrelin, many other gastrointestinal signals communicate short-term alterations in nutritional status to the brain via humoral and neural stimuli. A number of satiety signals that are released from the intestine include cholecystokinin (CCK), pancreatic polypeptide (PP), peptide-YY (PYY), oxyntomodulin, enterostatin, and glucagonlike peptide-1 (GLP-1) [5][6][7][8][9][10]. Another satiety signal, amylin, is cosecreted with insulin from the pancreas. ...
... Several neurotransmitters (serotonin, noradrenaline, dopamine, and histamine), peptides (neuromedin U, urocortin, bombesin, amylin, galanin), hormones (thyroid hormone, growth hormone) and cytokines (ciliary neurotrophic factor) also play a role in modulating feeding behavior and energy expenditure [5][6][7][8][9][10]. ...
... These include cholecystokinin (CKK), glucagonlike peptide 1(GLP-1), peptide YY (PYY), pancreatic polypeptide (PP), oxyntomodulin, amylin, and enterostatin. These peptides act in concert with other postprandial gastrointestinal signals (e.g., gastric distention) to cause satiation and promote meal termination [7][8][9][10]. Thus, stimulation of each is being researched to determine their potential as antiobesity targets. ...
The rising tide of obesity and its related disorders is one of the most pressing health concerns worldwide, yet existing medicines to combat the problem are disappointingly limited in number and effectiveness. Recent advances in mechanistic insights into the neuroendocrine regulation of body weight have revealed an expanding list of molecular targets for novel, rationally designed antiobesity pharmaceutical agents. Antiobesity drugs act via any of four mechanisms: 1) decreasing energy intake, 2) increasing energy expenditure or modulating lipid metabolism, 3) modulating fat stores or adipocyte differentiation, and 4) mimicking caloric restriction. Various novel drug candidates and targets directed against obesity are currently being explored. A few of them are also in the later phases of clinical trials. This review discusses the development of novel antiobesity drugs based on current understanding of energy homeostasis.
... Regardless of the high prevalence and increasing incidence of adult and paediatric NAFLD, no pharmacological therapy for NAFLD or NASH is approved at the present time, weight loss and exercise being the mainstay of treatment [14]. Considering that NAFLD is a multifactorial entity, it has been considered that combined therapies may achieve higher rates of responses and improved outcomes than monotherapies [14][15][16]. Supporting this contention, combined therapies using (i) thyroid hormone-(T 3 -) docosahexaenoic acid (DHA) prevent ischemia-reperfusioninduced liver inflammatory injury [17] and (ii) DHA-extra virgin olive oil (EVOO) attenuates HFD-dependent hepatic steatosis [18], whereas (iii) combination drug treatments have been proposed in the case of uncontrolled hypertension [19] and (iv) high-potency statins combined with ezetimibe or pioglitazone were recommended for the resolution of NAFLD or NASH [20]. Based on the hepatoprotective effects of the EVOO component hydroxytyrosol (HT) [21,22] and the n-3 LCPUFA eicosapentaenoic acid (EPA) [23], we hypothesized that the combined supplementation with EPA and HT could alter HFD-induced biochemical changes associated with steatosis. ...
... Additional mechanisms of HT action include (i) prevention of HFD-induced reduction in the desaturation capacity of the liver, with recovery in the activity of Δ5 and Δ6 desaturases promoting n-3 LCPUFA repletion [43]; (ii) reduction in the oxidative stress-dependent liver protein carbonylation triggered by HFD, thus decreasing the lipogenic response associated with the endoplasmic reticulum stress (ERS) developed [46,47], an effect that may be contributed by normalization of SFA levels increased by HFD, FAs that also trigger ERS [48]; and (iii) amelioration of drug-induced cardiotoxicity involving oxidative stress and mitochondrial dysfunction [49], which suggest enhancement in electron transport chain capacity and FA oxidation potential [21]. These considerations and the previous suggestions concerning the adequacy of combination therapies [14][15][16][17][18][19][20] reinforce the impact of dietary interventions including safety components addressing oxidative stress as a central mechanism underlying liver steatosis in obesity in particular and other noncommunicable diseases in general. ...
Pharmacological therapy for nonalcoholic fatty liver disease (NAFLD) is not approved at the present time. For this purpose, the effect of combined eicosapentaenoic acid (EPA; 50 mg/kg/day) modulating hepatic lipid metabolism and hydroxytyrosol (HT; 5 mg/kg/day) exerting antioxidant actions was evaluated on hepatic steatosis and oxidative stress induced by a high-fat diet (HFD; 60% fat, 20% protein, and 20% carbohydrates) compared to a control diet (CD; 10% fat, 20% protein, and 70% carbohydrates) in mice fed for 12 weeks. HFD-induced liver steatosis (i) was reduced by 32% by EPA, without changes in oxidative stress-related parameters and mild recovery of Nrf2 functioning affording antioxidation and (ii) was decreased by 42% by HT, concomitantly with total regain of the glutathione status diminished by HFD, 42% to 59% recovery of lipid peroxidation and protein oxidation enhanced by HFD, and regain of Nrf2 functioning, whereas (iii) combined EPA + HT supplementation elicited 74% reduction in liver steatosis, with total recovery of the antioxidant potential in a similar manner than HT. It is concluded that combined HT + EPA drastically decreases NAFLD development, an effect that shows additivity in HT and EPA effects that mainly relies on HT, strengthening the impact of oxidative stress as a central mechanism underlying liver steatosis in obesity.
... However, the beneficial effects of some of these agents on lipoprotein metabolism has been established [64]. Liraglutide monotherapy reduces TG by 22% [65] and 13% [66] compared with placebo. When liraglutide is combined with exenatide or oral hypoglycemic drugs (such as metformin and thiazolidinedione), TG and LDL-C are reduced by 0.38 ± 0.10 mmol/l and 0.28 ± 0.07 mmol/l, respectively (p < 0.05 vs placebo for both) [67]. ...
... However, this needs to be more fully elucidated with further studies. Finally, approaches to manipulating gut hormone expression also present an ambitious goal in anti-obesity drug development, but faces formidable challenges [65]. ...
Obesity is a health problem of global, epidemic proportions and a major risk factor for chronic diseases resulting in accelerated morbidity and mortality. Dyslipidemia with a predominance of small dense LDL, impaired functionality of HDL particles, and increased serum levels of remnant particles due to impaired clearance of triglyceride-rich lipoproteins significantly heightens cardiovascular events in obese subjects. Pharmacotherapy in combination with lifestyle modification is the primary approach to reduce obesity-related cardiovascular risk. Although there are several potential anti-obesity drugs, orlistat is the only agent that remains available in the market. Lorcaserin and Qsymia®, approved by the US FDA last year, and contrave with potential approval in 2014, are new anti-obesity drugs with promising therapeutic effects. Although these drugs can be associated with adverse side-effects, these agents have favorable effects on lipid profiles. However, the need for safer anti-obesity agents is clear.
... We hypothesised that cells within the IGL/VLG can sense the metabolic states of the organism based on signals derived directly from blood, since many hormones we tested ex vivo (e.g. GLP-1, OXM, Ghrl) circulate in plasma and their transport across the blood-brain barrier changes in a circadian manner (Chrobok et al., 2020;Dietrich & Horvath, 2009;Field et al., 2009;Maida et al., 2008;Pulido et al., 2021;Rhea et al., 2018;Seon et al., 2021;Song et al., 2019;Stadlbauer et al., 2013;Tamura et al., 2002;Yi et al., 2015). ...
The intergeniculate leaflet and ventral lateral geniculate nucleus (IGL/VLG) are subcortical structures involved in entrainment of the brain's circadian system to photic and non‐photic (e.g. metabolic and arousal) cues. Both receive information about environmental light from photoreceptors, exhibit infra‐slow oscillations (ISO) in vivo, and connect to the master circadian clock. Although current evidence demonstrates that the IGL/VLG communicate metabolic information and are crucial for entrainment of circadian rhythms to time‐restricted feeding, their sensitivity to food intake‐related peptides has not been investigated yet. We examined the effect of metabolically relevant peptides on the spontaneous activity of IGL/VLG neurons. Using ex vivo and in vivo electrophysiological recordings as well as in situ hybridisation, we tested potential sensitivity of the IGL/VLG to anorexigenic and orexigenic peptides, such as cholecystokinin, glucagon‐like peptide 1, oxyntomodulin, peptide YY, orexin A and ghrelin. We explored neuronal responses to these drugs during day and night, and in standard vs. high‐fat diet conditions. We found that IGL/VLG neurons responded to all the substances tested, except peptide YY. Moreover, more neurons responded to anorexigenic drugs at night, while a high‐fat diet affected the IGL/VLG sensitivity to orexigenic peptides. Interestingly, ISO neurons responded to light and orexin A, but did not respond to the other food intake‐related peptides. In contrast, non‐ISO cells were activated by metabolic peptides, with only some being responsive to light. Our results show for the first time that peptides involved in the body's energy homeostasis stimulate the thalamus and suggest functional separation of the IGL/VLG cells. image
Key points
The intergeniculate leaflet and ventral lateral geniculate nucleus (IGL/VLG) of the rodent thalamus process various signals and participate in circadian entrainment.
In both structures, cells exhibiting infra‐slow oscillatory activity as well as non‐rhythmically firing neurons being observed.
Here, we reveal that only one of these two groups of cells responds to anorexigenic (cholecystokinin, glucagon‐like peptide 1 and oxyntomodulin) and orexigenic (ghrelin and orexin A) peptides. Neuronal responses vary depending on the time of day (day vs. night) and on the diet (standard vs. high‐fat diet).
Additionally, we visualised receptors to the tested peptides in the IGL/VLG using in situ hybridisation.
Our results suggest that two electrophysiologically different subpopulations of IGL/VLG neurons are involved in two separate functions: one related to the body's energy homeostasis and one associated with the subcortical visual system.
... 10,11 On the other hand, the surgery is not recommended for management of obesity due to the hazards of complications. 12 Accordingly, the discovery of alternative medications of safe, and effective properties is necessary. 13,14 Numerous plant based drugs revealed noticeable anti-obesity properties. ...
... In contrast, surgery is only suggested for patients with severe obesity, especially when the implementation of dietary changes and physical activities does not produce significant weight loss [5]. For example, weight loss surgery, such as bariatric surgery, is effective in term of weight loss, but can cause surgical complications and frequent reoperation [6]. ...
Fruits and vegetables are important components of a healthy diet. They are rich sources of vitamins and minerals, dietary fibre and a host of beneficial non-nutrient substances including plant sterols, flavonoids and other antioxidants. It has been reported that reduced intake of fruits and vegetables may increase the risk of non-communicable diseases (NCDs). Chili pepper, is a common and important spice used to enhance taste and nutrition. Over the years, reports have shown its potential as antioxidant and an anti-obesity agent. Obesity is a serious health concern as it may initiate other common chronic diseases. Due to the side effects of synthetic antioxidants and anti-obesity drugs, scientists are now focusing on natural products which produce similar effects to synthetic chemicals. This up-to-date review addresses this research gap and presents, in an accessible format, the nutritional, antioxidant and anti-obesity properties of different chili peppers. This review article serves as a reference guide for use of chili peppers as anti-obesity agents.
... The increased prevalence of obesity and extreme obesity could lead to a global average reduction in life expectancy in the next decade [6,7]. Therefore, there is an urgent need to improve the toolset to reduce the burden of obesity [8][9][10]. Identifying more effective points of intervention to treat obesity is difficult because obesity is a complex disease influenced by various interacting factors including socioeconomic status, physical activity, eating habits, microbiota, and multiple genes acting in multiple tissues [11]. ...
Obesity and its associated metabolic syndrome are a leading cause of morbidity and mortality in the United States. Given the disease’s heavy burden on patients and the healthcare system, there has been increased interest in identifying pharmacological targets for the treatment and prevention of obesity. Towards this end, genome-wide association studies (GWAS) have identified hundreds of human genetic variants associated with obesity. The next challenge is to experimentally define which of these variants are causally linked to obesity, and could therefore become targets for the treatment or prevention of obesity. Here we employ high-throughput in vivo RNAi screening to test for causality 293 C . elegans orthologs of human obesity-candidate genes reported in GWAS. We RNAi screened these 293 genes in C . elegans subject to two different feeding regimens: (1) regular diet, and (2) high-fructose diet, which we developed and present here as an invertebrate model of diet-induced obesity (DIO). We report 14 genes that promote obesity and 3 genes that prevent DIO when silenced in C . elegans . Further, we show that knock-down of the 3 DIO genes not only prevents excessive fat accumulation in primary and ectopic fat depots but also improves the health and extends the lifespan of C . elegans overconsuming fructose. Importantly, the direction of the association between expression variants in these loci and obesity in mice and humans matches the phenotypic outcome of the loss-of-function of the C . elegans ortholog genes, supporting the notion that some of these genes would be causally linked to obesity across phylogeny. Therefore, in addition to defining causality for several genes so far merely correlated with obesity, this study demonstrates the value of model systems compatible with in vivo high-throughput genetic screening to causally link GWAS gene candidates to human diseases.
... Molecules that mimic endogenous peptides like glucagon-like peptide 1 (GLP1) characterize alternative potential types of anti-osteogenic drugs, but these require intravenous, intranasal or subacute admission. Furthermore, they are quickly absorbed by the body and their long-term effectiveness remains elusive [12,13]. Overall, there is an ongoing need for efficient, simple and safe treatments to fight obesity. ...
... Bariatric surgery such as Roux-en-ϒ bypass or gastric banding are much more effective in the management of obesity due to weight loss, comorbidity reduction, and enhanced survival (Kral and Naslund 2007; Sjostrom et al. 2007). However, they are reserved for the morbidly obese owing risks such as perioperative mortality, surgical implications, and the frequent need for reoperation (Field et al. 2009;Melnikova and Wages 2006). ...
Obesity is one of the leading causes of death because it is associated with most metabolic disorders in the body such as diabetes, cardiovascular diseases, stroke, and cancers. Herbs are known to be natural sources of medicines. Scientists are working toward making plants the best alternative to synthetic drugs, majorly because it has no side effects, is low price and easily accessible, and offers solution to most chronic diseases, among others. Medicinally, constituents of plants are safer for consumption when based on therapeutic formulations. Important phytomolecules such as alkaloids, phenols, saponin, terpenoids, and flavonoids have been discovered to have anti-obesity properties. Most of these plant extracts are a mixture of different molecules, and not a single compound. The phytomolecules would exert their anti-obesity effect through their mechanism by acting on certain organ and cellular systems. This review tends to discuss briefly some of the major phytometabolities that have anti-obesity properties and the mechanism in which they execute their effects.
... Besides, few other effective strategies like bariatric surgery, such as Roux-en-Y bypass or gastric banding, which is even more effective in terms of weight loss, reduced comorbidity, and enhanced survival (Kral & Näslund, 2007;Sjöström et al., 2007). But, due to the associated complications such as perioperative mortality, surgical complications, and frequent need of reoperation, these procedures are advisable only for the morbidly obese individuals (Field, Chaudhri, & Bloom, 2009;Melnikova & Wages, 2006). An alternative strategy to surgery is to develop therapeutic agents that can reduce body weight by decreasing the consumption or absorption of food, and/or by increasing energy expenditure (Cooke & Bloom, 2006;Sargent & Moore, 2009). ...
Obesity is an abnormal condition in which excessive fat is accumulated in adipose tissue. It has emerged as one of the biggest public health concerns today as it is a major risk factor for developing type 2 diabetes, cardiovascular disease, hypertension, and certain types of cancer. Carotenoids play a key role in maintaining health and preventing diseases because of their remarkable structural and physical properties involving antioxidant, antiinflammatory, and anticancer activities, which render them a remarkable position in the amelioration of various metabolic syndromes. In vitro and in vivo as well as human-interventional studies dealing with carotenoids shed light on the targets of major regulatory mechanisms of adipogenesis and pathophysiology concerning obesity and related metabolic disorders. This chapter primarily focuses on the antiobese molecular mechanisms of carotenoids particularly targeting adipocyte differentiation, thermogenesis, inflammation, and lipogenesis in view toward the management of obesity.
... This peptide plays a critical role in regulating adipose tissue mass and energy balance. 104,105 The actions of other hormones in addition to leptin may also be affected, and perhaps disrupted, by antipsychotic drug treatment. ...
The atypical antipsychotics (AAPs) have been used as first-line drugs in psychiatric practice for a wide range of psychotic disorders, including schizophrenia and bipolar mania. While effectively exerting therapeutic effects on positive and negative symptoms, as well as cognitive impairments in schizophrenia patients, these drugs are less likely to induce extrapyramidal symptoms compared to typical antipsychotics. However, the increasing application of them has raised questions on their tolerability and adverse effects over the endocrine, metabolic, and cardiovascular axes. Specifically, AAPs are associated to different extents, with weight gain, metabolic syndrome (MetS), and nonalcoholic fatty liver disease (NAFLD). This article summarized clinical evidence showing the metabolic side effects of AAPs in patients with schizophrenia, and experimental evidence of AAPs-induced metabolic side effects observed in animals and cell culture studies. In addition, it discussed potential mechanisms involved in the APPs-induced MetS and NAFLD.
... [21][22][23][24] Its mechanism of action supports the use of dual agonism in the treatment of obesity. [25][26][27] The weight-loss effect of OXM is likely mediated by both components: GLP-1 agonism, which reduces energy This article is protected by copyright. All rights reserved. ...
Aims
To evaluate the safety, pharmacokinetics, and pharmacodynamics of SAR425899, a novel polypeptide active as an agonist at both the glucagon‐like peptide‐1 receptor (GLP‐1 R) and the glucagon receptor, in healthy volunteers and in patients with overweight/obesity and type 2 diabetes.
Methods
Subcutaneous administrations of SAR425899 were tested in two randomized, placebo‐controlled, double‐blind clinical trials. In the first trial, healthy overweight volunteers (BMI: 25─30 kg/m²; n = 32) received single‐ascending doses (0.01─0.1 mg) of SAR425899 or placebo. In the second, a multiple‐ascending‐dose trial (NCT02411825), healthy normal‐to‐overweight volunteers (BMI: 20─30 kg/m²; n = 40) and patients with overweight/obesity and type 2 diabetes (BMI: 28─42 kg/m²; n = 36) received daily doses of SAR425899 or placebo over 21 or 28 days, respectively.
Results
Adverse events reported most frequently were gastrointestinal; gastrointestinal side effects were less pronounced in patients compared with healthy volunteers. SAR425899 significantly reduced levels of fasting plasma glucose (P < .05 versus placebo) and glycated haemoglobin (P < .001 versus placebo) in patients. Additionally, SAR425899 led to reductions in body weight, with a maximal reduction of 5.32 kg in healthy volunteers and 5.46 kg in patients (P < .001 versus placebo) at end of treatment.
Conclusions
SAR425899 was well tolerated and led to favourable glycaemic effects in patients with type 2 diabetes and weight reduction in both healthy volunteers and patients. Whether dual GLP‐1 R/glucagon receptor agonism represents a treatment modality superior to pure GLP‐1 R agonists for obesity and diabetes treatment remains to be confirmed.
This article is protected by copyright. All rights reserved.
... Oxyntomodulin (OXM), like GLP-1 and glucagon, is a peptide product derived from posttranslational modification of preproglucagon (1)(2)(3). It is secreted by the enteroendocrine cells of the small intestine in response to nutrient ingestion and has been shown in vitro to be a natural chimera, binding and activating both the GLP-1 receptor (GLP-1R) and the glucagon receptor (GCGR) (4). ...
Oxyntomodulin (OXM), an enteroendocrine hormone, causes appetite suppression, increased energy expenditure, and weight loss in obese humans via activation of GLP-1 and glucagon receptors. However, the effects of OXM on glucose homeostasis remain ill-defined. To address this gap, we evaluated the effects of an intravenous (IV) infusion of native OXM on insulin secretory rates (ISR) and glycemic excursion in a graded glucose infusion (GGI) procedure in two separate randomized, placebo-controlled, single dose crossover trials in 12 overweight and obese subjects without diabetes, and in 12 obese subjects with Type 2 diabetes (T2DM) respectively, using the GLP-1 analog, liraglutide as a comparator in the T2DM. In both groups, in the GGI, 3.0 pmol/kg/min of OXM significantly increased ISR and blunted glycemic excursion relative to placebo. In the T2DM, the effects of OXM were comparable to those of liraglutide, including restoration of beta cell glucose responsiveness to that of non-obese subjects without diabetes. Our findings indicate that native OXM significantly augments glucose-dependent insulin secretion acutely in obese subjects with and without diabetes, with effects comparable to pharmacologic GLP-1R activation and independent of weight loss. Native OXM has potential to improve hyperglycemia via complementary and independent induction of insulin secretion and weight loss.
... Overweight and obesity are major risk factors for a number of chronic diseases, including diabetes [1], cardiovascular diseases and cancer [2]. Since the turn of the century, the number of obese adults has increased to over 300 million. ...
Metabolic disorders due to over-nutrition are a major global health problem, often associated with obesity and related morbidities. Obesity is peculiar to humans, as it is associated with lifestyle and diet, and so difficult to reproduce in animal models. Here we describe a model of human central adiposity based on a 3-tissue system consisting of a series of interconnected fluidic modules. Given the causal link between obesity and systemic inflammation, we focused primarily on pro-inflammatory markers, examining the similarities and differences between the 3-tissue model and evidence from human studies in the literature. When challenged with high levels of adiposity, the in-vitro system manifests cardiovascular stress through expression of E-selectin and von Willebrand factor as well as systemic inflammation (expressing IL-6 and MCP-1) as observed in humans. Interestingly, most of the responses are dependent on the synergic interaction between adiposity and the presence of multiple tissue types. The set-up has the potential to reduce animal experiments in obesity research and may help unravel specific cellular mechanisms which underlie tissue response to nutritional overload.
... These centers are modulated by neural and hormonal signals coming from the periphery. Hormones synthesized by the adipose tissue, like leptin, refl ect the long-term nutritional status of the body and are able to infl uence long-term body weight regulation, while gastrointestinal hormones, like ghrelin, peptide tyrosine-tyrosine (PYY) and glucagon-like peptide 1 (GLP-1), among several other hormones, modulate these pathways acutely and are able to regulate food intake and energy expenditure [ 26 ] ( Fig. 28.1 ). In the hypothalamus are located the most important food intake-regulating nuclei, the arcuate (ARC) and the paraventricular nuclei (PVN). ...
Obesity is currently a major public health problem, due to the worldwide increasing rates of the disease and burden of the associated co-morbilities, such as, type 2 diabetes, cardiovascular disease and cancer. Despite its increasing clinical relevance, there are still very few tools to treat obesity. The cornerstones for obesity treatment are still diet and exercise; anti-obesity drugs, which cause anorexia or malabsorption of nutrients, can be used as adjuvant therapy, however achieve only a modest weight loss and often short-term due to weight regain. For severe obesity the only proven effective therapy is bariatric surgery, an invasive procedure that carries inherent risks and is only recommended for selected patients.
... Indirectly affecting the body weight reduction, the PP found itself in the center of attention of researchers who work on developing new treatments for obesity. 24 Experiments on animal models produced satisfactory results. It was found that PP regulated the body's energy balance. ...
The aim of the study was to demonstrate the effects of cigarette smoking and ongoing inflammation in chronic pancreatitis on the functioning of pancreatic polypeptide (PP)-secreting cells and to determine the relationship between the occurrence of an increased number of PP cells in the pancreas, the change in their location, and the intensity of their inflammatory changes in the course of pancreatitis and diabetes. Samples of tissues from healthy persons and from patients were verified histopathologically, and then PP was localized by immunohistochemical staining using the monoclonal anti-human PP antibody. The histopathologic evaluation of the hormone expression intensity in tissue sections was carried out using the semiquantitative method and was calculated with digital image analysis. The present study showed a very strong PP expression in the pancreatic tissue (especially in the head of the pancreas) derived from smoking patients with diabetes. The increase in the percentage of cells in the PP islets, between the acinar cells in smoking patients with diabetes and a statistically significant increase in the expression of PP, indicates a pancreatic endocrine dysfunction and suggests that cigarette smoking has a negative impact on the organ's efficiency. Because of its properties, the PP appears to be a useful marker of the endocrine insufficiency of the pancreas and a specific prognostic parameter of developing diabetes due to chronic pancreatitis. Copyright 2016 Wolters Kluwer Health, Inc. All rights reserved.
... Obesity, a major factor in the development of heart disease, cancer, hypertension, diabetes, and degenerative arthritis, is induced by adipocyte differentiation due to hormonal changes and imbalances in energy metabolism caused by excessive fat intake [1][2][3][4][5]. Adipogenesis in the body is the process of cell differentiation by which preadipocytes become adipocytes during fat accumulation. ...
The potent suppression of adipocyte differentiation by 4-(4-methylbenzamino)benzoate was discovered during the search for new antiobesity compounds. 4-(4-methylbenzamino)benzoate was observed to suppress adipocyte differentiation in 3T3-L1 cells by 96.8% at 50
μ
M without cytotoxicity. In addition, 4-(4-methylbenzamino)benzoate reduced the cellular expression of fatty acid synthase in a concentration-dependent manner, as well as suppressing PPAR-gamma activity, which controls fatty acid storage and glucose metabolism. Based on these results, 4-(4-methylbenzamino)benzoate shows potential as an antiobesity material.
... The role of gut hormones in the treatment of obesity has been widely recognized [1][2][3][4] . Glucagon-like peptide-1 (GLP-1) is a satiety factor [5][6][7] that is released into the circulation after a meal in proportion to the amount of food consumed, with the major source of postprandial GLP-1 release being L-cells in the intestine [5][6][7] . ...
The physiological mechanisms underlying the increases observed in glucagon-like peptide-1 (GLP-1) and peptide YY (PYY) plasma levels with exercise currently remain unknown. Previous studies reported that increases in plasma GLP-1 and PYY concentrations were mediated by a neural pathway, regardless of exercise. Therefore, we investigated the neural regulation of GLP-1 and PYY secretion during exercise in rats using a hindlimb muscle contraction model. Hindlimb muscle contraction was induced by electrically stimulating the sciatic nerve for 20 min (5 V, 5 Hz). A fasting arterial blood sample (Baseline) was taken. Rats were subjected to 20 min of hindlimb muscle contraction in vivo, and blood samples were collected at the end of the hindlimb muscle contraction protocol. Although GLP-1 and PYY levels were significantly increased after hindlimb muscle contraction (P < 0.001, respectively), no significant differences were observed in GLP-1 or PYY levels between sham and vagotomy trials. On the other hand, GLP-1 and PYY levels after hindlimb muscle contraction were significantly lower in the sciatic nerve deafferentation trial than in the sham trial (P < 0.01, respectively). These results indicate that the increases observed in GLP-1 and PYY plasma levels with exercise were mediated by the activation of skeletal muscle-derived afferent neurons, and not by mechanisms through the neural pathway of the vagus nerve.
... The metabolic syndrome disorder also shown in childhood obesity was associated with changes in brain volume and structure and alterations in appetite, hypertension and insulin resistance possibly associated with brain abnormalities in childhood obesity [125]. In obese individuals the loss of brain control is poorly understood and alterations in brain circuitry or feeding signals in obesity involve abnormal hormone regulation with poor control of appetite and body weight [12, [126][127][128][129][130][131][132][133][134][135]. ...
... By contrast, the neurotransmitter serotonin (5-HT) enhances satiety and regulates food intake, and the antagonism of the serotonin 2C (5-HT2C) receptor prevents satiety (Balt et al., 2011). Leptin has been associated with food intake and energy homeostasis (Correll and Malhotra, 2004;Field et al., 2009). Histamine H1 receptor blockade increases appetite, and H1 receptor also seems to be required for leptin effect (Balt et al., 2011). ...
The use of antipsychotic drugs for the treatment of mood disorders and psychosis has increased dramatically over the last decade. Despite its consumption being associated with beneficial neuropsychiatric effects in patients, atypical antipsychotics (which are the most frequently prescribed antipsychotics) use is accompanied by some secondary adverse metabolic effects such as weight gain, dyslipidemia and glucose intolerance. The molecular mechanisms underlying these adverse effects are not fully understood but have been suggested to involve a dysregulation of adipose tissue homeostasis. As such, the aim of this paper is to review and discuss the role of adipose tissue in the development of secondary adverse metabolic effects induced by atypical antipsychotics. Data analyzed in this article suggest that atypical antipsychotics may increase adipose tissue (particularly visceral adipose tissue) lipogenesis, differentiation/hyperplasia, pro-inflammatory mediator secretion and insulin resistance and decrease adipose tissue lipolysis. Consequently, patients receiving antipsychotic medication could be at risk of developing obesity, type 2 diabetes and cardiovascular disease. A better knowledge of the impact of these drugs on adipose tissue homeostasis may unveil strategies to develop novel antipsychotic drugs with less adverse metabolic effects and to develop adjuvant therapies (e.g. behavioral and nutritional therapies) to neuropsychiatric patients receiving antipsychotic medication.
Copyright © 2014 Elsevier B.V. and ECNP. All rights reserved.
... The number of bariatric interventions (i.e., metabolic surgery) for the treatment of obesity is in exponential increase. This is partly due to the most effective and durable weight loss; in addition, a good deal of improvement of co-morbidities after surgery compared with medical treatments such as diet and physical activity [12] , or actually applicable pharmacologic [13] or endoscopic [14] treatments was observed. Actually, bariatric surgery is greatly ap-proved by patients and physicians because the techniques are minimally invasive and well finished and standardized [15] . ...
Obesity and its associated diseases are a worldwide epidemic disease. Usual weight loss cures - as diets, physical activity, behavior therapy and pharmacotherapy - have been continuously implemented but still have relatively poor long-term success and mainly scarce adherence. Bariatric surgery is to date the most effective long term treatment for morbid obesity and it has been proven to reduce obesity-related co-morbidities, among them nonalcoholic fatty liver disease, and mortality. This article summarizes such variations in gut hormones following the current metabolic surgery procedures. The profile of gut hormonal changes after bariatric surgery represents a strategy for the individuation of the most performing surgical procedures to achieve clinical results. About this topic, experts suggest that the individuation of the crosslink among the gut hormones, microbiome, the obesity and the bariatric surgery could lead to new and more specific therapeutic interventions for severe obesity and its co-morbidities, also non surgical.
... A fim de evitar tais complicações, diversos tratamentos como dieta, atividade física e terapia medicamentosa são utilizados de modo a induzir um balanço energético negativo. Porém, tais condutas não vêm apresentando resultados satisfatórios, sendo a terapia cirúrgica a melhor opção atualmente (3) . ...
Background: In recent years, Sleeve Gastrectomy
(SG) has been increasing steadily and excelling as a
surgical treatment of morbid obesity. It was noticed
that in many patients, the SG alone had excellent
results in weight reduction and comorbidities
improvement, avoiding a second operation. Aim: To
evaluate anthropometric and comorbidities reduction
in patients with morbid obesity submitted to SG in the
period of one year. Methods: This is a retrospective
cross-sectional study using data drawn from medical
records and SG patients interviews. It has been
evaluated within 3, 6 and 12 months postoperatively,
the reduction in weight, BMI and percentage of excess
weight loss (% PEP). These data were compared with the
presence of comorbidities and their resolution after
surgery. Results: The average weight excess in the preoperative
is 58,54 ± 21,82 kg, was significantly higher
in males than in females (p < 0,001). After surgery, BMI
and %PEP at 12 months were respectively 43,11 ± 6,52
kg/m² and 63,47 ± 15,46%. It was noticed that younger
people respond better to weight loss than older
individuals. When comparing sex, ther eduction in BMIw as
significantly higher in males (p < 0,05), this data did not occur to evaluate the %PEP (p= 0,228). It was observed
that 80,64% of the patients had a comorbidity associated
with obesity being described 12,9% with type II DM
(como é primeira citação precisa do nome completo),
48,4% had hypertension, 25,8% had dyslipidemia and
51,6% to osteoarthropathy. Conclusion: The isolated
SG is a surgery that has shows excellent results in
treating obesity, being highly effective in weight loss and
comorbidities resolution.
... Both central [2,3,[12][13][14][15] and peripheral [16] administration of the peptide reduce food intake and body weight in rodents and birds, without the tachyphylaxis observed for other peptides such as CCK or amylin [17,18]. The sustained activity observed upon chronic infusion of NMU [16] was similar to other peptides, which are being considered for obesity treatment, like glucagon-like peptide-1 and oxyntomodulin [19]. Finally, independent of its weight loss effects, peripherally administered NMU markedly improved glucose tolerance in dietinduced obese (DIO) mice [16]. ...
Neuromedin U (NMU) is an endogenous peptide implicated in the regulation of feeding, energy homeostasis, and glycemic control, which is being considered for the therapy of obesity and diabetes. A key liability of NMU as a therapeutic is its very short half-life in vivo. We show here that conjugation of NMU to human serum albumin (HSA) yields a compound with long circulatory half-life, which maintains full potency at both the peripheral and central NMU receptors. Initial attempts to conjugate NMU via the prevalent strategy of reacting a maleimide derivative of the peptide with the free thiol of Cys34 of HSA met with limited success, because the resulting conjugate was unstable in vivo. Use of a haloacetyl derivative of the peptide led instead to the formation of a metabolically stable conjugate. HSA-NMU displayed long-lasting, potent anorectic, and glucose-normalizing activity. When compared side by side with a previously described PEG conjugate, HSA-NMU proved superior on a molar basis. Collectively, our results reinforce the notion that NMU-based therapeutics are promising candidates for the treatment of obesity and diabetes. Copyright © 2013 European Peptide Society and John Wiley & Sons, Ltd.
... The role of gut hormones in the treatment of obesity has been widely recognized (Derosa and Maffioli 2012;Field et al. 2009;Karra and Batterham 2010;Neary and Batterham 2009). Glucagon-like peptide-1 (GLP-1) is a satiety factor ( Barrera et al. 2011;Gallwitz 2012;Torekov et al. 2011), which is released into the circulation after a meal in proportion to the amount of food consumed, and the major source of postprandial GLP-1 release is Lcells of the intestine ( Barrera et al. 2011;Gallwitz 2012;Torekov et al. 2011). ...
The purpose of this study was to investigate the effects of 12 weeks of exercise training on gut hormone levels after a single bout of exercise in middle-aged Japanese women. Twenty healthy middle-aged women were recruited for this study. Several measurements were performed pre and post exercise training, including: body weight and composition, peak oxygen consumption (peak VO2), energy intake after the single bout of exercise, and the release of gut hormones with fasting and after the single bout of exercise. Exercise training resulted in significant increases in acylated ghrelin fasting levels (from 126.6 ± 5.6 to 135.9 ± 5.4 pmol/l, P < 0.01), with no significant changes in GLP-1 (from 0.54 ± 0.04 to 0.55 ± 0.03 pmol/ml) and PYY (from 1.20 ± 0.07 to 1.23 ± 0.06 pmol/ml) fasting levels. GLP-1 levels post exercise training after the single bout of exercise were significantly higher than those pre exercise training (areas under the curve (AUC); from 238.4 ± 65.2 to 286.5 ± 51.2 pmol/ml x 120 min, P < 0.001). There was a tendency for higher AUC for the time courses of PYY post exercise training than for those pre exercise training (AUC; from 519.5 ± 135.5 to 551.4 ± 128.7 pmol/ml x 120 min, P = 0.06). Changes in (delta) GLP-1 AUC were significantly correlated with decreases in body weight (r = -0.743, P < 0.001), body mass index (r = -0.732, P < 0.001), percent body fat (r = -0.731, P < 0.001), and energy intake after a single bout exercise (r = -0.649, P < 0.01) and increases in peak VO2 (r = 0.558, P < 0.05). These results suggest that the ability of exercise training to create a negative energy balance relies not only directly on its impact on energy expenditure, but also indirectly on its potential to modulate energy intake.
... Most of the centrally acting anti-obesity drugs in the past affected nonspecific neurotransmitter pathways and thus exhibited multiple adverse events. On the contrary, gut hormones, which affect specifically food intake and energy homeostasis, represent new opportunities for the development of anti-obesity drugs which may have relatively few nonspecific side effects compared with centrally acting drugs [72]. Several gut hormones such as glucagon-like peptide-1 (GLP-1), amylin, oxyntomodulin, pancreatic polypeptide, CCK and ghrelin have been investigated as potential peripheral targets in the development of novel anti-obesity drugs. ...
The increasing global prevalence of obesity urgently requires an implementation of efficient preventive and therapeutic measures. Weight loss and its maintenance should be considered one of the most important strategies to reduce the incidence of obesity-related co-morbidities such as diabetes and cardiovascular diseases. Lifestyle modification focused on diet and physical activity represents the essential component of any kind of weight management. However, only an intensive lifestyle intervention can be efficient in terms of long-term weight loss. Anti-obesity drugs affect different targets in the central nervous system or peripheral tissues and improve regulatory and metabolic disturbances that contribute to the development of obesity. Anti-obesity medications provide modest additional fat loss to that achieved by lifestyle modification alone, reduce visceral fat stores, improve programme adherence, weight loss maintenance, diminish obesity-related health risks and improve a quality of life. Anti-obesity drugs do play a role in weight management. Their replacement with placebo is followed by weight regain. Due to adverse events, several anti-obesity drugs were withdrawn from the market over the past few years and currently only orlistat remains available for long-term obesity management. Drug withdrawals, failure of clinical trials with several new anti-obesity compounds as well as inappropriate demands of drug regulating agencies concerning the study protocol led to scepticism about the perspectives in the pharmacotherapy of obesity. However, recently developed anti-obesity medications such as gut hormone analogues and drug combinations provided encouraging results in terms of weight loss, safety and improvement of cardio-metabolic health risks.
... Obese patients without this genetic disorder typically show increased leptin levels, and in these individuals leptin treatment does not result in substantial weight reduction owing to a phenomenon known as leptin resistance (32). Therefore, future clinical applications of this designer network may need to have leptin replaced by other anorectic peptides (33). Having the potential to address such a wide set of pathologies, the concept of drug-based gene therapies may improve treatment success and provide new therapies for multifactorial diseases. ...
Synthetic biology has significantly advanced the design of genetic devices that can reprogram cellular activities and provide novel treatment strategies for future gene- and cell-based therapies. However, many metabolic disorders are functionally linked while developing distinct diseases that are difficult to treat using a classic one-drug-one-disease intervention scheme. For example, hypertension, hyperglycemia, obesity, and dyslipidemia are interdependent pathologies that are collectively known as the metabolic syndrome, the prime epidemic of the 21st century. We have designed a unique therapeutic strategy in which the clinically licensed antihypertensive drug guanabenz (Wytensin) activates a synthetic signal cascade that stimulates the secretion of metabolically active peptides GLP-1 and leptin. Therefore, the signal transduction of a chimeric trace-amine-associated receptor 1 (cTAAR1) was functionally rewired via cAMP and cAMP-dependent phosphokinase A (PKA)-mediated activation of the cAMP-response element binding protein (CREB1) to transcription of synthetic promoters containing CREB1-specific cAMP response elements. Based on this designer signaling cascade, it was possible to use guanabenz to dose-dependently control expression of GLP-1-Fc(mIgG)-Leptin, a bifunctional therapeutic peptide hormone that combines the glucagon-like peptide 1 (GLP-1) and leptin via an IgG-Fc linker. In mice developing symptoms of the metabolic syndrome, this three-in-one treatment strategy was able to simultaneously attenuate hypertension and hyperglycemia as well as obesity and dyslipidemia. Using a clinically licensed drug to coordinate expression of therapeutic transgenes combines drug- and gene-based therapies for coordinated treatment of functionally related metabolic disorders.
... GLP1 has been found to decrease food intake and inhibit gastric emptying (Holst 2000, D'Alessio 2008). GLP1 is rapidly inactivated by dipeptidyl peptidase-4 (DPP4) and its renal clearance is relatively fast (Field et al. 2009). Accordingly, new drugs based on GLP1 receptor (GLP1R) agonism and DPP4 inhibition have been approved for the treatment of type 2 diabetes, but the magnitude of weight loss at tolerated doses is modest (Amori et al. 2007). ...
Oxyntomodulin (OXM) is a peptide secreted from the L-cells of the gut following nutrient ingestion. OXM is a dual agonist of the GLP-1 receptor (GLP1R) and the glucagon receptor (GCGR) combining the effects of GLP-1 and glucagon to act as a potentially more effective treatment for obesity than GLP-1 receptor agonists. Injections of OXM in humans cause a significant reduction in weight and appetite, as well as an increase in energy expenditure. Activation of GCGR is classically associated with an elevation in glucose levels, which would be deleterious in patients with T2DM, but the antidiabetic properties of GLP1R agonism would be expected to counteract this effect. Indeed, OXM administration improved glucose tolerance in diet-induced obese mice. Thus, dual agonists of the GCGR and GLP1R represent a new therapeutic approach for diabetes and obesity with the potential for enhanced weight loss and improvements in glycemic control beyond those of GLP1R agonists.
Metabolic dysfunctions linked to obesity carry the risk of co-morbidities such as diabetes, hepatorenal, and cardiovascular diseases. Coumarins are believed to display several biological effects on diverse adverse health conditions. This study was conducted to uncover the impact of cichoriin on high-fat diet (HFD)-induced obese rats. Methods: Obesity was induced in twenty rats by exposure to an HFD for six weeks. The rats were randomly divided into five groups; group I comprised five healthy rats and was considered the control one. On the other hand, the HFD-induced rats were divided into the following (five per each group): group II (the HFD group), groups III (cichoriin 50 mg/kg) and IV (cichoriin 100 mg/kg) as the treatment groups, and group V received atorvastatin (10 mg/kg) (as a standard). Triglycerides (TG), total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), alanine transaminase (ALT), aspartate transaminase (AST), creatine kinase MB (CK-MB), urea, creatinine, the hepatic and renal malondialdehyde (MDA) as well as reduced glutathione (GSH) levels were assessed. Histopathological analysis of the heart, kidney, and liver tissues was investigated. mRNA and protein expressions of the peroxisome proliferator-activated receptor gamma (PPAR-γ) were estimated. Results: The administration of cichoriin alleviated HFD-induced metabolic dysfunctions and improved the histopathological characteristics of the heart, kidney, and liver. Additionally, the treatment improved the lipid profile and hepatic and renal functions, as well as the oxidative balance state. Cichoriin demonstrated an upregulation of the mRNA and protein expressions of PPAR-γ. Taken together, these findings are the first report on the beneficial role of cichoriin in alleviating adverse metabolic effects in HFD-induced obesity and adapting it into an innovative obesity management strategy.
Metabolic disorders due to over-nutrition are a major global health problem, often associated with obesity and related morbidities. Obesity is peculiar to humans, as it is associated with lifestyle and diet, and so difficult to reproduce in animal models.
Here we describe a model of human central adiposity based on a 3-tissue system consisting of a series of interconnected fluidic modules. Given the causal link between obesity and systemic inflammation, we focused primarily on pro-inflammatory markers, examining the similarities and differences between the 3-tissue model and evidence from human studies in the literature. When challenged with high levels of adiposity, the in-vitro system manifests cardiovascular stress through expression of E-selectin and von Willebrand factor as well as systemic inflammation (expressing IL-6 and MCP-1) as observed in humans. Interestingly, most of the responses are dependent on the synergic interaction between adiposity and the presence of multiple tissue types. The set-up has the potential to reduce animal experiments in obesity research and may help unravel specific cellular mechanisms which underlie tissue response to nutritional overload.
Angiogenesis is regulated in a tissue-specific manner in all patients, especially those with diabetes. In this study, we describe a novel molecular pathway of angiogenesis regulation in diabetic rats with myocardial infarction (MI) and examine the cardioprotective effects of different doses of sitagliptin. Male rats were divided into 5 groups: normal vehicle group, diabetic group, diabetic + MI, diabetic + MI + 5 mg/kg sitagliptin, and diabetic + MI + 10 mg/kg sitagliptin. Isoproterenol in diabetic rats resulted in significant (p < 0.05) disturbance to the electrocardiogram, cardiac histopathological manifestations, and an increase in inflammatory markers compared with the vehicle and diabetic groups. Treatment with sitagliptin improved the electrocardiogram and histopathological sections, upregulated vascular endothelial growth factor (VEGF) and transmembrane phosphoglycoprotein protein (CD34) in cardiac tissues, and increased serum insulin-like growth factor 1 (IGF-1) and decreased cardiac tissue homogenate for interleukin 6 (IL-6) and cyclooxygenase 2 (COX-2). A relationship was found between serum IGF-1 and cardiac VEGF and CD34 accompanied by an improvement in cardiac function of diabetic rats with MI. Therefore, the observed effects of sitagliptin occurred at least partly through an improvement in angiogenesis and the mitigation of inflammation. Consequently, these data suggest that sitagliptin may contribute, in a dose-dependent manner, to protection against acute MI in diabetic individuals.
Obesity is a multifactorial chronic disease or syndrome caused by an imbalance in energy expenditure and intake. Obesity and its associated complications make it has the fifth leading cause for global mortality. The benefits of the current anti-obesity treatment regimen have been masked by high cost and numerous adverse effects. Therefore, many researchers focus on plant-derived/natural products or altered dietary pattern for the management of obesity and its related complications (co-morbidities). Several epidemiological studies also confirmed that the consumption of functional foods/nutraceuticals could considerably lower the risk of various chronic diseases like obesity, diabetic mellitus, and cancer but the underpinning mechanism is still unclear. This comprehensive review brief on the prevalence of obesity, complications related obesity, current treatment regimen and the importance of functional foods and nutraceuticals (molecular mechanism) for the management of body weight and alleviates its co-morbid conditions. This is the first comprehensive review revealing the in-depth anti-obesity mechanism of various popular functional foods and nutraceuticals with special reference to randomized clinical trials (RCTs). Overall, this contribution would signify the importance and beneficial role of functional foods/nutraceuticals on weight management (anti-obesity) to convey the current treatment status related to clinical trials which would help in the development of novel functional foods/nutraceuticals for combatting obesity and its co-morbidities.
When in 2012 the author of this textbook invited international vaccine experts to contribute to “Molecular Vaccines – From Prophylaxis to Therapy,” he used as working title “NINC vaccines” (noninfectious and noncancer) for sub-summarizing all vaccine developments which did not fall into the classification of infectious and cancer vaccines and meet very various indications as presented in Fig. 13.1 Meanwhile the term NINC vaccines becomes more and more popular in the scientific world simply by collecting all vaccines against other targets than pathogens and cancer.
Obesity is reaching global epidemic proportions as a result of factors such as high-calorie diets and lack of physical exercise. Obesity is now considered to be a medical condition, which not only contributes to the risk of developing type 2 diabetes mellitus, cardiovascular disease and cancer, but also negatively affects longevity and quality of life. To combat this epidemic, anti-obesogenic approaches are required that are safe, widely available and inexpensive. Several plants and mushrooms that are consumed in traditional Chinese medicine or as nutraceuticals contain antioxidants, fibre and other phytochemicals, and have anti-obesogenic and antidiabetic effects through the modulation of diverse cellular and physiological pathways. These effects include appetite reduction, modulation of lipid absorption and metabolism, enhancement of insulin sensitivity, thermogenesis and changes in the gut microbiota. In this Review, we describe the molecular mechanisms that underlie the anti-obesogenic and antidiabetic effects of these plants and mushrooms, and propose that combining these food items with existing anti-obesogenic approaches might help to reduce obesity and its complications.
Despite substantial progress in our understanding of the complex bio-machinery involved in the regulation of appetite and energy homeostasis, few weight loss drugs are currently government-approved in the USA or Europe. While acknowledging novel drug monotherapies (such as Belviq(®) & Saxenda(®)), this review focuses on the various drug polytherapies that are currently attracting so much research interest. Unfortunately, however, the dependent variables in these new studies remain firmly rooted in outcome measures i.e. reduced food intake and bodyweight. Such evidence is clearly essential, as are physiological data bearing upon potential 'off-target' effects of any new treatment. However, as emphasised by many authors, this profiling has to be matched by sophisticated behavioural analysis addressing fundamental 'process' questions such as how such reductions in intake and/or bodyweight have been achieved. The value of behavioural analysis is exemplified, and it is argued that such a process-led approach should optimise the translation from preclinical to clinical development of candidate drugs, and avoid yet further expensive blind alleys.
Obesity is a leading threaten of health, with increasing prevalence in the world. Because of the limited therapy options, obesity cannot be effectively controlled. All marketed anti-obesity drugs have serious side-effects, and many of them have been withdrawn from the market in the last decade. New anti-obesity drug is urgently needed by the market. Several molecules play roles in the regulation of food intake, energy metabolism and body-weight. New drugs targeting these molecules are under research and development. In present paper, we summarize the anti-obesity targets and the mechanisms, aiming to provide information for developing safer and more effective anti-obesity drugs.
It is well-known that the drug discovery and development process is lengthy, expensive and prone to failure. This high failure rate is a significant factor in the pharma industry's productivity problems, subsequent mergers and downsizing. Starting from the selection of a novel target in the discovery stage, through the multiple stages of development to regulatory approval, the overall probability of success is less than 1%. Given the time and resources needed to investigate a novel biological mechanism, i.e. one that has not been tested in humans before, success rates as low as these yield an unsustainable business model. In the face of a negative return-on-investment for new chemical entity drug discovery and development and constricted healthcare budgets that demand improved drugs to warrant reimbursement, an alternative approach must be identified to provide patients with new and better therapies as well as sustain the industry. The therapy of type II diabetes and obesity is currently based on seven approved drug classes encompassing both small molecule chemicals (metformin, sulfonylureas, glitazones, DPP-IV inhibitors, pancreatic lipase inhibitors) and (unmodified or modified) proteins (insulin and analogues, glucagon-like polypeptide-I and analogues). Clearly, this repertoire does not meet the requirements for the individualized treatment of metabolic diseases with estimated 2000 to 3000 susceptibility and protective genes and even higher numbers of underlying polymorphisms and combinations thereof, that is thought to form the basis for personalised therapy in the future. As a consequence, novel strategies for the identification of targets that can be addressed by the oral delivery as well as tissue and intracellular targeting of therapeutic proteins and nucleic acids are required. The identified and validated targets emerging will hopefully enable the future development of personalised polypharmacy based on multiple and individual combinations of susceptibility gene products that contribute to the common complex metabolic diseases.
The inductions of chronic diseases and neurodegeneration have become a major
concern in various countries in the developed and developing world. Central coordination
and homeostasis of neuroendocrine systems and renin-angiotensin
systems (RAS) are influenced by external stressors, diet and lifestyles that lead to
abnormal nitric oxide and neural pathways, appetite dysregulation and organ
disease. The alteration in circadian photic signals in the neuroendocrine system
involve the hypothalamus and the suprachiasmatic nucleus that are linked to
apelinergic dysregulation associated with appetite disorders and various organ
diseases. The peripheral sink amyloid beta hypothesis indicates that amyloid beta
(Aβ) is rapidly removed by the liver and chronic diseases are connected to
apelinergic dysfunction with abnormal amyloidogenic pathways that do not allow
the rapid hepatic metabolism of low n Aβ structures. Anti-aging processes cease as
environmental pollutants induce senescent changes in various cells and tissues and
do not allow the metabolism of various sizes of Aβ structures with the induction of
cell suicide. Environmental pollutants associated with unhealthy nutritional habits
increase xenobiotics in plasma and may further promote neuroendocrine disease,
kidney disease and non alcoholic fatty liver disease (NAFLD) with poor Aβ
metabolism. Furthermore stress and unhealthy nutritional lifestyles increase
oxidative stress with abnormal apelin and RAS regulation associated with poor
nitric oxide and vascular Aβ metabolism with the acceleration of neuroendocrine
diseases that include obesity, diabetes, cardiovascular disease and
neurodegenerative diseases.
Effective treatment of obesity could reduce the burden of diseases primarily driven by excess body weight (e.g., Type 2 diabetes). At present, effective nonsurgical weight management tools are scarce. This paper reviews the investigational combination of phentermine, a weight-loss drug available for over half a century, and topiramate, an antiepileptic drug with known weight-loss effects, as a proposed anti-obesity intervention. The combination therapy achieves weight loss of a magnitude that meets the expectations of the US FDA along with improvement of some obesity-related risks. The safety profile is consistent with known adverse effects of individual constituents; cognitive and psychiatric adverse events were dose dependent. Other safety concerns include a small increase in heart rate and potential teratogenicity associated with topiramate.
The field of endocrine pharmacology is very wide but most of studies in the recent years from the world and Iran have focused on diabetes, osteoporosis, and lipid disorders. In the present review, we tried to evaluate the improvements and publications in that field briefly. Interestingly, many of studies have focused on agents that have traditional and natural origin. Although few basic studies have gone on the direct line to complete preclinical and some clinical trial studies, there are many non-clinical studies that have proved efficacy of many compounds in endocrine diseases but these studies were not continued at clinical stages to reach a drug. However, it is appreciable that, some researchers have given novel ideas that deserve investment by grant bodies to reach out valuable works. We believe that science of endocrine pharmacology is still young and more quality studies are still needed to introduce effective medications for diseases like diabetes and osteoporosis or even obesity and lipid disorders.
In this study, the adipogenesis-suppressing effect of 3,5-dimethoxy(4-methoxyphenyl)benzamide (DMPB), a derivative of the anti-obesity substance resveratrol, was measured in 3T3-L1 cells. The results show that DMPB effectively suppressed the hormone-induced differentiation of 3T3-L1 cells, compared to resveratrol at the same concentration, and reduced the protein expression of fatty acid synthase and acetyl-CoA carboxylase. In addition, DMPB was observed to decrease the PPAR-gamma transcription activity, which was increased by rosiglitazone, in a concentration-dependent manner. From the above results, it is considered that DMPB shows strong potential as an anti-obesity substance.
Obesity is one of the largest and fastest growing public health problem in the world. Last century social changes have set an obesogenic milieu that calls for micro and macro environment interventions for disease prevention, while treatment is mandatory for individuals already obese. The cornerstone of overweight and obesity treatment is diet and physical exercise. However, many patients find lifestyle modifications difficult to comply and prone to failure in the long-term; therefore many patients consider anti-obesity drugs an important adjuvant if not a better alternative to behavioral approach or obesity surgery. Since the pharmacological options for obesity treatment remain quite limited, this is an exciting research area, with new treatment targets and strategies on the horizon. This review discusses the development of innovative therapeutic agents, focusing in energy homeostasis regulation and the use of molecular vaccines, targeting hormones such as somatostatin, GIP and ghrelin, to reduce body weight.
The switching Takagi-Sugeno (T-S) fuzzy model-based position control design for a differentially driven wheeled mobile robot is considered in this paper. In this work, the kinematic equations of the differentially driven wheeled mobile robot are firstly represented by exact T-S fuzzy systems. Then the switching section method is further employed to avoid uncontrollable problem of the derived T-S fuzzy model. Consequently, the switching parallel distributed compensation is utilized to control the switching fuzzy system. Moreover, the guaranteed cost control concept is utilized to improve the performance of the control system. Finally, the experimental results illustrate the effectiveness of the control design.
Gastrointestinal sistemin obezitenin yönetimindeki rolü karmaşıktır. Barsaktan beyine gelen bilgiler ve uyarılar iştahın kontrolü ve enerjinin regülasyonu için önemlidir. Birçok peptid yapıda hormona kaynak olan gastrointestinal sistem, bunların çoğu ile iştah üzerine etkilidir. İnsan barsağında çok fazla miktarda ortak yaşam süren (kommensal ve simbiyotik) bakteri vardır. Bu içeriğin obezitenin gelişiminde çok önemli rolü vardır. Barsak florası obezite için çevresel bir neden olabilir.
The disease of obesity is one of the greatest healthcare challenges of our time. The increasing urgency for effective treatment is driving an intensive search for new targets for anti-obesity drug discovery. The TRP channel super family represents a class of proteins now recognized to serve many functions in physiology related to maintenance of health and the development of diseases. A few of these might offer new potential for therapeutic intervention in obesity. Among the TRP channels, TRPV1 appears most closely associated with body weight homeostasis through its influence on energy expenditure. TRPM5 has been thoroughly characterized as a critical component of taste signaling and recently has been implicated in insulin release. Because of its role in taste signaling, we argue that drugs designed to modulate TRPM5 could be useful in controlling energy consumption by impacting taste sensory signals. As drug targets for obesity, both TRPV1 and TRPM5 offer the advantage of operating in compartments that could limit drug distribution to the site of action. The potential for other TRP channels as anti-obesity drug targets also is discussed.
Over the past 30 years, it has been established that hormones produced by the gut, pancreas, and adipose tissue are key players in the control of body weight. These hormones act through a complex neuroendocrine system, including the hypothalamus, to regulate metabolism and energy homeostasis. In obesity, this homeostatic balance is disrupted, either through alterations in the levels of these hormones or through resistance to their actions. Alterations in gut hormone secretion following gastric bypass surgery are likely to underlie the dramatic and persistent loss of weight following this procedure, as well as the observed amelioration in type 2 diabetes mellitus. Medications based on the gut hormone GLP-1 are currently in clinical use to treat type 2 diabetes mellitus and have been shown to produce weight loss. Further therapies for obesity based on other gut hormones are currently in development.
The ratio of GLP-1/glucagon receptor (GLP1R/GCGR) co-agonism that achieves maximal weight loss without evidence of hyperglycemia was determined in diet-induced obese (DIO) mice chronically treated with GLP1R/GCGR co-agonist peptides differing in their relative receptor agonism. Using glucagon-based peptides, a spectrum of receptor selectivity was achieved by a combination of selective incorporation of GLP-1 sequences, C-terminal modification, backbone lactam stapling to stabilize helical structure, and unnatural amino acid substitutions at the N-terminal dipeptide. In addition to α-amino-isobutyric acid (Aib) substitution at position two, we show that α,α'-dimethyl imidazole acetic acid (Dmia) can serve as a potent replacement for the highly conserved histidine at position one. Selective site-specific pegylation was used to further minimize enzymatic degradation and provide uniform, extended in vivo duration of action. Maximal weight loss devoid of any sign of hyperglycemia was achieved with a co-agonist comparably balanced for in vitro potency at murine GLP1R and GCGR. This peptide exhibited superior weight loss and glucose lowering compared to a structurally matched pure GLP1R agonist, and to co-agonists of relatively reduced GCGR tone. Any further enhancement of the relative GCGR agonist potency yielded increased weight loss but at the expense of elevated blood glucose. We conclude that GCGR agonism concomitant with GLP1R agonism constitutes a promising approach to treatment of the metabolic syndrome. However, the relative ratio of GLP1R/GCGR co-agonism needs to be carefully chosen for each species to maximize weight loss efficacy and minimize hyperglycemia. © 2012 Wiley Periodicals, Inc. Biopolymers (Pept Sci) 98: 443-450, 2012.
Background:
Cardiac consequences of obesity include inflammation, hypertrophy, and compromised energy metabolism. Glucagon-like peptide-1 is an incretin hormone capable of cytoprotective actions that reduces inflammation and endoplasmic reticulum stress in other tissues. Here we examine the cardiac effects of the glucagon-like peptide-1 analog liraglutide in a model of obesity, independent of changes in body weight.
Methods and results:
C57Bl6 mice were placed on a 45% high-fat diet (HFD) or a regular chow diet. Mice on HFD developed 46±2% and 60±2% greater body weight relative to regular chow diet-fed mice at 16 and 32 weeks, respectively (both P<0.0001), manifesting impaired glucose tolerance, insulin resistance, and cardiac ceramide accumulation by 16 weeks. One-week treatment with liraglutide (30 µg/kg twice daily) did not reduce body weight, but reversed insulin resistance, cardiac tumor necrosis factor-α expression, nuclear factor kappa B translocation, obesity-induced perturbations in cardiac endothelial nitric oxide synthase, connexin-43, and markers of hypertrophy and fibrosis, in comparison with placebo-treated HFD controls. Liraglutide improved the cardiac endoplasmic reticulum stress response and also improved cardiac function in animals on HFD by an AMP-activated protein kinase-dependent mechanism. Supporting a direct mechanism of action, liraglutide (100 nmol/L) prevented palmitate-induced lipotoxicity in isolated mouse cardiomyocytes and primary human coronary smooth muscle cells and prevented adhesion of human monocytes to tumor necrosis factor-α-activated human endothelial cells in vitro.
Conclusions:
Weight-neutral treatment with a glucagon-like peptide-1 analog activates several cardioprotective pathways, prevents HFD-induced insulin resistance and inflammation, reduces monocyte vascular adhesion, and improves cardiac function in vivo by activating AMP-activated protein kinase. These data support a role for glucagon-like peptide-1 analogs in limiting the cardiovascular risks of obesity.
Obesity and type 2 diabetes are chronic lifestyle diseases which are dramatically increasing worldwide leading to high costs and an enormous burden on the public health care system. Both biological and psychosocial factors, environment and lifestyle are involved in the pathogenesis of these metabolic disorders and thus important sex- and gender-based differences can be found. These differences have also important implications for lifestyle intervention (nutrition and exercise) and drug therapy.
Objective: To examine the relation between adult weight change and the risk for clinical diabetes mellitus among middle-aged women. • Design: Prospective cohort study with follow-up from 1976 to 1990. • Setting: 11 U.S. states. • Participants: I'll 281 female registered nurses aged 30 to 55 years who did not have diagnosed diabetes mellitus, coronary heart disease, stroke, or cancer in 1976. • Outcome Measures: Non-insulin-dependent diabetes mellitus. • Results: 2204 cases of diabetes were diagnosed during 1.49 million person-years of follow-up. After adjustment for age, body mass index was the dominant predictor of risk for diabetes mellitus. Risk increased with greater body mass index, and even women with average weight (body mass index, 24.0 kg/m 2) had an elevated risk. Compared with women with stable weight (those who gained or lost less than 5 kg between age 18 years and 1976) and after adjustment for age and body mass index at age 18 years, the relative risk for diabetes mellitus among women who had a weight gain of 5.0 to 7.9 kg was 1.9 (95% CI, 1.5 to 2.3). The corresponding relative risk for women who gained 8.0 to 10.9 kg was 2.7 (CI, 2.1 to 3.3). In contrast, women who lost more than 5.0 kg reduced their risk for diabetes mellitus by 50% or more. These results were independent of family history of diabetes. • Conclusion: The excess risk for diabetes with even modest and typical adult weight gain is substantial. These findings support the importance of maintaining a constant body weight throughout adult life and suggest that the 1990 U.S. Department of Agriculture guidelines that allow a substantial weight gain after 35 years of age are misleading.
Context The prevalence of obesity and overweight increased in the United States
between 1978 and 1991. More recent reports have suggested continued increases
but are based on self-reported data.Objective To examine trends and prevalences of overweight (body mass index [BMI]
≥25) and obesity (BMI ≥30), using measured height and weight data.Design, Setting, and Participants Survey of 4115 adult men and women conducted in 1999 and 2000 as part
of the National Health and Nutrition Examination Survey (NHANES), a nationally
representative sample of the US population.Main Outcome Measure Age-adjusted prevalence of overweight, obesity, and extreme obesity
compared with prior surveys, and sex-, age-, and race/ethnicity–specific
estimates.Results The age-adjusted prevalence of obesity was 30.5% in 1999-2000 compared
with 22.9% in NHANES III (1988-1994; P<.001).
The prevalence of overweight also increased during this period from 55.9%
to 64.5% (P<.001). Extreme obesity (BMI ≥40)
also increased significantly in the population, from 2.9% to 4.7% (P = .002). Although not all changes were statistically significant,
increases occurred for both men and women in all age groups and for non-Hispanic
whites, non-Hispanic blacks, and Mexican Americans. Racial/ethnic groups did
not differ significantly in the prevalence of obesity or overweight for men.
Among women, obesity and overweight prevalences were highest among non-Hispanic
black women. More than half of non-Hispanic black women aged 40 years or older
were obese and more than 80% were overweight.Conclusions The increases in the prevalences of obesity and overweight previously
observed continued in 1999-2000. The potential health benefits from reduction
in overweight and obesity are of considerable public health importance.
Several peptides have been proposed as regulators of nutrient release from the stomach and subsequent uptake from the gut. Using a phenol red gavage method, we compared the potencies of subcutaneously preinjected amylin, glucagon-like peptide-1 (7–36)amide (GLP-1), cholecystokinin octapeptide (CCK-8), gastric inhibitory peptide (GIP), glucagon, and pancreatic peptide on slowing the release of an acaloric gel from rat stomach. The latter three peptides did not fully inhibit gastric emptying at subcutaneous doses up to 100 μg. Amylin, GLP-1, and CCK-8 fully inhibited gastric emptying, with ED50s of 0.42 ± 0.07, 6.1 ± 0.12, and 8.5 ± 0.20 nmol/kg ± SE of log, respectively.
Human studies and assays Test meals were prepared using conventional pasta (Sainsbury, London UK) or high- protein pasta (Atkins, Shelton, CT, USA) with a tomato based sauce. Additional protein, carbohydrate and fat supplements were added (Maxipro, UK, Maxijuel and Calogen, SHS International, Merseyside, UK) to the tomato sauce and dessert. Blood was collected into EDTA tubes containing 5000 kallikrein inhibitor units of aprotonin (Bayer, Newbury, Berks, U.K.) per ml. Plasma samples were separated immediately by centrifugation at 4°C. For subsequent PYY (total and PYY3-36) and active GLP-1 DPPIV inhibitor (Linco Research Inc., St Louis, MO, USA) was added to plasma samples to give a final concentration of 100 µM. Samples for analysis of active ghrelin had 100 µl of 1M HCL added per ml of plasma. ELISA kits were used to quantify desacyl-ghrelin, active-ghrelin,
Food intake and body weight are determined by a complex interaction of regulatory pathways. To elucidate the contribution of the endogenous peptide cholecystokinin, mice lacking functional cholecystokinin-A receptors were generated by targeted gene disruption. To explore the role of the cholecystokinin-A receptor in mediating satiety, food intake of cholecystokinin-A receptor(-/-) mice was compared with the corresponding intakes of wild-type animals and mice lacking the other known cholecystokinin receptor subtype, cholecystokinin-B/gastrin. Intraperitoneal administration of cholecystokinin failed to decrease food intake in mice lacking cholecystokinin-A receptors. In contrast, cholecystokinin diminished food intake by up to 90% in wild-type and cholecystokinin-B/gastrin receptor(-/-) mice. Together, these findings indicate that cholecystokinin-induced inhibition of food intake is mediated by the cholecystokinin-A receptor. To explore the long-term consequences of either cholecystokinin-A or cholecystokinin-B/gastrin receptor absence, body weight as a function of age was compared between freely fed wild-type and mutant animals. Both cholecystokinin-A and cholecystokinin-B/gastrin receptor(-/-) mice maintained normal body weight well into adult life. In addition, each of the two receptor(-/-) strains had normal pancreatic morphology and were normoglycemic. Our results suggest that although cholecystokinin plays a role in the short-term inhibition of food intake, this pathway is not essential for the long-term maintenance of body weight.
To evaluate the efficacy and safety of taspoglutide (R1583/BIM51077), a human once-weekly glucagon-like peptide-1 analog, in patients with type 2 diabetes inadequately controlled with metformin.
Type 2 diabetic (n = 306) patients who failed to obtain glycemic control (A1C 7-9.5%) despite 1,500 mg metformin daily were randomly assigned to 8 weeks of double-blind subcutaneous treatment with placebo or taspoglutide, either 5, 10, or 20 mg once weekly or 10 or 20 mg once every 2 weeks, and followed for 4 additional weeks. All patients received their previously established dose of metformin throughout the study. Glycemic control was assessed by change in A1C (percent) from baseline.
Significantly greater (P < 0.0001) reductions in A1C from a mean +/- SD baseline of 7.9 +/- 0.7% were observed in all taspoglutide groups compared with placebo after 8 weeks of treatment: -1.0 +/- 0.1% (5 mg once weekly), -1.2 +/- 0.1% (10 mg once weekly), -1.2 +/- 0.1% (20 mg once weekly), -0.9 +/- 0.1% (10 mg Q2W), and -1.0 +/- 0.1% (20 mg Q2W) vs. -0.2 +/- 0.1% with placebo. After 8 weeks, body weight loss was significantly greater in the 10 mg (-2.1 +/- 0.3 kg, P = 0.0035 vs. placebo) and 20 mg (-2.8 +/- 0.3 kg, P < 0.0001) once-weekly groups and the 20 mg once every 2 weeks (-1.9 +/- 0.3 kg, P = 0.0083) group than with placebo (-0.8 +/- 0.3 kg). The most common adverse event was dose-dependent, transient, mild-to-moderate nausea; the incidence of hypoglycemia was very low.
Taspoglutide used in combination with metformin significantly improves fasting and postprandial glucose control and induces weight loss, with a favorable tolerability profile.
To compare the effects of combining liraglutide (0.6, 1.2 or 1.8 mg/day) or rosiglitazone 4 mg/day (all n >or= 228) or placebo (n = 114) with glimepiride (2-4 mg/day) on glycaemic control, body weight and safety in Type 2 diabetes.
In total, 1041 adults (mean +/- sd), age 56 +/- 10 years, weight 82 +/- 17 kg and glycated haemoglobin (HbA(1c)) 8.4 +/- 1.0% at 116 sites in 21 countries were stratified based on previous oral glucose-lowering mono : combination therapies (30 : 70%) to participate in a five-arm, 26-week, double-dummy, randomized study.
Liraglutide (1.2 or 1.8 mg) produced greater reductions in HbA(1c) from baseline, (-1.1%, baseline 8.5%) compared with placebo (+0.2%, P < 0.0001, baseline 8.4%) or rosiglitazone (-0.4%, P < 0.0001, baseline 8.4%) when added to glimepiride. Liraglutide 0.6 mg was less effective (-0.6%, baseline 8.4%). Fasting plasma glucose decreased by week 2, with a 1.6 mmol/l decrease from baseline at week 26 with liraglutide 1.2 mg (baseline 9.8 mmol/l) or 1.8 mg (baseline 9.7 mmol/l) compared with a 0.9 mmol/l increase (placebo, P < 0.0001, baseline 9.5 mmol/l) or 1.0 mmol/l decrease (rosiglitazone, P < 0.006, baseline 9.9 mmol/l). Decreases in postprandial plasma glucose from baseline were greater with liraglutide 1.2 or 1.8 mg [-2.5 to -2.7 mmol/l (baseline 12.9 mmol/l for both)] compared with placebo (-0.4 mmol/l, P < 0.0001, baseline 12.7 mmol/l) or rosiglitazone (-1.8 mmol/l, P < 0.05, baseline 13.0 mmol/l). Changes in body weight with liraglutide 1.8 mg (-0.2 kg, baseline 83.0 kg), 1.2 mg (+0.3 kg, baseline 80.0 kg) or placebo (-0.1 kg, baseline 81.9 kg) were less than with rosiglitazone (+2.1 kg, P < 0.0001, baseline 80.6 kg). Main adverse events for all treatments were minor hypoglycaemia (< 10%), nausea (< 11%), vomiting (< 5%) and diarrhoea (< 8%).
Liraglutide added to glimepiride was well tolerated and provided improved glycaemic control and favourable weight profile.
To determine the efficacy and safety of liraglutide (a glucagon-like peptide-1 receptor agonist) when added to metformin and rosiglitazone in type 2 diabetes.
This 26-week, double-blind, placebo-controlled, parallel-group trial randomized 533 subjects (1:1:1) to once-daily liraglutide (1.2 or 1.8 mg) or liraglutide placebo in combination with metformin (1 g twice daily) and rosiglitazone (4 mg twice daily). Subjects had type 2 diabetes, A1C 7-11% (previous oral antidiabetes drug [OAD] monotherapy >or=3 months) or 7-10% (previous OAD combination therapy >or=3 months), and BMI <or=45 kg/m(2).
Mean A1C values decreased significantly more in the liraglutide groups versus placebo (mean +/- SE -1.5 +/- 0.1% for both 1.2 and 1.8 mg liraglutide and -0.5 +/- 0.1% for placebo). Fasting plasma glucose decreased by 40, 44, and 8 mg/dl for 1.2 and 1.8 mg and placebo, respectively, and 90-min postprandial glucose decreased by 47, 49, and 14 mg/dl, respectively (P < 0.001 for all liraglutide groups vs. placebo). Dose-dependent weight loss occurred with 1.2 and 1.8 mg liraglutide (1.0 +/- 0.3 and 2.0 +/- 0.3 kg, respectively) (P < 0.0001) compared with weight gain with placebo (0.6 +/- 0.3 kg). Systolic blood pressure decreased by 6.7, 5.6, and 1.1 mmHg with 1.2 and 1.8 mg liraglutide and placebo, respectively. Significant increases in C-peptide and homeostasis model assessment of beta-cell function and significant decreases in the proinsulin-to-insulin ratio occurred with liraglutide versus placebo. Minor hypoglycemia occurred more frequently with liraglutide, but there was no major hypoglycemia. Gastrointestinal adverse events were more common with liraglutide, but most occurred early and were transient.
Liraglutide combined with metformin and a thiazolidinedione is a well-tolerated combination therapy for type 2 diabetes, providing significant improvements in glycemic control.
Oxyntomodulin (Oxm) is an intestinal peptide that inhibits food intake and body weight in rodents and humans. These studies used peptide analogs to study aspects of structure and function of Oxm, and the sensitivity of parts of the Oxm sequence to degradation. Analogs of Oxm were synthesized and studied using receptor binding and degradation studies in vitro. Their effects on food intake and conditioned taste avoidance were measured in vivo in rodents. Oxm breakdown by the enzyme dipeptidyl peptidase IV (DPPIV) was demonstrated in vitro and in vivo. In vitro degradation was reduced and in vivo bioactivity increased by inhibitors of DPPIV. Modifications to the N terminus of Oxm modulated binding to the glucagon-like peptide (GLP)-1 receptor and degradation by DPPIV. Modifications to the midsection of Oxm modulated binding to the GLP-1 receptor and degradation by neutral endopeptidase. These modifications also altered bioactivity in vivo. The C-terminal octapeptide of Oxm was shown to contribute to the properties of Oxm in vitro and in vivo but was not alone sufficient for the effects of the peptide. Elongation and acylation of the C terminus of Oxm altered GLP-1 receptor binding and duration of action in vivo, which may be due to changes in peptide clearance. An Oxm analog was developed with enhanced pharmaceutical characteristics, with greater potency and longevity with respect to effects on food intake. These studies suggest that Oxm is a potential target for antiobesity drug design.
We have used manganese-enhanced magnetic resonance imaging (MEMRI) to show distinct patterns of neuronal activation within the hypothalamus and brainstem of fasted mice in response to peripheral injection of the anorexigenic agents glucagon-like peptide-1 (GLP-1), oxyntomodulin (OXM) and lithium chloride. Administration of both GLP-1 and OXM resulted in a significant increase in signal intensity (SI) in the area postrema of fasted mice, reflecting an increase in neuronal activity within the brainstem. In the hypothalamus, GLP-1 administration induced a significant reduction in SI in the paraventricular nucleus and an increase in the ventromedial hypothalamic nucleus whereas OXM reduced SI in the arcuate and supraoptic nuclei of the hypothalamus. These data indicate that whilst these related peptides both induce a similar effect on neuronal activity in the brainstem they generate distinct patterns of activation within the hypothalamus. Furthermore, the hypothalamic pattern of signal intensity generated by GLP-1 closely matches that generated by peripheral injection of LiCl, suggesting the anorexigenic effects of GLP-1 may be in part transmitted via nausea circuits. This work provides a framework by which the temporal effects of appetite modulating agents can be recorded simultaneously within hypothalamic and brainstem feeding centres.
Growth hormone secretion and muscle mass decline from midpuberty throughout life, culminating in sarcopenia, frailty, decreased function, and loss of independence. The decline of growth hormone in the development of sarcopenia is one of many factors, and its etiologic role needs to be demonstrated.
To determine whether MK-677, an oral ghrelin mimetic, increases growth hormone secretion into the young-adult range without serious adverse effects, prevents the decline of fat-free mass, and decreases abdominal visceral fat in healthy older adults.
2-year, double-blind, randomized, placebo-controlled, modified-crossover clinical trial.
General clinical research center study performed at a university hospital.
65 healthy adults (men, women receiving hormone replacement therapy, and women not receiving hormone replacement therapy) ranging from 60 to 81 years of age.
Oral administration of MK-677, 25 mg, or placebo once daily.
Growth hormone and insulin-like growth factor I levels. Fat-free mass and abdominal visceral fat were the primary end points after 1 year of treatment. Other end points were body weight, fat mass, insulin sensitivity, lipid and cortisol levels, bone mineral density, limb lean and fat mass, isokinetic strength, function, and quality of life. All end points were assessed at baseline and every 6 months.
Daily administration of MK-677 significantly increased growth hormone and insulin-like growth factor I levels to those of healthy young adults without serious adverse effects. Mean fat-free mass decreased in the placebo group but increased in the MK-677 group (change, -0.5 kg [95% CI, -1.1 to 0.2 kg] vs. 1.1 kg [CI, 0.7 to 1.5 kg], respectively; P < 0.001), as did body cell mass, as reflected by intracellular water (change, -1.0 kg [CI, -2.1 to 0.2 kg] vs. 0.8 kg [CI, -0.1 to 1.6 kg], respectively; P = 0.021). No significant differences were observed in abdominal visceral fat or total fat mass; however, the average increase in limb fat was greater in the MK-677 group than the placebo group (1.1 kg vs. 0.24 kg; P = 0.001). Body weight increased 0.8 kg (CI, -0.3 to 1.8 kg) in the placebo group and 2.7 kg (CI, 2.0 to 3.5 kg) in the MK-677 group (P = 0.003). Fasting blood glucose level increased an average of 0.3 mmol/L (5 mg/dL) in the MK-677 group (P = 0.015), and insulin sensitivity decreased. The most frequent side effects were an increase in appetite that subsided in a few months and transient, mild lower-extremity edema and muscle pain. Low-density lipoprotein cholesterol levels decreased in the MK-677 group relative to baseline values (change, -0.14 mmol/L [CI, -0.27 to -0.01 mmol/L]; -5.4 mg/dL [CI, -10.4 to -0.4 mg/dL]; P = 0.026); no differences between groups were observed in total or high-density lipoprotein cholesterol levels. Cortisol levels increased 47 nmol/L (CI, 28 to 71 nmol/L (1.7 microg/dL [CI, 1.0 to 2.6 microg/dL]) in MK-677 recipients (P = 0.020). Changes in bone mineral density consistent with increased bone remodeling occurred in MK-677 recipients. Increased fat-free mass did not result in changes in strength or function. Two-year exploratory analyses confirmed the 1-year results.
Study power (duration and participant number) was insufficient to evaluate functional end points in healthy elderly persons.
Over 12 months, the ghrelin mimetic MK-677 enhanced pulsatile growth hormone secretion, significantly increased fat-free mass, and was generally well tolerated. Long-term functional and, ultimately, pharmacoeconomic, studies in elderly persons are indicated.
The efficacy and safety of adding liraglutide (a glucagon-like peptide-1 receptor agonist) to metformin were compared with addition of placebo or glimepiride to metformin in subjects previously treated with oral antidiabetes (OAD) therapy.
In this 26-week, double-blind, double-dummy, placebo- and active-controlled, parallel-group trial, 1,091 subjects were randomly assigned (2:2:2:1:2) to once-daily liraglutide (either 0.6, 1.2, or 1.8 mg/day injected subcutaneously), to placebo, or to glimepiride (4 mg once daily). All treatments were in combination therapy with metformin (1g twice daily). Enrolled subjects (aged 25-79 years) had type 2 diabetes, A1C of 7-11% (previous OAD monotherapy for > or =3 months) or 7-10% (previous OAD combination therapy for > or =3 months), and BMI < or =40 kg/m(2).
A1C values were significantly reduced in all liraglutide groups versus the placebo group (P < 0.0001) with mean decreases of 1.0% for 1.8 mg liraglutide, 1.2 mg liraglutide, and glimepiride and 0.7% for 0.6 mg liraglutide and an increase of 0.1% for placebo. Body weight decreased in all liraglutide groups (1.8-2.8 kg) compared with an increase in the glimepiride group (1.0 kg; P < 0.0001). The incidence of minor hypoglycemia with liraglutide ( approximately 3%) was comparable to that with placebo but less than that with glimepiride (17%; P < 0.001). Nausea was reported by 11-19% of the liraglutide-treated subjects versus 3-4% in the placebo and glimepiride groups. The incidence of nausea declined over time.
In subjects with type 2 diabetes, once-daily liraglutide induced similar glycemic control, reduced body weight, and lowered the occurrence of hypoglycemia compared with glimepiride, when both had background therapy of metformin.
Native glucagon-like peptide-1 increases insulin secretion, decreases glucagon secretion, and reduces appetite but is rapidly inactivated by dipeptidyl peptidase-4. Albiglutide is a novel dipeptidyl peptidase-4-resistant glucagon-like peptide-1 dimer fused to human albumin designed to have sustained efficacy in vivo.
The objectives were to investigate pharmacodynamics, pharmacokinetics, safety, and tolerability of albiglutide in type 2 diabetes subjects.
In a single-blind dose-escalation study, 54 subjects were randomized to receive placebo or 9-, 16-, or 32-mg albiglutide on d 1 and 8. In a complementary study, 46 subjects were randomized to a single dose (16 or 64 mg) of albiglutide to the arm, leg, or abdomen.
Significant dose-dependent reductions in 24-h mean weighted glucose [area under the curve((0-24 h))] were observed, with placebo-adjusted least squares means difference values in the 32-mg cohort of -34.8 and -56.4 mg/dl [95% confidence interval (-54.1, -15.5) and (-82.2, -30.5)] for d 2 and 9, respectively. Placebo-adjusted fasting plasma glucose decreased by -26.7 and -50.7 mg/dl [95% confidence interval (-46.3, -7.06) and (-75.4, -26.0)] on d 2 and 9, respectively. Postprandial glucose was also reduced. No hypoglycemic episodes were detected in the albiglutide cohorts. The frequency and severity of the most common adverse events, headache and nausea, were comparable with placebo controls. Albiglutide half-life ranged between 6 and 7 d. The pharmacokinetics or pharmacodynamic of albiglutide was unaffected by injection site.
Albiglutide improved fasting plasma glucose and postprandial glucose with a favorable safety profile in subjects with type 2 diabetes. Albiglutide's long half-life may allow for once-weekly or less frequent dosing.
To assess long-term weight loss efficacy and safety of pramlintide used at different dosing regimens and in conjunction with lifestyle intervention (LSI).
In a 4-month, double-blind, placebo-controlled, dose-ranging study, 411 obese subjects were randomized to receive pramlintide (six arms: 120, 240, and 360 microg b.i.d. and t.i.d.) or placebo in conjunction with a structured LSI program geared toward weight loss. Of the 4-month evaluable subjects (n = 270), 77% opted to continue preexisting treatment during an 8-month single-blind extension (LSI geared toward weight maintenance).
At month 4, mean weight loss from baseline in the pramlintide arms ranged from 3.8 +/- 0.7 to 6.1 +/- 0.8 kg (2.8 +/- 0.8 kg with placebo). By month 12, initial 4-month weight loss was regained in the placebo group but was maintained in all but the 120-microg b.i.d. group. Placebo-corrected weight loss with 120 microg t.i.d. and 360 microg b.i.d. averaged 3.2 +/- 1.2 kg (3.1 +/- 1.1% body wt) and 3.3 +/- 1.1 kg (3.1 +/- 1.0% body wt), respectively, at month 4 (both P < 0.01; 4-month evaluable n = 270) and 6.1 +/- 2.1 kg (5.6 +/- 2.1% body wt) and 7.2 +/- 2.3 kg (6.8 +/- 2.3% body wt), respectively, at month 12 (both P < 0.01; 12-month evaluable n = 146). At month 12, 40 and 43% of subjects treated with 120 microg t.i.d. and 360 microg b.i.d., respectively, achieved >or=10% weight loss (vs. 12% for placebo). Nausea, the most common adverse event with pramlintide in the 4-month study (9-29% pramlintide vs. 2% placebo), was generally mild to moderate and occurred in <10% of subjects during the extension.
When used over 12 months as an adjunct to LSI, pramlintide treatment, with low-dose three-times-daily or higher-dose two-times-daily regimens, helped obese subjects achieve greater initial weight loss and enhanced long-term maintenance of weight loss.
Pure bovine pancreatic polypeptide (PP) was infused into 23 healthy subjects at doses of 1, 3, and 5 pmol/kg/min over 60 minutes and plasma PP was measured by radioimmunoassay. During the infusions mean plasma levels of 203 +/- 34, 575 +/- 73, and 930 +/- 48 pmol/l respectively were achieved. Mean disappearance half time on stopping the infusion was 6.9 +/- 0.3 min (mean +/- SEM). The metabolic clearance rate was 5.1 +/- 0.2 ml/kg/min (mean +/- SEM) and the apparent volume of distribution was calculated to be 51 +/- 3 ml/kg (mean +/- SEM). This study provides for the first time pharmacokinetic data for PP in man.
THE EFFECT OF EFFERENT, PARASYMPATHETIC STIMULATION UPON PANCREATIC POLYPEPTIDE (PP) SECRETION WAS STUDIED IN THREE WAYS: (a) Plasma PP concentrations increased in response to insulin-induced hypoglycemia in both normal subjects, from 11 pM (9.5-12.5) to 136 pM (118-147), n = 8 (median and interquartile range) and in duodenal ulcer patients, from 33 pM (21-52) to 213 pM (157-233), n = 7. The PP response to hypoglycemia was diminished by atropine in normal subjects (P < 0.005) and completely abolished by vagotomy in the duodenal ulcer patients. (b) Electrical stimulation, 8 Hz, of the vagal nerves in anesthetized pigs induced an increase in portal PP concentrations within 30 s from 32 pM (28-39) to 285 pM (248-294), n = 12. Minimal stimulatory frequency was 0.5 Hz and maximal stimulatory frequency 8-12 Hz. Atropine inhibited the PP response to electrical stimulation. Median inhibition with 0.5 mg of atropine/kg body wt was 74%, range 31-90%, n = 6. The response was eliminated by hexamethonium. Adrenergic alpha and beta blockade did not influence the release of PP in response to vagal stimulation. (c) Acetylcholine stimulated, in a dose-dependent manner, the secretion of PP from the isolated perfused porcine pancreas, half-maximal effective dose being 0.19 muM; maximal PP output in response to 5 min stimulation was 228 pmol, range 140-342 pmol, n = 5. Atropine completely abolished this response.The results of the present study together with the previously demonstrated poor PP response to food in vagotomized patients, indicate that vagal, cholinergic stimulation is a major regulator of PP secretion.
A simple and reliable radioimmunoassay has been developed for a new gut hormone, HPP. In the primate 93% of the total PP was found in the pancreas with a small amount throughout the remaining gastrointestinal tract. HPP has been shown to be produced by a number of pancreatic apudomas and their metastases. The immunoreactive PP from these tumours and from normal pancreas was chromatographically indistinguishable from the pure peptide. The plasma PP concentration rose rapidly after a meal in normal subjects and was still raised six hours later. Fasting plasma PP levels in patients with PP cell containing pancreatic endocrine tumours were higher than even the postprandial level in normal subjects. PP measurements is thus useful in diagnosis of pancreatic endocrine tumours.
In comparison with a saline infusion, the infusion of the C-terminal octapeptide of cholecystokinin (4 ng/kg/min) decreased food intake by an average of 122 g in a group of 12 lean men without objective evidence of untoward side effects. Shapes of the cumulative intake curves under the two conditions were similar, but subjects ate less and stopped eating sooner when receiving octapeptide than when receiving saline. These results are consistent with the hypothesis that cholecystokinin is an endogenous signal for postprandial satiety. The results offer promise for the possible use of the octapeptide as an appetite suppressant.
Glucose homeostasis in mammals is maintained by insulin secretion from the β-cells of the islets of Langerhans. Type 2 diabetes results either from primary β-cell failure alone and/or a failure to secrete enough insulin to overcome insulin resistance. Here, we show that continuous infusion of glucagon-like peptide-1 (7–36) (GLP-1; an insulinotropic agent), to young and old animals, had effects on the β-cell of the pancreas other than simply on the insulin secretory apparatus. Our previous studies on a rodent model of glucose intolerance, the aging Wistar rat, show that a plateau in islet size, insulin content, and β-cell mass is reached at 13 months, despite a continuing increase in body weight. Continuous sc infusion of GLP-1 (1.5 pm/kg·min), over 5 days, resulted in normal glucose tolerance. Our current results in both young and old rats demonstrate that treatment caused an up-regulation of pancreatic-duodenum homeobox-1 (PDX-1) expression in islets and total pancreas, induced pancreatic cell proliferation, and β-cell neogenesis. The effects on levels of PDX-1 messenger RNA were abrogated by simultaneous infusion of Exendin (9–39), a specific antagonist of GLP-1. PDX-1 protein levels increased 4-fold in whole pancreata and 6-fold in islets in response to treatment.β -cell mass increased to 7.2 ± 0.58 from 4.88 ± 0.38 mg, treated vs. control, respectively, P< 0.02. Total pancreatic insulin content also increased from 0.55± 0.02 to 1.32 ± 0.11 μg/mg total pancreatic protein. Therefore, GLP-1 would seem to be a unique therapy that can stimulate pancreatic cell proliferation and β-cell differentiation in the pancreas of rodents.
A radioimmunoassay has been developed for the new intestinal hormonal peptide tyrosine tyrosine [peptide YY (PYY)]. Peptide YY concentrations were measured in separated layers of the human gastrointestinal tract, where PYY was found exclusively in the mucosal epithelium which contained the endocrine cells. Peptide YY was found throughout the small intestine, in very low concentrations (5 pmol/g) in duodenum (6 pmol/g) and jejunum (5 pmpl/g), but in higher concentrations in the terminal ileum (84 pmol/g). High concentrations were found throughout the colon (ascending 82 pmol/g, sigmoid 196 pmol/g), being maximum in the rectum (480 pmol/g). The major molecular form of PYY-like immunoreactivity in human intestine appeared to be identical to pure porcine hormone, both as judged by gel permeation chromatography and by reversephase high-pressure liquid chromatography. Basal plasma concentrations of PYY were low but rose in response to food, remaining elevated for several hours postprandially. The known potent biologic actions of PYY, its high concentrations in gut endocrine cells, and its release into the circulation after a normal meal suggest that this peptide may function physiologically as a circulating gut hormone.
The three peptides pancreatic polypeptide (PP), peptide YY (PYY), and neuropeptide Y (NPY) share a similar structure known as the PP-fold. There are four known human G-protein coupled receptors for the PP-fold peptides, namely Y1, Y2, Y4, and Y5, each of them being able to bind at least two of the three endogenous ligands. All three peptides are found in the circulation acting as hormones. Although NPY is only released from neurons, PYY and PP are primarily found in endocrine cells in the gut, where they exert such effects as inhibition of gall bladder secretion, gut motility, and pancreatic secretion. However, when PYY is administered in an experimental setting to animals, cloned receptors, or tissue preparations, it can mimic the effects of NPY in essentially all studies, making it difficult to study the effects of PP-fold peptides and to delineate what receptor and peptide accounts for a particular effect. Initial studies with transgenic animals confirmed the well-established action of NPY on metabolism, food-intake, vascular systems, memory, mood, neuronal excitability, and reproduction. More recently, using transgenic techniques and novel antagonists for the Y1, Y2, and Y5 receptors, NPY has been found to be a key player in the regulation of ethanol consumption and neuronal development.
Ghrelin, a novel GH-releasing acylated peptide, was recently isolated from rat stomach. It stimulated the release of GH from the anterior pituitary through the GH secretagogue receptor (GHS-R). Ghrelin messenger RNA and the peptide are present in rat stomach, but its cellular source has yet to be determined. Using two different antibodies against the N- and C-terminal regions of rat ghrelin, we identified ghrelin-producing cells in the gastrointestinal tracts of rats and humans by light and electron microscopic immunohistochemistry and in situ hybridization combined with immunohistochemistry. Ghrelin-immunoreactive cells, which are not enterochromaffin-like cells, D cells, or enterochromaffin cells, accounted for about 20% of the endocrine cell population in rat and human oxyntic glands. Rat ghrelin was present in round, compact, electron-dense granules compatible with those of X/A-like cells whose hormonal product and physiological functions have not previously been clarified. The localization, population, and ultrastructural features of ghrelin-producing cells (Gr cells) indicate that they are X/A-like cells. Ghrelin also was found in enteric endocrine cells of rats and humans. Using two RIAs for the N- and C-terminal regions of ghrelin, we determined its content in the rat gastrointestinal tract. Rat ghrelin was present from the stomach to the colon, with the highest content being in the gastric fundus. Messenger RNAs of ghrelin and GHS-R also were found in these organs. Ghrelin probably functions not only in the control of GH secretion, but also in the regulation of diverse processes of the digestive system. Our findings provide clues to additional, as yet undefined, physiological functions of this novel gastrointestinal hormone.
Background: Physicians may use either insulin or exenatide injections for patients with type 2 diabetes mellitus who have poor glycemic control despite taking oral blood glucose-lowering drugs. Objective: To compare effects of exenatide and insulin glargine on glycemic control in patients with type 2 diabetes mellitus that is suboptimally controlled with metformin and a sulfonylurea. Design: 26-week multicenter, open-label, randomized, controlled trial. Setting: 82 outpatient study centers in 13 countries. Patients: 551 patients with type 2 diabetes and inadequate glycemic control (defined as hemoglobin A 1c level ranging from 7.0% to 10.0%) despite combination metformin and sulfonylurea therapy. Intervention: Exenatide, 10 μg twice daily, or insulin glargine, 1 daily dose titrated to maintain fasting blood glucose levels of less than 5.6 mmol/L (<100 mg/dL). Measurements: Hemoglobin A 1c level, fasting plasma glucose level, body weight, 7-point self-monitored blood glucose, standardized test-meal challenge, safety, and tolerability. Results: Baseline mean hemoglobin A 1c level was 8.2% for patients receiving exenatide and 8.3% for those receiving insulin glargine. At week 26, both exenatide and insulin glargine reduced hemoglobin A 1c levels by 1.11% (difference, 0.017 percentage point [95% Cl, -0.123 to 0.157 percentage point]). Exenatide reduced postprandial glucose excursions more than insulin glargine, while insulin glargine reduced fasting glucose concentrations more than exenatide. Body weight decreased 2.3 kg with exenatide and increased 1.8 kg with insulin glargine (difference, -4.1 kg [Cl, -4.6 to -3.5 kg]). Rates of symptomatic hypoglycemia were similar, but nocturnal hypoglycemia occurred less frequently with exenatide (0.9 event/patient-year versus 2.4 events/ patient-year; difference, -1.6 events/patient-year [Cl, -2.3 to -0.9 event/patient year]). Gastrointestinal symptoms were more common in the exenatide group than in the insulin glargine group, including nausea (57.1% vs. 8.6%), vomiting (17.4% vs. 3.7%) and diarrhea (8.5% vs. 3.0%). Limitations: The trial was open-label and did not assess clinical complications related to diabetes. Of the 551 participants, 19.4% of those receiving exenatide and 9.7% of those receiving insulin glargine withdrew from the study. Only 21.6% of the insulin glargine group and 8.6% of the exenatide group achieved the target level for fasting plasma glucose of less than 5.6 mmol/L (<100 mg/dL). Conclusions: Exenatide and insulin glargine achieved similar improvements in overall glycemic control in patients with type 2 diabetes that was suboptimally controlled with oral combination therapy. Exenatide was associated with weight reduction and had a higher incidence of gastrointestinal adverse effects than insulin glargine.
Context: The scarcity of data addressing the health effects of popular diets is an important public health concern, especially since patients and physicians are interested in using popular diets as individualized eating strategies for disease prevention. Objective: To assess adherence rates and the effectiveness of 4 popular diets (Atkins, Zone, Weight Watchers, and Ornish) for weight loss and cardiac risk factor reduction. Design, Setting, and Participants: A single-center randomized trial at an academic medical center in Boston, Mass, of overweight or obese (body mass index: mean, 35; range, 27-42) adults aged 22 to 72 years with known hypertension, dyslipidemia, or fasting hyperglycemia. Participants were enrolled starting July 18, 2000, and randomized to 4 popular diet groups until January 24, 2002. Intervention: A total of 160 participants were randomly assigned to either Atkins (carbohydrate restriction, n=40). Zone (macronutrient balance, n=40), Weight Watchers (calorie restriction, n=40), or Ornish (fat restriction, n=40) diet groups. After 2 months of maximum effort, participants selected their own levels of dietary adherence. Main Outcome Measures: One-year changes in baseline weight and cardiac risk factors, and self-selected dietary adherence rates per self-report. Results: Assuming no change from baseline for participants who discontinued the study, mean (SD) weight loss at 1 year was 2.1 (4.8) kg for Atkins (21 [53 %] of 40 participants completed, P=.009), 3.2 (6.0) kg for Zone (26 [65%] of 40 completed, P=.002), 3.0 (4.9) kg for Weight Watchers (26 [65%] of 40 completed, P<.001), and 3.3 (7.3) kg for Ornish (20 [50%] of 40 completed, P=.007). Greater effects were observed in study completers. Each diet significantly reduced the low-density lipoprotein/high-density lipoprotein (HDL) cholesterol ratio by approximately 10% (all P<.05), with no significant effects on blood pressure or glucose at 1 year. Amount of weight loss was associated with self-reported dietary adherence level (r=0.60; P<.001) but not with diet type (r=0.07; P= .40). For each diet, decreasing levels of total/HDL cholesterol, C-reactive protein, and insulin were significantly associated with weight loss (mean r=0.36, 0.37, and 0.39, respectively) with no significant difference between diets (P= .48, P= .57, P= .31, respectively). Conclusions: Each popular diet modestly reduced body weight and several cardiac risk factors at 1 year. Overall dietary adherence rates were low, although increased adherence was associated with greater weight loss and cardiac risk factor reductions for each diet group.
The Swedish Obese Subjects Study is a prospective investigation involving obese subjects who underwent bariatric surgery or conventional treatment for obesity. This report documents follow-up data for subjects (mean age, 48 years; mean body mass index, 41 kg/m²) who were enrolled in the study for at least 2 years (4047 subjects) or 10 years (1703 subjects). The follow-up rate for laboratory examinations was 86.6% at 2 years and 74.5% at 10 years.
The nutrient-dependent glucagon-like peptide-1 (7-36) amide (GLP-1) release was studied in comparison to the glucose-dependent insulin-releasing polypeptide (GIP) response in 10 healthy volunteers each undergoing various protocols. Plasma samples were saved up to 120 min after challenges by oral, intravenous or intraduodenal administration of nutrients. Basal plasma-GLP-1 concentrations ranged between 0.4 and 1.4 pM, maximal postprandial GLP-1 levels peaked between 10 and 12 pM. Intravenous glucose (25 g i.v.) did not change basal GLP-1 levels. Oral administration of glucose (50 g) induced a biphasic GLP-1 release peaking at 30-60 min and a biphasic GIP release peaking at 5 and 45 min. This increase paralleled the secretion of insulin. Oral galactose (100 g) and amino acids (25 g) also induced a rapid plasma GLP-1 response. After fat (67 g corn oil) a strong and long-lasting ( > 120 min) increase of GLP-1 plasma levels occurred. When a mixed liquid meal was given (6 g soybean oil, 5g casein, 13 g glucose) immunoreactive (IR)-GLP-l rapidly increased and peaked after 5 min with declining levels after 30 min. In response to an intraduodenal infusion of a small glucose load (5.34 g within 120 min) a rapid, short-lasting GLP-1 response occurred whereas plasma GIP and insulin levels remained unaltered. Luminal perfusion of an isolated vascularly perfused rat ileum with a polydiet induced a rapid rise of portally released IR-GLP-1 which was followed by a sustained release. Glucose evoked sodium-dependently a sharp increase of IR-GLP-1 levels followed by a plateau release. The intraluminal infusion of a mixture of amino acids or fat was without any effect on IR-GLP-1. We hypothesize that in contrast to GIP the GLP-1 release from L cells is triggered by nervous reflexes, by putative humoral factor(s) being released from the upper small intestine in addition to nutrient stimuli acting at the luminal surface of the gut.Copyright © 1995 S. Karger AG, Basel
Pancreatic polypeptide (PP) has been shown to mitigate the hyperphagia of genetically obese mice. These animals have low concentrations of PP. Patients with Prader-Willi Syndrome (P-W,S) are characterized by obesity and hyperphagia. Serum levels of PP, glucose, insulin and gastroinhibitory polypeptide (GIP) were obtained at 15 min. intervals for 180 min. after a 300 calorie meal in 7 pts with P-W,S and were compared to responses obtained in 10 normal and 13 obese controls. P-W,S had a mean (X) age of 12.3 years (y) (range 7-16Y) and a X body weight (wt) 230% of ideal. Obese controls had a X age of 30.5y (17-44y) and a X body wt 200% of ideal. Normal controls had a X age of 34.ly (19-64y) and X body wt 106% of ideal. Basal and peak responses of glucose, insulin and GIP for pts with P-W,S were slightly but significantly less when compared to normal or obese controls. No significant differences in basal or peak PP responses were noted between normal and obese controls (basal, 103±30 vs 111±19: peak, 561±140 vs 603±107 pg/ml, X ± SE). All 7 pts with P-W,S had abnormal PP responses. Five failed to show significant PP release after the stimulation; one had a peak response to 130 pg/ml while the 7th pt had a supernormal response to > 2000 pg/ml. The 6 pts with low or no response had basal PP values of 62±12 pg/ml and a X peak response of 78±15 pg/ml. This observation of blunted PP response in a human model of hyperphagia and obesity suggests that PP may have a significant role in appetite control.
Plasma levels of glucagon-like peptide-1 (GLP-1) rise rapidly after nutrient ingestion, suggesting the existence of a proximal gut signal regulating GLP-1 release from the L cells of the distal small intestine. Glucose-dependent insulinotropic peptide (GIP) has been shown to be one such proximal signal; however, the dependence of GIP on gastrin- releasing peptide, a neuromodulator, suggested a role for the nervous system in this proximal-distal loop. Investigations into the nature of this proximal signal were therefore conducted in an in situ model of the rat gastrointestinal system. Infusions of corn oil into a 10-cm segment of duodenum that was isolated by loose ligation (to ensure that the luminal contents did not progress to the ileal L cell) increased the secretion of GLP-1 in parallel with that of gut glucagon-like immunoreactivity (gGLI; r 5 0.85; P , 0.05). Infusion of fat into a transected segment of duodenum also significantly raised gGLI se- cretion compared with saline infusion, reaching a peak value of 132 6 37 pg/ml above basal (P , 0.05). However, peak secretion was sig- nificantly delayed when the gut was transected compared with that after ligation alone (19 6 4 vs. 6 6 1 min, respectively; P , 0.05). Furthermore, bilateral subdiaphragmatic vagotomy in conjunction with gut transection completely abolished the fat-induced rise in gGLI secretion (P , 0.001). Consistent with a role for the vagus in the regulation of the L cell, stimulation of the distal end of the celiac branch of the subdiaphragmatic vagus nerve significantly stimulated the secretion of gGLI to a level of 71 6 14 pg/ml above basal (P , 0.05). As found previously, supraphysiological infusion of GIP significantly increased gGLI secretion in control animals by 123 6 32 pg/ml (P , 0.05); this was not prevented by hepatic branch vagotomy (96 6 25 pg/ml; P , 0.05). In contrast, although infusion of GIP at physiological levels into sham-vagotomized animals also increased gGLI secretion, by 40 6 6 pg/ml (P , 0.05), selective hepatic branch vagotomy abol- ished GIP-induced gGLI secretion (P , 0.05). The results of these experiments therefore demonstrate that the secretion of GLP-1 and gGLI from the ileal L cell in response to fat is regulated by a complex neuroendocrine loop, involving the enteric nervous system, the af- ferent and efferent vagus nerves, as well as the duodenal hormone GIP. (Endocrinology 140: 1687-1694, 1999)
The ability to maintain adequate nutrient intake is critical for survival. Complex interrelated neuronal circuits have developed in the mammalian brain to regulate many aspects of feeding behaviour, from food-seeking to meal termination. The hypothalamus and brainstem are thought to be the principal homeostatic brain areas responsible for regulating body weight1, 2. However, in the current ‘obesogenic’ human environment food intake is largely determined by non-homeostatic factors including cognition, emotion and reward, which are primarily processed in corticolimbic and higher cortical brain regions3. Although the pleasure of eating is modulated by satiety and food deprivation increases the reward value of food, there is currently no adequate neurobiological account of this interaction between homeostatic and higher centres in the regulation of food intake in humans1, 4, 5. Here we show, using functional magnetic resonance imaging, that peptide YY3–36 (PYY), a physiological gut-derived satiety signal, modulates neural activity within both corticolimbic and higher-cortical areas as well as homeostatic brain regions. Under conditions of high plasma PYY concentrations, mimicking the fed state, changes in neural activity within the caudolateral orbital frontal cortex predict feeding behaviour independently of meal-related sensory experiences. In contrast, in conditions of low levels of PYY, hypothalamic activation predicts food intake. Thus, the presence of a postprandial satiety factor switches food intake regulation from a homeostatic to a hedonic, corticolimbic area. Our studies give insights into the neural networks in humans that respond to a specific satiety signal to regulate food intake. An increased understanding of how such homeostatic and higher brain functions are integrated may pave the way for the development of new treatment strategies for obesity.
We studied the effects of intravenous infusion of synthetic oxyntomodulin (proglucagon 33–69), a potential hormone from the ileal mucosa, on fasting and postprandial gastric acid secretion, gastric emptying, gastroduodenal motility, and pancreatic secretion of trypsin and lipase measured simultaneously in six normal volunteers using multilumen tubes for infusion of markers, manometry, and aspiration of gastric and duodenal contents. The infusion resulted in plasma concentrations of 20321 pmollliter (meansem) of oxyntomodulin, regarded as high but not unphysiological concentrations of the peptide. Oxyntomodulin almost abolished basal acid secretion and inhibited postprandial acid secretion by 3510%. Gastric emptying decreased significantly; the time for 50% to leave the stomach increased from 17.32.2 min to 34.78.0 min. The postprandial gastroduodenal motility was massively inhibited by oxyntomodulin. Postprandial trypsin and lipase output was significantly inhibited by 5612% and 4211%, respectively, during oxyntomodulin infusion. However, pancreatic enzyme output was linearly related to gastric emptying and oxyntomodulin did not influence this relationship, suggesting that oxyntomodulins effect was due to its effect on gastric emptying. Oxyntomodulin seems to play an important role in the small intestinal inhibitory control of gastropancreatic functions.
Pancreatic polypeptide (PP) is a recently identified hormone produced by pancreatic endocrine cells. The islets of genetically obese mice (ob/ob, C57 BL/6J), which are suspected to lack a circulating satiety factor, contain relatively few of the PP-producing cells. Administration of bovine pancreatic polypeptide (bPP) reduces food intake and suppresses body weight gain in the hyperphagic obese mice. It is postulated that PP participates in the regulation of food intake in a manner as yet undefined.
Lutz, T. A., M. Senn, J. Althaus, E. Del Prete, F. Ehrensperger and E. Scharrer. Lesion of the area postrema/nucleus of the solitary tract (AP/NTS) attenuates the anorectic effects of amylin and calcitonin gene-related peptide (CGRP) in rats. Peptides 19(2) 309–317, 1998.—The area postrema/nucleus of the solitary tract (AP/NTS) region plays an important role in the control of food intake since it receives peripheral satiety signals via splanchnic and vagal afferents. Due to the lack of the blood brain barrier in this region, blood borne signals can directly be monitored in the AP/NTS. Furthermore, receptors for anorectic peptides such as amylin or calcitonin gene-related peptide (CGRP) have been found in the AP/NTS. It was therefore the aim of the present study to investigate the role of the AP/NTS region in mediating the anorectic effects of these peptides. Thermal ablation of the AP/NTS resulted in a significant reduction of the anorectic effects of IP injected amylin (5 μg/kg) and CGRP (5 μg/kg) in food deprived rats. The anorectic actions of CCK and BBS were also reduced by the AP/NTS lesion which agrees with previous studies. We conclude that the AP/NTS region is an important brain site for mediating the anorectic effects of amylin and CGRP. It remains to be clarified whether this effect is due to amylin and CGRP action on receptors within the AP/NTS region or peripheral receptors on afferent nerves projecting to the AP/NTS.
Glucagon-like peptide-I(GLP-I), encoded by the glucagon gene and released from the gut in response to nutrients, is a potent stimulator of glucose-induced insulin secretion. In human subjects GLP-I exerts its physiological effect as an incretin. The incretin effect of GLP-I is preserved in patients with Type II diabetes mellitus (NIDDM), suggesting that GLP-I receptor agonist can be used therapeutically in this group of patients. In these studies we addressed the question of whether GLP-I has broader actions in human physiology. To investigate this issue we examined the tissue distribution of GLP-I receptor using RNAse protection assay in order to avoid the cross-reactivities with structurally related receptors and to increase the sensitivity of detection. The riboprobe was synthetized from the human pancreatic GLP-I receptor cDNA and used in hybridization experiments with total RNA isolated from different human tissues. In addition to the pancreas, we found expression of GLP-I receptor mRNA in lung, brain, kidney, stomach and heart. Peripheral tissues which are the major sites of glucose turnover, such as liver, skeletal muscle and adipose did not express the pancreatic form of the GLP-I receptor. We also cloned and sequenced GLP-I receptor cDNA from human brain and heart. The deduced amino acid sequences are the same as the sequence found in the pancreas. These results indicate that GLP-I might have effects beyond the pancreas, including the cardiovascular and central nervous systems where a receptor with the same ligand binding specificity is found.
This study was designed to investigate the effects of synthetic mouse pancreatic polypeptide (mPP) on feeding and anxiety in mice. The intracerebroventricular (ICV) injection of mPP (0.003–3 nmol) dose-dependently increased food intake. A significant increase was observed 20 min after ICV injection and continued for 4 h. The intraperitoneal (IP) injection of mPP (0.03–30 nmol) dose-dependently decreased food intake. A significant decrease was observed 20 min after IP injection and continued for 4 h. In the elevated plus maze test, the ICV injection of mPP (0.003–3 nmol) did not affect anxiety behavior. These results suggest that mPP modulates food intake and the Y4 receptor in the brain may contribute to the regulation of feeding, whereas appearing not to influence anxiety in mice.
The patterns of Fos-like immunoreactivity (Fos-ir) in rat brain were compared following treatment of rats with two anorectic `gut' peptides. Central administration of GLP-1 produced dose-related increases in Fos-ir in the area postrema (AP) and caudal nucleus of the solitary tract (cNTS) as well as strong activation in the lateral parabrachial nucleus (LPBE), hypothalamic paraventricular nucleus (PVN), bed nucleus of the stria terminalis (BNST) and central nucleus of the amygdala (CeA). At centrally-active doses, peripheral administration of GLP-1 did not induce Fos-ir in brain. In contrast, peripheral administration of amylin produced strong Fos-ir in the AP and cNTS, as well as the BNST and CeA, but not in the PVN. The common activation of the LPB-BNST-CeA by these and other previously-studied anorectics suggest this is an important circuit involved in satiety.
Peptide YY (3-36) [PYY (3-36)] is postulated to act as a hormonal signal from the gut to the brain to inhibit food intake and gastric emptying. A mixed-nutrient meal produces a prolonged 2-3 h increase in plasma levels of both PYY (3-36) and PYY (1-36). We determined the dose-dependent effects of 3-h iv infusions of PYY (3-36) and PYY (1-36) (0.5-50 pmol.kg(-1).min(-1)) at dark onset on food intake in non-food-deprived rats. PYY (3-36) dose-dependently inhibited food intake: the minimal effective dose was 5 pmol.kg(-1).min(-1); the estimated potency (mean effective dose) and efficacy (maximal percent inhibition) were 15 pmol.kg(-1).min(-1) (2.6 nmol/kg) and 47%, respectively. PYY (1-36) was an order of magnitude less potent than PYY (3-36). Similar total doses of PYY (3-36) (0.9-30 nmol/kg) infused during the 15-min period just before dark onset also dose-dependently inhibited food intake, albeit with a lower potency and efficacy. Other experiments showed that PYY (3-36) inhibited food intake in sham-feeding rats and was more effective in reducing intake of a mixed-nutrient liquid diet than 15% aqueous sucrose. We conclude that: 1) iv infusions of PYY (3-36), which are more likely than ip injections to mimic postprandial increases in plasma PYY (3-36), potently inhibit food intake in a dose-dependent manner; 2) PYY (1-36) is an order of magnitude less potent than PYY (3-36); and 3) PYY (3-36) can inhibit food intake independently of its action to inhibit gastric emptying. It remains to be determined whether iv doses of PYY (3-36) that reproduce postprandial increases in plasma PYY (3-36) are sufficient to inhibit food intake.
The main associations of body-mass index (BMI) with overall and cause-specific mortality can best be assessed by long-term prospective follow-up of large numbers of people. The Prospective Studies Collaboration aimed to investigate these associations by sharing data from many studies.
Collaborative analyses were undertaken of baseline BMI versus mortality in 57 prospective studies with 894 576 participants, mostly in western Europe and North America (61% [n=541 452] male, mean recruitment age 46 [SD 11] years, median recruitment year 1979 [IQR 1975-85], mean BMI 25 [SD 4] kg/m(2)). The analyses were adjusted for age, sex, smoking status, and study. To limit reverse causality, the first 5 years of follow-up were excluded, leaving 66 552 deaths of known cause during a mean of 8 (SD 6) further years of follow-up (mean age at death 67 [SD 10] years): 30 416 vascular; 2070 diabetic, renal or hepatic; 22 592 neoplastic; 3770 respiratory; 7704 other.
In both sexes, mortality was lowest at about 22.5-25 kg/m(2). Above this range, positive associations were recorded for several specific causes and inverse associations for none, the absolute excess risks for higher BMI and smoking were roughly additive, and each 5 kg/m(2) higher BMI was on average associated with about 30% higher overall mortality (hazard ratio per 5 kg/m(2) [HR] 1.29 [95% CI 1.27-1.32]): 40% for vascular mortality (HR 1.41 [1.37-1.45]); 60-120% for diabetic, renal, and hepatic mortality (HRs 2.16 [1.89-2.46], 1.59 [1.27-1.99], and 1.82 [1.59-2.09], respectively); 10% for neoplastic mortality (HR 1.10 [1.06-1.15]); and 20% for respiratory and for all other mortality (HRs 1.20 [1.07-1.34] and 1.20 [1.16-1.25], respectively). Below the range 22.5-25 kg/m(2), BMI was associated inversely with overall mortality, mainly because of strong inverse associations with respiratory disease and lung cancer. These inverse associations were much stronger for smokers than for non-smokers, despite cigarette consumption per smoker varying little with BMI.
Although other anthropometric measures (eg, waist circumference, waist-to-hip ratio) could well add extra information to BMI, and BMI to them, BMI is in itself a strong predictor of overall mortality both above and below the apparent optimum of about 22.5-25 kg/m(2). The progressive excess mortality above this range is due mainly to vascular disease and is probably largely causal. At 30-35 kg/m(2), median survival is reduced by 2-4 years; at 40-45 kg/m(2), it is reduced by 8-10 years (which is comparable with the effects of smoking). The definite excess mortality below 22.5 kg/m(2) is due mainly to smoking-related diseases, and is not fully explained.
To estimate risk and relative risk (RR) of acute pancreatitis among patients using incretin-based diabetes therapies (exenatide or sitagliptin) compared to patients treated with agents with established safety profiles (metformin or glyburide).
The study population was derived from a large US commercial health insurance transaction database using an active drug safety surveillance system (i3 Aperio). This analysis is based on data from June 2005 through June 2008. Cohorts of exenatide and sitagliptin initiators were each matched to an equal number of metformin or glyburide (met/gly) initiators using propensity scores to reduce confounding in the comparison of outcomes during follow-up. Patients with claims suggesting pancreatic disease in the 6 months prior to cohort entry were excluded.
Claims for hospitalizations associated with a primary diagnosis of acute pancreatitis (ICD-9 577.0).
There were 27 996 exenatide initiators and 16 276 sitagliptin initiators and approximately equal numbers of matched comparators. During follow-up of up to 1 year, acute pancreatitis occurred among 0.13% of patients treated with exenatide and 0.12% of patients treated with sitagliptin. The risk of acute pancreatitis was comparable for initiators of exenatide (RR 1.0; 95% confidence interval (CI) 0.6-1.7) and sitagliptin (RR 1.0; 95% CI 0.5-2.0) relative to the comparison cohorts.
These data do not provide evidence for an association of acute pancreatitis among initiators of exenatide or sitagliptin compared to met/gly initiators. These results are limited by the data available in an administrative, healthcare database.
Liraglutide, a human glucagon-like peptide 1 (GLP-1) analogue with high homology to native GLP-1, has structural modifications sufficient to amend pharmacokinetics for once-daily administration without compromising biological activity. Data from large, controlled, clinical studies have confirmed the therapeutic profile of liraglutide, with robust reductions in HbA(1c), low risk of hypoglycaemia and clinically relevant reductions in body weight and systolic blood pressure.
New treatments for type 2 diabetes mellitus are needed to retain insulin-glucose coupling and lower the risk of weight gain and hypoglycaemia. We aimed to investigate the safety and efficacy of liraglutide as monotherapy for this disorder.
In a double-blind, double-dummy, active-control, parallel-group study, 746 patients with early type 2 diabetes were randomly assigned to once daily liraglutide (1.2 mg [n=251] or 1.8 mg [n=247]) or glimepiride 8 mg (n=248) for 52 weeks. The primary outcome was change in proportion of glycosylated haemoglobin (HbA(1c)). Analysis was done by intention-to-treat. This trial is registered with ClinicalTrials.gov, number NTC00294723.
At 52 weeks, HbA(1c) decreased by 0.51% (SD 1.20%) with glimepiride, compared with 0.84% (1.23%) with liraglutide 1.2 mg (difference -0.33%; 95% CI -0.53 to -0.13, p=0.0014) and 1.14% (1.24%) with liraglutide 1.8 mg (-0.62; -0.83 to -0.42, p<0.0001). Five patients in the liraglutide 1.2 mg, and one in 1.8 mg groups discontinued treatment because of vomiting, whereas none in the glimepiride group did so.
Liraglutide is safe and effective as initial pharmacological therapy for type 2 diabetes mellitus and leads to greater reductions in HbA(1c), weight, hypoglycaemia, and blood pressure than does glimepiride.
Exenatide is an incretin mimetic that shares glucoregulatory properties with glucagon-like peptide 1 (GLP-1), and improves glycaemic control, with progressive bodyweight reductions, when administered twice a day in patients with type 2 diabetes. We compared the efficacy of a once-weekly formulation of exenatide to that of a twice daily dose.
A 30-week, randomised, non-inferiority study compared a long-acting release formulation of exenatide 2 mg administered once weekly to 10 mug exenatide administered twice a day, in 295 patients with type 2 diabetes (haemoglobin A(1c) [HbA(1c)] 8.3% [SD 1.0], mean fasting plasma glucose 9 [SD 2] mmol/L, weight 102 [SD 20] kg, diabetes duration 6.7 [SD 5.0] years). The patients were naive to drug therapy, or on one or more oral antidiabetic agents. The primary endpoint was the change in HbA(1c) at 30 weeks. This study is registered with ClinicalTrials.gov, number NCT00308139.
At 30 weeks, the patients given exenatide once a week had significantly greater changes in HbA(1c) than those given exenatide twice a day (-1.9 [SE 0.1%] vs -1.5 [0.1%], 95% CI -0.54% to -0.12%; p=0.0023). A significantly greater proportion of patients receiving treatment once a week versus twice a day achieved target HbA(1c) levels of 7.0% or less (77%vs 61% of evaluable patients, p=0.0039).
Exenatide once weekly resulted in significantly greater improvements in glycaemic control than exenatide given twice a day, with no increased risk of hypoglycaemia and similar reductions in bodyweight.
Cholecystokinin (C.C.K.)-producing cells were identified in the mucosa of the upper small intestine in man and other mammals by immunocytochemical techniques and electron microscopy on semi-thin and serial thin sections. Ultrastructural studies suggested that the C.C.K.-producing cells resemble I cells of the modified Wiesbaden classification. The combination of these techniques provides a simple and reliable method of identifying C.C.K. cells in human biopsy material and will be useful in the investigation and diagnosis of gut endocrine dysfunctions.
Intraperitoneal injections of avian pancreatic polypeptide (APP) and bovine pancreatic polypeptide (BPP) are capable of returning to normal the hyperinsulinaemia, hyperglycaemia and weight gain of New Zealand obese mice. The lag glucose tolerance also becomes indistinguishable from normal. The mechanism whereby these polypeptides cause reversion is not known. Reversion can also be brought about by the intraperitoneal implantation of islets from white mice into New Zealand obese animals. The implanted islets secrete mouse pancreatic polypeptide. We conclude that the New Zealand obese syndrome arises from a genetic lack of mouse pancreatic polypeptide. We suggest that in humans a lack of pancreatic polypeptide might manifest as a syndrome analogous to that found in New Zealand obese mice.