The investigators and research assistants were in contact with each subject on a weekly basis to ensure compliance with the exercise training program. Compliance was determined via measurements of volume load (repetitions sets weight) which should have increased over the course of the treatment period. Furthermore, subjects were instructed to not perform any aerobic exercise during the treatment period.
The redundancy of the system to regulate food intake and body weight led to suggestions that multiple signaling pathways would need to be targeted for effective medical treatment of obesity [1]. Proof-of-concept studies were reported using simultaneous administration of peptides, e.g. leptin and amylin, to cause greater weight loss in rodent models [2]. In 2009, Day and colleagues reported the development of novel peptides engineered to agonize both the GLP-1 and glucagon receptors (GLP-1R and GCGR; [3]). The rationale for these agents was that combining the satiety effects of GLP-1 signaling with purported effects of glucagon to increase energy expenditure would lead to a more effective weight loss agent. In fact, this was demonstrated quite convincingly in obese mice, with some variability in effect depending on the relative balance of potency at the GLP-1R and GCGR. Of perhaps greater importance was the establishment of the process of iterative chemical refinement as a means of modifying the amino acid sequence of a known peptide to add agonism for multiple receptors [4]. Using this model an obvious strategy was to combine activity for GLP-1 with that of glucose-dependent insulinotropic polypeptide (GIP) to treat diabetes. Together GLP-1 and GIP account for the bulk of the incretin effect, a physiologic system evolved to augment insulin secretion following the ingestion of nutrients [5]. Both the GLP-1R and the GIP receptor (GIPR) are expressed on pancreatic β-cells and activation of these in the context of even modest elevations of blood glucose potently stimulate insulin secretion [6]. Activation of the GLP-1R lowers blood glucose in persons with type 2 diabetes while the GIPR is much less effective for this [7, 8]. Nonetheless, an engineered peptide with activity at both the GIPR and GLP-1R was more effective at reducing body weight and blood glucose in obese mice than a selective GLP-1R agonist (GLP-1RA) [9]. This compound was also superior to a GLP-1RA for stimulating insulin secretion in non-human primates, and reduced blood glucose in humans with diabetes. While the insulinotropic properties of a GIPR/GLP-1R co-agonist were expected, the effects on food intake and weight loss were not. However, recent work in rodents has demonstrated that the GIPR is expressed on neurons in the arcuate nucleus and other parts of the hypothalamus [10], and their activation reduces food intake and body weight [11], in particular when co-administered with GLP-1 [12]. This initial work, and other studies, heralded the development of a number of different multi-receptor peptides that have become the latest advances in therapeutics of diabetes and obesity.
A Course In Weight Loss Epub Download
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Given the impressive results of the tirzepatide clinical trials, understanding pharmacologic mechanisms of action is likely to provide insight into the pathogenesis and correction of diabetes and obesity. Moreover, differentiating a GIP/GLP-1 receptor co-agonist from a selective GLP-1 receptor agonist has implications for the broader scope of multi-receptor targeting in metabolic disease. Are there footprints of GIP receptor agonism in the studies to date? An experiment based on the general protocol of the SURPASS-2 study, but including physiological outcomes, was recently reported. At baseline and after 28 weeks of treatment, Heise et al. performed a hyperinsulinaemic, euglycaemic clamp experiment to estimate insulin sensitivity, followed by a hyperglycaemic clamp (216 mg/dl;12.0 mmol/l) to estimate insulin secretory responses. On a second day of study, plasma glucose, insulin and glucagon responses were recorded following a mixed meal test with concurrent assessment of ratings (visual analogue scales) of hunger, satiety, prospective food consumption, and fullness; energy intake was measured on the occasion of an ad libitum meal [49, 50]. The clinical results of this trial mimicked the primary findings of SURPASS-2 with comparable HbA1c reduction and loss of body weight. Insulin sensitivity as measured by the glucose infusion rate needed to maintain euglycaemia rose by 65.7% with tirzepatide (as compared to 37.5% with semaglutide 1.0 mg). Thus, the rise in insulin sensitivity was 20.5% greater with tirzepatide as compared to semaglutide. Some of this effect is likely due to the difference in body weight reduction (average 11.2 kg with tirzepatide vs. 6.9 kg with semaglutide) [50], and in fact, the improvement in insulin sensitivity was related to the individual degree of body weight reduction. However, the slope of the regression line relating insulin sensitivity to amount of weight loss was significantly steeper for tirzepatide compared to semaglutide [49]. These results suggest that there may be weight-dependent and weight-independent components to the improvement in insulin sensitivity accompanying tirzepatide treatment, and that there is a greater improvement in insulin sensitivity per unit weight loss with tirzepatide as compared to semaglutide [49].
Tirzepatide (compared to insulin degludec) has been shown to reduce intrahepatic triglycerides in type 2 diabetes [80], and may offer novel treatment options for patients with fatty liver disease (as previously described for selective GLP-1 RAs [81]). It will be important to understand how much of the effect to reduce steatosis is due to weight loss and whether there are also effects independent of this.
Tirzepatide now is the first peptide dual agonist targeting GIP and GLP-1 receptors approved for the therapy of diabetes in the USA, Europe, and the UAE. Clinical trials employing this once-weekly injected compound impress with unprecedented effectiveness regarding glycaemic control (often resulting in normoglycaemia) and body weight reduction, in quantities that are likely to substantially change the underlying pathogenesis of type 2 diabetes [82] and have been associated with diabetes remission [83, 84]). The magnitude of the effects of tirzepatide on glycemia and weight loss opens a new era in diabetes therapy with the promise that a large percentage of patients can be treated to currently established targets. In addition, the clinical efficacy indicates large changes to diabetic physiology and should allow novel questions regarding pathogenesis to be addressed. For example, what does major weight loss added to excellent glycaemic control mean in terms of disease progression and long-term prognosis? And, what effect does the combination of weight loss and dramatic HbA1c reduction have on micro- and macrovascular complications? The next important step will be more information on the cardiovascular consequences of using tirzepatide in type 2 diabetes. The SURPASS CVOT results are eagerly awaited, since there has not been any previous experience with long-term GIPR agonism in clinical medicine. GIP has been described to have anti-atherosclerotic and other beneficial cardiovascular effects [85, 86], but some findings (e.g., stimulation of endothelin-1 in endothelial cells) raise concerns that have not been fully explored [85]. Further, elevated plasma concentrations of GIP in human subjects have been found to be associated with increased carotid intima-media thickness [87] and an increased risk for cardiovascular events and mortality [88]. However, two recent publications examining effects of genetically predicted GIP plasma concentrations on cardiovascular risk factors come to an opposite conclusion and rather suggest beneficial effects of higher exposure to circulating GIP [89, 90]. Thus, probing the cardiovascular effects of tirzepatide is answering a question for which we do not have the answer beforehand, even given the favorable preliminary cardiovascular preliminary analysis [20]. Certainly, this will be an opportunity to learn whether the hitherto unmatched reduction in HbA1c and body weight observed with tirzepatide translates into additional cardiovascular benefits compared to the selective GLP-1 RA dulaglutide.
These results indicate that dietary restriction increases LDL particle size, while endurance training augments HDL particle size, with minimal weight loss. None of these interventions concomitantly increased both LDL and HDL particle size, however.
Only the ADF and CR groups participated in the diet intervention. Baseline energy needs were assessed using the Mifflin equation [17]. ADF subjects were restricted by 75% of their baseline needs on the fast day, and ate ad libitum on each alternating feed day. The feed/fast days began at midnight each day, and all fast day meals were consumed between 12.00 pm and 2.00 pm. ADF subjects were provided with calorie-restricted meals on each fast day, and ate ad libitum at home on the feed day. CR subjects were restricted by 25% of their baseline energy needs each day, and were provided with all of their calorie-restricted meals throughout the trial. Study diets were provided as a 3-day rotating menu, and were formulated based on the American Heart Association guidelines (30% kcal from fat, 15% kcal from protein, 55% kcal from carbohydrate). Subjects in the control and exercise groups were permitted to eat ad libitum every day, and were not provided with meals from the research center. The ADF and CR diets were designed to produce 5% weight loss after 12 weeks of treatment.
This study is the first to show that diet and exercise interventions that achieve similar degrees of weight loss have differential effects on LDL versus HDL particle size. More specifically, we show here that ADF and CR regimens that achieve 5% weight loss increase LDL size, but have no effect on HDL size. In contrast, exercise training that results in 5% weight loss increases the proportion of large HDL particles, but has no impact on LDL size. Thus, none of these interventions are able to beneficially modulate both LDL and HDL particle size with only a minimal amount of weight loss. 2ff7e9595c
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