Substantial weight reduction is often associated with loss of muscle mass. Tirzepatide has been associated with significant reductions in body weight in type 2 diabetes trials and a beneficial effect on body fat distribution in the SURPASS-3 MRI substudy. This post-hoc exploratory analysis studied the association of tirzepatide treatment with changes in thigh muscle volume, muscle volume Z score, and muscle fat infiltration, and aimed to contextualise the results using longitudinal MRI data from UK Biobank participants.

SURPASS-3 was a randomised, open-label, parallel-group, phase 3 trial. The multicentre (45 sites) and multinational (eight countries) MRI substudy of SURPASS-3 enrolled insulin-naive adults (aged ≥18 years) with type 2 diabetes who were on treatment with metformin with or without a sodium-glucose co-transporter-2 (SGLT-2) inhibitor, had an HbA1c of 7·0-10·5% (53-91 mmol/mol), a BMI of at least 25 kg/m2, and a fatty liver index of at least 60. Participants were randomly assigned (1:1:1:1) to receive subcutaneous injection once per week of tirzepatide (5, 10, or 15 mg), or subcutaneous injection once per day of titrated insulin degludec. Thigh muscle fat infiltration, muscle volume, and muscle volume Z score (invariant to sex, height, weight, and BMI) were quantified by MRI at baseline and week 52. In this post-hoc analysis, we assessed the differences between mean baseline and week 52 muscle composition values in the tirzepatide groups (pooled 5 mg, 10 mg, and 15 mg group, and per dose group) and insulin degludec group using paired t tests, and the differences in muscle composition changes with pooled tirzepatide versus insulin degludec via adjusted ANCOVA models. Observed changes in muscle fat infiltration, muscle volume, and muscle volume Z scores were compared using paired t tests to population-based estimates calculated from multiple linear regression models fitted to UK Biobank data (n=2942), capturing associations with change in body weight. Analyses were done by modified intention to treat, in the participants enrolled in the MRI substudy with a valid MRI scan at week 52. The SURPASS-3 clinical trial is registered with ClinicalTrials.gov, NCT03882970, and is complete.

Participants were assessed for eligibility and recruited from April 1, 2019, to Nov 15, 2019. Among 502 participants assessed for eligibility to participate in the MRI substudy, 296 were enrolled, and 246 had a valid week 52 MRI scan and were included in the post-hoc analyses (tirzepatide 5 mg, n=63; tirzepatide 10 mg, n=60; tirzepatide 15 mg, n=67; insulin degludec, n=56; 147 [59·8%] male participants and 99 [40·2%] female participants). At baseline, overall mean age was 56·0 years (SD 9·9), median duration of type 2 diabetes was 6·7 years (IQR 3·7 to 10·7), mean HbA1c was 8·3% (SD 0·9), mean BMI was 33·4 kg/m2 (SD 4·8), and 76 (30·9%) were on an SGLT-2 inhibitor. Mean baseline muscle fat infiltration, muscle volume, and muscle volume Z scores were similar between the pooled tirzepatide group and insulin degludec group. For the pooled and individual tirzepatide dose groups, significant reductions were observed from baseline to week 52 in muscle fat infiltration (for pooled tirzepatide, mean change -0·36 percentage points [95% CI -0·48 to -0·25], p<0·0001), muscle volume (-0·64 L [95% CI -0·74 to -0·54], p<0·0001), and muscle volume Z score (-0·22 [95% CI -0·29 to -0·15], p<0·0001), which occurred in the context of significant weight reduction. Insulin degludec was associated with a modest and significant increase in bodyweight and muscle volume, but no significant change in the other variables. The changes in all three muscle composition variables with pooled tirzepatide were significantly different compared to those with insulin degludec. In tirzepatide-treated participants, observed muscle volume changes across all tirzepatide doses were similar to population-based estimated changes (for pooled tirzepatide, mean difference vs population-based estimate, -0·04 L [95% CI -0·11 to 0·03], p=0·22); whereas, observed reductions in muscle fat infiltration across all doses were significantly greater than population-based estimates (for pooled tirzepatide, mean difference -0·42 percentage points [95% CI -0·54 to -0·31], p<0·0001), and the observed reduction in muscle volume Z score with tirzepatide 15 mg was significantly greater than the population-based estimate (mean difference -0·18 [95% CI -0·29 to -0·07], p=0·0016).

In the SURPASS-3 MRI substudy, in the context of significant improvements in bodyweight and fat distribution, tirzepatide treatment was associated with potentially favourable changes in muscle fat infiltration and reductions in muscle volume broadly in accordance with the general association between changes in muscle volume and bodyweight. The present findings provide additional information on the potential effect of tirzepatide on muscle health that might help health-care providers when deciding among treatment options for individual patients.

Eli Lilly and Company.

Incretin receptor agonists have been effective in combatting obesity and diabetes. While the body of knowledge regarding the signaling mechanisms of glucagon-like peptide 1 (GLP-1) receptor agonists is ever-growing, glucose-dependent insulinotropic polypeptide receptor (GIPR) agonists are less understood. The previewed papers offer insight into the impact of adipose GIPR on energy and weight homeostasis.

Adipose tissue (AT) represents a plastic organ that can undergo significant remodeling in response to metabolic demands. With its numerous checkpoints, the incretin system seems to play a significant role in controlling glucose homeostasis and energy balance. The importance of the incretin hormones, namely the glucagon-like peptide-1 (GLP-1) and the glucose-dependent insulinotropic peptide (GIP), in controlling the function of adipose cells has been brought to light by recent studies. Notably, a "paradigm shift" in reevaluating the role of the incretin system in AT as a potential target to treat obesity-linked metabolic disorders resulted from the demonstration that a disruption of the GIP and GLP-1 signaling axis in fat is associated with adiposity-induced insulin-resistance (IR) and/or type 2 diabetes mellitus (T2D). We will briefly discuss the (patho)physiological functions of GLP-1 and GIP signaling in AT in this review, emphasizing their potential impacts on lipid storage, adipogenesis, glucose metabolism and inflammation. We will also address the conundrum with the perturbation of the incretin axis in white or brown fat tissue and the emergence of metabolic disorders. In order to reduce or avoid adiposity-related metabolic complications, we will finally go over a potential scientific rationale for suggesting AT as a novel target for GLP-1 and GIP receptor agonists and co-agonists.

Patients with morbid obesity and concomitant hip or knee osteoarthritis represent a challenging patient demographic to treat as these patients often present earlier in life, have more severe symptoms, and have worse surgical outcomes following total hip and total knee arthroplasty. Previously, bariatric and metabolic surgeries represented one of the few weight loss interventions that morbidly obese patients could undergo prior to total joint arthroplasty. However, data regarding the reduction in complications with preoperative bariatric surgery remain mixed. Glucagon-like peptide receptor-1 (GLP-1) agonists have emerged as an effective treatment option for obesity in patients with and without diabetes mellitus. Furthermore, recent data suggest these medications may serve as potential anti-inflammatory and disease-modifying agents for numerous chronic conditions, including osteoarthritis. This review will discuss the GLP-1 agonists and GLP-1/glucose-dependent insulinotropic polypeptide dual agonists currently available, along with GLP-1/glucose-dependent insulinotropic polypeptide/glucagon triple agonists presently being developed to address the obesity epidemic. Furthermore, this review will address the potential problem of GLP-1-related delayed gastric emptying and its impact on the timing of elective total joint arthroplasty. The review aims to provide arthroplasty surgeons with a primer for implementing this class of medication in their current and future practice, including perioperative instructions and perioperative safety considerations when treating patients taking these medications.

Diabetes prevalence is increasing rapidly in older people, and sarcopenia is prevalent as a novel complication, particularly in patients with type 2 diabetes mellitus (T2DM). Therefore, sarcopenia prevention and treatment in these people is necessary. Diabetes accelerates sarcopenia through several mechanisms, such as hyperglycemia, chronic inflammation and oxidative stress. The effects of diet, exercise, and pharmacotherapy on sarcopenia in patients with T2DM need to be considered. In diet, low intake of energy, protein, vitamin D, and ω-3 fatty acid are associated with sarcopenia risk. In exercises, although intervention studies in people, especially older and non-obese patients with diabetes, are few, accumulating evidence shows the usefulness of exercise, particularly resistance exercise for muscle mass and strength, and aerobic exercise for physical performance in sarcopenia. In pharmacotherapy, certain classes of anti-diabetes compounds have possibility of preventing sarcopenia. However, much data on diet, exercise, and pharmacotherapy were obtained in obese and non-elderly patients with T2DM, demanding actual clinical data on non-obese and older patients with diabetes.

Glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide 1 (GLP1) exhibit incretin activity, meaning that they potentiate glucose-dependent insulin secretion. The emergence of GIP receptor (GIPR)-GLP1 receptor (GLP1R) co-agonists has fostered growing interest in the actions of GIP and GLP1 in metabolically relevant tissues. Here, we update concepts of how these hormones act beyond the pancreas. The actions of GIP and GLP1 on liver, muscle and adipose tissue, in the control of glucose and lipid homeostasis, are discussed in the context of plausible mechanisms of action. Both the GIPR and GLP1R are expressed in the central nervous system, wherein receptor activation produces anorectic effects enabling weight loss. In preclinical studies, GIP and GLP1 reduce atherosclerosis. Furthermore, GIPR and GLP1R are expressed within the heart and immune system, and GLP1R within the kidney, revealing putative mechanisms linking GIP and GLP1R agonism to cardiorenal protection. We interpret the clinical and mechanistic data obtained for different agents that enable weight loss and glucose control for the treatment of obesity and type 2 diabetes mellitus, respectively, by activating or blocking GIPR signalling, including the GIPR-GLP1R co-agonist tirzepatide, as well as the GIPR antagonist-GLP1R agonist AMG-133. Collectively, we update translational concepts of GIP and GLP1 action, while highlighting gaps, areas of uncertainty and controversies meriting ongoing investigation.

Heart failure (HF) patients are at risk of developing type 2 diabetes. This study examined the association between adherence to the Dietary Approaches to Stop Hypertension (DASH) diet and insulin resistance among U.S. adults with HF.

Using data from National Health and Nutrition Examination Survey 1999-2016 cycles, we included 348 individuals aged 20+ years with HF and no history of diabetes. DASH diet adherence index quartile 1 indicated the lowest and quartile 4 indicated the highest adherence. The highest level of insulin resistance was defined by the upper tertile of the Homeostatic Model Assessment of Insulin Resistance (HOMA-IR). Associations between level of insulin resistance and DASH diet adherence and its linear trends were examined using logistic regressions. Trend analyses showed that participants in upper DASH diet adherence index quartiles were more likely older, female, non-Hispanic White, of normal weight, and had lower levels of fasting insulin than those in lower quartiles. Median values of HOMA-IR from lowest to highest DASH diet adherence index quartiles were 3.1 (interquartile range, 1.8-5.5), 2.9 (1.7-5.6), 2.1 (1.1-3.7), and 2.1 (1.3-3.5). Multivariable logistic analyses indicated that participants with the highest compared to the lowest DASH adherence showed 77.1% lower odds of having the highest level of insulin resistance (0.229, 95% confidence interval: 0.073-0.716; p = 0.017 for linear trend).

Good adherence to the DASH diet was associated with lower insulin resistance among community-dwelling HF patients. Heart healthy dietary patterns likely protect HF patients from developing type 2 diabetes.

Glucose-dependent insulinotropic peptide (GIP) is one of two incretin hormones that communicate nutrient intake with systemic metabolism. Although GIP was the first incretin hormone to be discovered, the understanding of GIP's biology was quickly outpaced by research focusing on the other incretin hormone, glucagon-like peptide 1 (GLP-1). Early work on GIP produced the theory that GIP is obesogenic, limiting interest in developing GIPR agonists to treat type 2 diabetes. A resurgence of GIP research has occurred in the last five years, reinvigorating interest in this peptide. Two independent approaches have emerged for treating obesity, one promoting GIPR agonism and the other antagonism. In this report, evidence supporting both cases is discussed and hypotheses are presented to reconcile this apparent paradox.

This review presents evidence to support targeting GIPR to reduce obesity. Most of the focus is on the effect of singly targeting the GIPR using both a gain- and loss-of-function approach, with additional sections that discuss co-targeting of the GIPR and GLP-1R.

There is substantial evidence to support that GIPR agonism and antagonism can positively impact body weight. The long-standing theory that GIP drives weight gain is exclusively derived from loss-of-function studies, with no evidence to support that GIPR agonisms increases adiposity or body weight. There is insufficient evidence to reconcile the paradoxical observations that both GIPR agonism and antagonism can reduce body weight; however, two independent hypotheses centered on GIPR antagonism are presented based on new data in an effort to address this question. The first discusses the compensatory relationship between incretin receptors and how antagonism of the GIPR may enhance GLP-1R activity. The second discusses how chronic GIPR agonism may produce desensitization and ultimately loss of GIPR activity that mimics antagonism. Overall, it is clear that a deeper understanding of GIP biology is required to understand how modulating this system impacts metabolic homeostasis.

Glucose is used aerobically and anaerobically to generate energy for cells. Glucose transporters (GLUTs) are transmembrane proteins that transport glucose across the cell membrane. Insulin promotes glucose utilization in part through promoting glucose entry into the skeletal and adipose tissues. This has been thought to be achieved through insulin-induced GLUT4 translocation from intracellular compartments to the cell membrane, which increases the overall rate of glucose flux into a cell. The insulin-induced GLUT4 translocation has been investigated extensively. Recently, significant progress has been made in our understanding of GLUT4 expression and translocation. Here, we summarized the methods and reagents used to determine the expression levels of Slc2a4 mRNA and GLUT4 protein, and GLUT4 translocation in the skeletal muscle, adipose tissues, heart and brain. Overall, a variety of methods such real-time polymerase chain reaction, immunohistochemistry, fluorescence microscopy, fusion proteins, stable cell line and transgenic animals have been used to answer particular questions related to GLUT4 system and insulin action. It seems that insulin-induced GLUT4 translocation can be observed in the heart and brain in addition to the skeletal muscle and adipocytes. Hormones other than insulin can induce GLUT4 translocation. Clearly, more studies of GLUT4 are warranted in the future to advance of our understanding of glucose homeostasis.

Enteroendocrine cells (EECs) in the intestine regulate many aspects of whole-body physiology and metabolism. EECs sense luminal and circulating nutrients and respond by secreting hormones that act on multiple organs and organ systems, such as the brain, gallbladder, and pancreas, to control satiety, digestion, and glucose homeostasis. In addition, EECs act locally, on enteric neurons, endothelial cells, and the gastrointestinal epithelium, to facilitate digestion and absorption of nutrients. Many recent reports raise the possibility that EECs and the enteric nervous system may coordinate to regulate gastrointestinal functions. Loss of all EECs results in chronic malabsorptive diarrhea, placing EECs in a central role regulating nutrient absorption in the gut. Because there is increasing evidence that EECs can directly modulate the efficiency of nutrient absorption, it is possible that EECs are master regulators of a feed-forward loop connecting appetite, digestion, metabolism, and abnormally augmented nutrient absorption that perpetuates metabolic disease. This review focuses on the roles that specific EEC hormones play on glucose, peptide, and lipid absorption within the intestine.

Incretin hormones are gut peptides that are secreted after nutrient intake and stimulate insulin secretion together with hyperglycaemia. GIP (glucose-dependent insulinotropic polypeptide) und GLP-1 (glucagon-like peptide-1) are the known incretin hormones from the upper (GIP, K cells) and lower (GLP-1, L cells) gut. Together, they are responsible for the incretin effect: a two- to three-fold higher insulin secretory response to oral as compared to intravenous glucose administration. In subjects with type 2 diabetes, this incretin effect is diminished or no longer present. This is the consequence of a substantially reduced effectiveness of GIP on the diabetic endocrine pancreas, and of the negligible physiological role of GLP-1 in mediating the incretin effect even in healthy subjects. However, the insulinotropic and glucagonostatic effects of GLP-1 are preserved in subjects with type 2 diabetes to the degree that pharmacological stimulation of GLP-1 receptors significantly reduces plasma glucose and improves glycaemic control. Thus, it has become a parent compound of incretin-based glucose-lowering medications (GLP-1 receptor agonists and inhibitors of dipeptidyl peptidase-4 or DPP-4). GLP-1, in addition, has multiple effects on various organ systems. Most relevant are a reduction in appetite and food intake, leading to weight loss in the long term. Since GLP-1 secretion from the gut seems to be impaired in obese subjects, this may even indicate a role in the pathophysiology of obesity. Along these lines, an increased secretion of GLP-1 induced by delivering nutrients to lower parts of the small intestines (rich in L cells) may be one factor (among others like peptide YY) explaining weight loss and improvements in glycaemic control after bariatric surgery (e.g., Roux-en-Y gastric bypass). GIP and GLP-1, originally characterized as incretin hormones, have additional effects in adipose cells, bone, and the cardiovascular system. Especially, the latter have received attention based on recent findings that GLP-1 receptor agonists such as liraglutide reduce cardiovascular events and prolong life in high-risk patients with type 2 diabetes. Thus, incretin hormones have an important role physiologically, namely they are involved in the pathophysiology of obesity and type 2 diabetes, and they have therapeutic potential that can be traced to well-characterized physiological effects.

The gastrointestinal (GI) tract plays a critical role in delivering carbohydrate and fluid during prolonged exercise and can therefore be a major determinant of performance. The incidence of GI problems in athletes participating in endurance events is high, indicating that GI function is not always optimal in those conditions. A substantial body of evidence suggests that the GI system is highly adaptable. Gastric emptying as well as stomach comfort can be "trained" and perceptions of fullness decreased; some studies have suggested that nutrient-specific increases in gastric emptying may occur. Evidence also shows that diet has an impact on the capacity of the intestine to absorb nutrients. Again, the adaptations that occur appear to be nutrient specific. For example, a high-carbohydrate diet will increase the density of sodium-dependent glucose-1 (SGLT1) transporters in the intestine as well as the activity of the transporter, allowing greater carbohydrate absorption and oxidation during exercise. It is also likely that, when such adaptations occur, the chances of developing GI distress are smaller. Future studies should include more human studies and focus on a number of areas, including the most effective methods to induce gut adaptations and the timeline of adaptations. To develop effective strategies, a better understanding of the exact mechanisms underlying these adaptations is important. It is clear that "nutritional training" can improve gastric emptying and absorption and likely reduce the chances and/or severity of GI problems, thereby improving endurance performance as well as providing a better experience for the athlete. The gut is an important organ for endurance athletes and should be trained for the conditions in which it will be required to function.