Molecular dynamics-guided optimization of BGM0504 enhances dual-target agonism for combating diabetes and obesity.

The dual activation of glucagon-like peptide-1 receptor (GLP-1R) and glucose-dependent insulinotropic polypeptide receptor (GIPR) has emerged as a promising therapeutic strategy for managing type 2 diabetes and obesity. Tirzepatide, a dual agonist peptide, has exhibited superior clinical efficacy in glycemic and weight control compared to selective GLP-1R agonists. Nevertheless, the structural basis of Tirzepatide's extended half-life, attributed to an acylation side chain on the parent peptide, raises questions regarding its partial agonistic activity. Employing molecular dynamics simulations, we explored the dynamic processes of peptide-receptor interactions. We uncovered a crucial salt bridge between parent peptide and GLP-1R/GIPR at K20, a feature not discernible in cryo-electron microscopy structures. Building upon these insights, we developed an optimization strategy based on the parent peptide which involved repositioning the acylation side chain. The results of both in vitro and in vivo experiments demonstrated that the optimized peptide has twofold to threefold increase in agonistic activity compared to Tirzepatide while maintaining its extended half-life in plasma. This led to the design of BGM0504, which proved to be more effective than its predecessor, Tirzepatide, in both laboratory and animal studies.

Bridging the gap between GLP1-receptor agonists and cardiovascular outcomes: evidence for the role of tirzepatide.

Tirzepatide is a new drug targeting glucagon-like peptide 1(GLP1) and gastric inhibitory polypeptide (GIP) receptors. This drug has demonstrated great potential in improving the clinical outcomes of patients with type 2 diabetes. It can lead to weight loss, better glycemic control, and reduced cardiometabolic risk factors. GLP1 receptor agonists have been proven effective antidiabetic medications with possible cardiovascular benefits. Even though they have been proven to reduce the risk of major adverse cardiovascular events, their effectiveness in treating heart failure is unknown. Unlike traditional GLP1 receptor agonists, tirzepatide is more selective for the GIP receptor, resulting in a more balanced activation of these receptors. This review article discusses the possible mechanisms tirzepatide may use to improve cardiovascular health. That includes the anti-inflammatory effect, the ability to reduce cell death and promote autophagy, and also its indirect effects through blood pressure, obesity, and glucose/lipid metabolism. Additionally, tirzepatide may benefit atherosclerosis and lower the risk of major adverse cardiac events. Currently, clinical trials are underway to evaluate the safety and efficacy of tirzepatide in patients with heart failure. Overall, tirzepatide's dual agonism of GLP1 and GIP receptors appears to provide encouraging cardiovascular benefits beyond glycemic control, offering a potential new therapeutic option for treating cardiovascular diseases and heart failure.

Gut microbiota DPP4-like enzymes are increased in type-2 diabetes and contribute to incretin inactivation.

BACKGROUND: The gut microbiota controls broad aspects of human metabolism and feeding behavior, but the basis for this control remains largely unclear. Given the key role of human dipeptidyl peptidase 4 (DPP4) in host metabolism, we investigate whether microbiota DPP4-like counterparts perform the same function. RESULTS: We identify novel functional homologs of human DPP4 in several bacterial species inhabiting the human gut, and specific associations between Parabacteroides and Porphyromonas DPP4-like genes and type 2 diabetes (T2D). We also find that the DPP4-like enzyme from the gut symbiont Parabacteroides merdae mimics the proteolytic activity of the human enzyme on peptide YY, neuropeptide Y, gastric inhibitory polypeptide (GIP), and glucagon-like peptide 1 (GLP-1) hormones in vitro. Importantly, administration of E. coli overexpressing the P. merdae DPP4-like enzyme to lipopolysaccharide-treated mice with impaired gut barrier function reduces active GIP and GLP-1 levels, which is attributed to increased DPP4 activity in the portal circulation and the cecal content. Finally, we observe that linagliptin, saxagliptin, sitagliptin, and vildagliptin, antidiabetic drugs with DPP4 inhibitory activity, differentially inhibit the activity of the DPP4-like enzyme from P. merdae. CONCLUSIONS: Our findings confirm that proteolytic enzymes produced by the gut microbiota are likely to contribute to the glucose metabolic dysfunction that underlies T2D by inactivating incretins, which might inspire the development of improved antidiabetic therapies.

Tirzepatide against obesity and insulin-resistance: pathophysiological aspects and clinical evidence.

Obesity is a chronic, multifactorial disease in which accumulated excess body fat has a negative impact on health. Obesity continues to rise among the general population, resulting in an epidemic that shows no significant signs of decline. It is directly involved in development of cardiometabolic diseases, ischemic coronary heart disease peripheral arterial disease, heart failure, and arterial hypertension, producing global morbidity and mortality. Mainly, abdominal obesity represents a crucial factor for cardiovascular illness and also the most frequent component of metabolic syndrome. Recent evidence showed that Tirzepatide (TZP), a new drug including both Glucagon Like Peptide 1 (GLP-1) and Glucose-dependent Insulinotropic Polypeptide (GIP) receptor agonism, is effective in subjects with type 2 diabetes (T2D), lowering body weight, fat mass and glycated hemoglobin (HbA1c) also in obese or overweight adults without T2D. This review discusses the pathophysiological mechanisms and clinical aspects of TZP in treating obesity.

Therapeutic potentials of glucose-dependent insulinotropic polypeptide (GIP) in T2DM: Past, present, and future.

Type 2 diabetes mellitus (T2DM) is a worldwide health problem that has raised major concerns to the public health community. This chronic condition typically results from the cell's inability to respond to normal insulin levels. Glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) are the primary incretin hormones secreted from the intestinal tract. While clinical research has extensively explored the therapeutic potential of GLP-1R in addressing various T2DM-related abnormalities, the possibility of GIPR playing an important role in T2DM treatment is still under investigation. Evidence suggests that GIP is involved in the pathophysiology of T2DM. This chapter focuses on examining the role of GIP as a therapeutic molecule in combating T2DM, comparing the past, present, and future scenarios. Our goal is to delve into how GIP may impact pancreatic ß-cell function, adipose tissue uptake, and lipid metabolism. Furthermore, we will elucidate the mechanistic functions of GIP and its receptors in relation to other clinical conditions like cardiovascular diseases, non-alcoholic fatty liver diseases, neurodegenerative diseases, and renal disorders. Additionally, this chapter will shed light on the latest advancements in pharmacological management for T2DM, highlighting potential structural modifications of GIP and the repurposing of drugs, while also addressing the challenges involved in bringing GIP-based treatments into clinical practice.

Foetal gluten immunogenic peptides during pregnancy: a new determinant on the coeliac exposome.

BACKGROUND: The increasing incidence of coeliac disease is leading to a growing interest in active search for associated factors, even the intrauterine and early life. The exposome approach to disease encompasses a life course perspective from conception onwards has recently been highlighted. Knowledge of early exposure to gluten immunogenic peptides (GIP) in utero could challenge the chronology of early prenatal tolerance or inflammation, rather than after the infant's solid diet after birth. METHODS: We developed an accurate and specific immunoassay to detect GIP in amniotic fluid (AF) and studied their accumulates, excretion dynamics and foetal exposure resulting from AF swallowing. One hundred twenty-five pregnant women with different gluten diets and gestational ages were recruited. RESULTS: GIP were detectable in AF from at least the 16th gestational week in gluten-consuming women. Although no significant differences in GIP levels were observed during gestation, amniotic GIP late pregnancy was not altered by maternal fasting, suggesting closed-loop entailing foetal swallowing of GIP-containing AF and subsequent excretion via the foetal kidneys. CONCLUSIONS: The study shows evidence, for the first time, of the foetal exposure to gluten immunogenic peptides and establishes a positive correlation with maternal gluten intake. The results obtained point to a novel physiological concept as they describe a plausible closed-loop circuit entailing foetal swallowing of GIP contained in AF and its subsequent excretion through the foetal kidneys. The study adds important new information to understanding the coeliac exposome.

Tirzepatide ameliorates eating behaviors regardless of prior exposure to glucagon-like peptide receptor agonists in Japanese patients with type 2 diabetes mellitus.

AIMS: To investigate effects of tirzepatide, a dual receptor agonist for glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 (GLP-1), on eating behaviors. METHODS: Eating behaviors were evaluated by using a validated questionnaire survey in 33 Japanese patients with type 2 diabetes mellitus (T2DM) (mean age: 51.8 years) who were treated with tirzepatide (2.5 mg/week for 4 weeks and then 5.0 mg/week) for 6 months (M). RESULTS: Treatment with tirzepatide significantly decreased median hemoglobin A1c (HbA1c) (baseline/3 M/6 M: 7.3 %/6.0 %/5.8 %), mean body weight (BW) (baseline/3 M/6 M: 87.7 kg/82.0 kg/79.6 kg) and mean relative score of eating behaviors (baseline/3 M/6 M: 57.0/50.7/45.9). In the GLP-1 receptor agonist (GLP-1RA) naïve group (n = 20, men/women: 13/7), HbA1c and BW were continuously decreased up to 6 M. Changes in eating behaviors were mainly observed in the first 3 M. In the GLP-1RA non-naïve group (n = 13, men/women: 8/5), reductions in HbA1c and BW were predominant in the first 3 M, and changes in eating behaviors were observed up to 6 M. There were no significant correlations of changes in scores of eating behaviors with changes in glycemic control or those in BW. CONCLUSIONS: Tirzepatide ameliorates eating behaviors as well as glycemic management and obesity in Japanese patients with T2DM, and the patterns of improvement are partially dependent on prior exposure to GLP-1RAs.

Impact of chickpea hummus on postprandial blood glucose, insulin and gut hormones in healthy humans combined with mechanistic studies of food structure, rheology and digestion kinetics.

Slowing the rate of carbohydrate digestion leads to low postprandial glucose and insulin responses, which are associated with reduced risk of type 2 diabetes. There is increasing evidence that food structure plays a crucial role in influencing the bioaccessibility and digestion kinetics of macronutrients. The aims of this study were to compare the effects of two hummus meals, with different degrees of cell wall integrity, on postprandial metabolic responses in relation to the microstructural and rheological characteristics of the meals. A randomised crossover trial in 15 healthy participants was designed to compare the acute effect of 27 g of starch, provided as hummus made from either intact chickpea cells (ICC) or ruptured chickpea cells (RCC), on postprandial metabolic responses. In vitro starch digestibility, microstructural and rheological experiments were also conducted to evaluate differences between the two chickpea hummus meals. Blood insulin and GIP concentrations were significantly lower (P < 0.02, P < 0.03) after the consumption of the ICC meal than the meal containing RCC. In vitro starch digestion for 90 min was slower in ICC than in RCC. Microscopic examination of hummus samples digested in vitro for 90 min revealed more intact chickpea cells in ICC compared to the RCC sample. Rheological experiments showed that fracture for ICC hummus samples occurred at smaller strains compared to RCC samples. However, the storage modulus for ICC was higher than RCC, which may be explained by the presence of intact cells in ICC. Food structure can affect the rate and extent of starch bioaccessibility and digestion and may explain the difference in the time course of metabolic responses between meals. The rheological properties were measured on the two types of meals before ingestion, showing significant differences that may point to different breakdown mechanisms during subsequent digestion. This trial was registered at clinicaltrial.gov as NCT03424187.

Molecular design of peptide therapeutics via N-terminal modification.

Glucagon-like peptide-1, glucose-dependent insulinotropic polypeptide, and glucagon are three naturally occurring peptide hormones that mediate glucoregulation. Several agonists representing appropriately modified native ligands have been developed to maximize metabolic benefits with reduced side-effects and many have entered the clinic as type 2 diabetes and obesity therapeutics. In this work, we describe strategies for improving the stability of the peptide ligands by making them refractory to dipeptidyl peptidase-4 catalyzed hydrolysis and inactivation. We describe a series of alkylations with variations in size, shape, charge, polarity, and stereochemistry that are able to engender full activity at the receptor(s) while simultaneously resisting enzyme-mediated degradation. Utilizing this strategy, we offer a novel method of modulating receptor activity and fine-tuning pharmacology without a change in peptide sequence.

GIP attenuates neuronal oxidative stress by regulating glucose uptake in spinal cord injury of rat.

AIM: Glucose-dependent insulinotropic polypeptide (GIP) is a ligand of glucose-dependent insulinotropic polypeptide receptor (GIPR) that plays an important role in the digestive system. In recent years, GIP has been regarded as a hormone-like peptide to regulate the local metabolic environment. In this study, we investigated the antioxidant role of GIP on the neuron and explored the possible mechanism. METHODS: Cell counting Kit-8 (CCK-8) was used to measure cell survival. TdT-mediated dUTP Nick-End Labeling (TUNEL) was used to detect apoptosis in vitro and in vivo. Reactive oxygen species (ROS) levels were probed with 2', 7'-Dichloro dihydrofluorescein diacetate (DCFH-DA), and glucose intake was detected with 2-NBDG. Immunofluorescence staining and western blot were used to evaluate the protein level in cells and tissues. Hematoxylin-eosin (HE) staining, immunofluorescence staining and tract-tracing were used to observe the morphology of the injured spinal cord. Basso-Beattie-Bresnahan (BBB) assay was used to evaluate functional recovery after spinal cord injury. RESULTS: GIP reduced the ROS level and protected cells from apoptosis in cultured neurons and injured spinal cord. GIP facilitated wound healing and functional recovery of the injured spinal cord. GIP significantly improved the glucose uptake of cultured neurons. Meanwhile, inhibition of glucose uptake significantly attenuated the antioxidant effect of GIP. GIP increased glucose transporter 3 (GLUT3) expression via up-regulating the level of hypoxia-inducible factor 1α (HIF-1α) in an Akt-dependent manner. CONCLUSION: GIP increases GLUT3 expression and promotes glucose intake in neurons, which exerts an antioxidant effect and protects neuronal cells from oxidative stress both in vitro and in vivo.

Characterization of genetic variants of GIPR reveals a contribution of ß-arrestin to metabolic phenotypes.

Incretin-based therapies are highly successful in combatting obesity and type 2 diabetes1. Yet both activation and inhibition of the glucose-dependent insulinotropic polypeptide (GIP) receptor (GIPR) in combination with glucagon-like peptide-1 (GLP-1) receptor (GLP-1R) activation have resulted in similar clinical outcomes, as demonstrated by the GIPR-GLP-1R co-agonist tirzepatide2 and AMG-133 (ref. 3) combining GIPR antagonism with GLP-1R agonism. This underlines the importance of a better understanding of the GIP system. Here we show the necessity of ß-arrestin recruitment for GIPR function, by combining in vitro pharmacological characterization of 47 GIPR variants with burden testing of clinical phenotypes and in vivo studies. Burden testing of variants with distinct ligand-binding capacity, Gs activation (cyclic adenosine monophosphate production) and ß-arrestin 2 recruitment and internalization shows that unlike variants solely impaired in Gs signalling, variants impaired in both Gs and ß-arrestin 2 recruitment contribute to lower adiposity-related traits. Endosomal Gs-mediated signalling of the variants shows a ß-arrestin dependency and genetic ablation of ß-arrestin 2 impairs cyclic adenosine monophosphate production and decreases GIP efficacy on glucose control in male mice. This study highlights a crucial impact of ß-arrestins in regulating GIPR signalling and overall preservation of biological activity that may facilitate new developments in therapeutic targeting of the GIPR system.

Does glucose-dependent insulinotropic polypeptide receptor blockade as well as agonism have a role to play in management of obesity and diabetes?

Recent approval of the dual glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) receptor agonist, tirzepatide, for the management of type 2 diabetes mellitus (T2DM) has reinvigorated interest in exploitation of GIP receptor (GIPR) pathways as a means of metabolic disease management. However, debate has long surrounded the use of the GIPR as a therapeutic target and whether agonism or antagonism is of most benefit in management of obesity/diabetes. This controversy appears to be partly resolved by the success of tirzepatide. However, emerging studies indicate that prolonged GIPR agonism may desensitise the GIPR to essentially induce receptor antagonism, with this phenomenon suggested to be more pronounced in the human than rodent setting. Thus, deliberation continues to rage in relation to benefits of GIPR agonism vs antagonism. That said, as with GIPR agonism, it is clear that the metabolic advantages of sustained GIPR antagonism in obesity and obesity-driven forms of diabetes can be enhanced by concurrent GLP-1 receptor (GLP-1R) activation. This narrative review discusses various approaches of pharmacological GIPR antagonism including small molecule, peptide, monoclonal antibody and peptide-antibody conjugates, indicating stage of development and significance to the field. Taken together, there is little doubt that interesting times lie ahead for GIPR agonism and antagonism, either alone or when combined with GLP-1R agonists, as a therapeutic intervention for the management of obesity and associated metabolic disease.

Gut hormone multi-agonists for the treatment of type 2 diabetes and obesity: advances and challenges.

The rapidly rising incidence of obesity, coupled with type 2 diabetes mellitus (T2DM), is a growing concern. Glucagon-like peptide 1 (GLP-1), an endogenous peptide secreted by enteroendocrine L-cells, demonstrates exceptional pharmacological potential for the treatment of T2DM and obesity, primarily through its pivotal roles in regulating glucose homeostasis, stimulating glucose-dependent insulin secretion, and promoting satiety. Considering its proven efficacy in glucoregulation and weight loss, GLP-1 receptor agonists (GLP-1RAs) have emerged as a revolutionary breakthrough in the arena of diabetes management and weight control. Additional gastrointestinal hormones, such as glucose-dependent insulinotropic peptide (GIP) and glucagon, exhibit structural similarities to GLP-1 and work synergistically to lower blood glucose levels or aid in weight loss. Today, various classes of gut hormone receptor multiple agonists are steadily progressing through development and clinical trials, including dual GLP-1/glucagon receptor agonists (first discovered in 2009), dual GLP-1/GIP receptor agonists (first described in 2013), and triple GLP-1/GIP/glucagon receptor agonists (initially designed in 2015). The GLP-1/GIP receptor co-agonist, tirzepatide, was approved by the U.S. Food and Drug Administration (FDA) for the treatment of T2DM, outperforming basal insulin or selective GLP-1RAs by providing superior HbA1c reductions. Remarkably, tirzepatide also facilitated unprecedented weight loss of up to 22.5% in non-diabetic individuals living with obesity. This result is comparable to those achieved with certain types of bariatric surgery. Therefore, the advent of gut hormone multi-agonists signifies the dawn of an exciting new era in peptide-based therapy for obesity and T2DM. This review offers a comprehensive summary of the various types of gut hormone multiple agonists, including their discovery, development, action of mechanisms, and clinical effectiveness. We further delve into potential hurdles, limitations, and prospective advancements in the field.

Tirzepatide for Metabolic Dysfunction-Associated Steatohepatitis with Liver Fibrosis.

BACKGROUND: Metabolic dysfunction-associated steatohepatitis (MASH) is a progressive liver disease associated with liver-related complications and death. The efficacy and safety of tirzepatide, an agonist of the glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 receptors, in patients with MASH and moderate or severe fibrosis is unclear. METHODS: We conducted a phase 2, dose-finding, multicenter, double-blind, randomized, placebo-controlled trial involving participants with biopsy-confirmed MASH and stage F2 or F3 (moderate or severe) fibrosis. Participants were randomly assigned to receive once-weekly subcutaneous tirzepatide (5 mg, 10 mg, or 15 mg) or placebo for 52 weeks. The primary end point was resolution of MASH without worsening of fibrosis at 52 weeks. A key secondary end point was an improvement (decrease) of at least one fibrosis stage without worsening of MASH. RESULTS: Among 190 participants who had undergone randomization, 157 had liver-biopsy results at week 52 that could be evaluated, with missing values imputed under the assumption that they would follow the pattern of results in the placebo group. The percentage of participants who met the criteria for resolution of MASH without worsening of fibrosis was 10% in the placebo group, 44% in the 5-mg tirzepatide group (difference vs. placebo, 34 percentage points; 95% confidence interval [CI], 17 to 50), 56% in the 10-mg tirzepatide group (difference, 46 percentage points; 95% CI, 29 to 62), and 62% in the 15-mg tirzepatide group (difference, 53 percentage points; 95% CI, 37 to 69) (P<0.001 for all three comparisons). The percentage of participants who had an improvement of at least one fibrosis stage without worsening of MASH was 30% in the placebo group, 55% in the 5-mg tirzepatide group (difference vs. placebo, 25 percentage points; 95% CI, 5 to 46), 51% in the 10-mg tirzepatide group (difference, 22 percentage points; 95% CI, 1 to 42), and 51% in the 15-mg tirzepatide group (difference, 21 percentage points; 95% CI, 1 to 42). The most common adverse events in the tirzepatide groups were gastrointestinal events, and most were mild or moderate in severity. CONCLUSIONS: In this phase 2 trial involving participants with MASH and moderate or severe fibrosis, treatment with tirzepatide for 52 weeks was more effective than placebo with respect to resolution of MASH without worsening of fibrosis. Larger and longer trials are needed to further assess the efficacy and safety of tirzepatide for the treatment of MASH. (Funded by Eli Lilly; SYNERGY-NASH ClinicalTrials.gov number, NCT04166773.).

NPYR modulation: Potential for the next major advance in obesity and type 2 diabetes management?

The approval of the glucagon-like peptide 1 (GLP-1) mimetics semaglutide and liraglutide for management of obesity, independent of type 2 diabetes (T2DM), has initiated a resurgence of interest in gut-hormone derived peptide therapies for the management of metabolic diseases, but side-effect profile is a concern for these medicines. However, the recent approval of tirzepatide for obesity and T2DM, a glucose-dependent insulinotropic polypeptide (GIP), GLP-1 receptor co-agonist peptide therapy, may provide a somewhat more tolerable option. Despite this, an increasing number of non-incretin alternative peptides are in development for obesity, and it stands to reason that other hormones will take to the limelight in the coming years, such as peptides from the neuropeptide Y family. This narrative review outlines the therapeutic promise of the neuropeptide Y family of peptides, comprising of the 36 amino acid polypeptides neuropeptide Y (NPY), peptide tyrosine-tyrosine (PYY) and pancreatic polypeptide (PP), as well as their derivatives. This family of peptides exerts a number of metabolically relevant effects such as appetite regulation and can influence pancreatic beta-cell survival. Although some of these actions still require full translation to the human setting, potential therapeutic application in obesity and type 2 diabetes is conceivable. However, like GLP-1 and GIP, the endogenous NPY, PYY and PP peptide forms are subject to rapid in vivo degradation and inactivation by the serine peptidase, dipeptidyl-peptidase 4 (DPP-4), and hence require structural modification to prolong circulating half-life. Numerous protective modification strategies are discussed in this regard herein, alongside related impact on biological activity profile and therapeutic promise.

Tirzepatide modulates the regulation of adipocyte nutrient metabolism through long-acting activation of the GIP receptor.

Tirzepatide, a glucose-dependent insulinotropic polypeptide/glucagon-like peptide 1 receptor (GIPR/GLP-1R) agonist, has, in clinical trials, demonstrated greater reductions in glucose, body weight, and triglyceride levels compared with selective GLP-1R agonists in people with type 2 diabetes (T2D). However, cellular mechanisms by which GIPR agonism may contribute to these improved efficacy outcomes have not been fully defined. Using human adipocyte and mouse models, we investigated how long-acting GIPR agonists regulate fasted and fed adipocyte functions. In functional assays, GIPR agonism enhanced insulin signaling, augmented glucose uptake, and increased the conversion of glucose to glycerol in a cooperative manner with insulin; however, in the absence of insulin, GIPR agonists increased lipolysis. In diet-induced obese mice treated with a long-acting GIPR agonist, circulating triglyceride levels were reduced during oral lipid challenge, and lipoprotein-derived fatty acid uptake into adipose tissue was increased. Our findings support a model for long-acting GIPR agonists to modulate both fasted and fed adipose tissue function differentially by cooperating with insulin to augment glucose and lipid clearance in the fed state while enhancing lipid release when insulin levels are reduced in the fasted state.

Achievement of normoglycemia with tirzepatide in type 2 diabetes mellitus: A step closer to drug-induced diabetes remission?

We sought to determine whether treatment with tirzepatide in type 2 diabetes mellitus (T2DM) patients can increase the odds for achieving normoglycemia, compatible with glycated hemoglobin levels lower than 5.7 %. We demonstrated that treatment with tirzepatide versus control increased the odds for achievement of normoglycemia by >16 times.

Chronic exposure to incretin metabolites GLP-1(9-36) and GIP(3-42) affect islet morphology and beta cell health in high fat fed mice.

The incretin hormones, glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), are rapidly degraded by dipeptidyl peptidase-4 (DPP-4) to their major circulating metabolites GLP-1(9-36) and GIP(3-42). This study investigates the possible effects of these metabolites, and the equivalent exendin molecule Ex(9-39), on pancreatic islet morphology and constituent alpha and beta cells in high-fat diet (HFD) fed mice. Male Swiss TO-mice (6-8 weeks-old) were maintained on a HFD or normal diet (ND) for 4 months and then received twice-daily subcutaneous injections of GLP-1(9-36), GIP(3-42), Ex(9-39) (25 nmol/kg bw) or saline vehicle (0.9% (w/v) NaCl) over a 60-day period. Metabolic parameters were monitored and excised pancreatic tissues were used for immunohistochemical analysis. Body weight and assessed metabolic indices were not changed by peptide administration. GLP-1(9-36) significantly (p<0.001) increased islet density per mm2 tissue, that was decreased (p<0.05) by HFD. Islet, beta and alpha cell areas were increased (p<0.01) following HFD and subsequently reduced (p<0.01-p<0.001) by GIP(3-42) and Ex(9-39) treatment. While GLP-1(9-36) did not affect islet and beta cell areas in HFD mice, it significantly (p<0.01) decreased alpha cell area. Compared to ND and HFD mice, GIP(3-42) treatment significantly (p<0.05) increased beta cell proliferation. Whilst HFD increased (p<0.001) beta cell apoptosis, this was reduced (p<0.01-p<0.001) by both GLP-1(9-36) and GIP(3-42). These data indicate that the major circulating forms of GLP-1 and GIP, namely GLP-1(9-36) and GIP(3-42) previously considered largely inactive, may directly impact pancreatic morphology, with an important protective effect on beta cell health under conditions of beta cell stress.

Characterization of tirzepatide-treated patients achieving different glycemic control levels in SURPASS-AP-Combo.

OBJECTIVE: The study objective was to characterize subgroups of Asia-Pacific patients with type 2 diabetes who achieved different glycated hemoglobin (HbA1c) targets on tirzepatide treatment. METHODS: This was a post hoc analysis of the SURPASS AP-Combo study. Baseline characteristics, changes in metabolic markers, and safety were compared between tirzepatide-treated patients achieving HbA1c <7.0% (<53 mmol/mol) and those achieving ≥7.0% (≥53 mmol/mol) at week 40. Among patients achieving HbA1c <7.0% (<53 mmol/mol), further comparisons were conducted among subgroups achieving HbA1c <5.7% (<39 mmol/mol), 5.7% to 6.5% (39 to 48 mmol/mol), and >6.5% to <7.0% (>48 to <53 mmol/mol). RESULTS: Five hundred ninety-eight patients on tirzepatide treatment without rescue medication were included (56.9% male; mean age: 53.1 years; mean baseline HbA1c: 8.7% [71.6 mmol/mol]). Patients achieving HbA1c <7.0% (<53 mmol/mol) versus ≥7.0% (≥53 mmol/mol) were slightly younger with a shorter disease duration and lower HbA1c at baseline, and they had greater improvements in HbA1c, fasting serum glucose, body weight, BMI, waist circumference, waist-height ratio, diastolic blood pressure, lipids, and self-monitored blood glucose at week 40. Patients achieving HbA1c <5.7% (<39 mmol/mol) versus those achieving 5.7% to 6.5% (39 to 48 mmol/mol) and those achieving >6.5% to <7.0% (>48 to <53 mmol/mol) were much younger, had much lower HbA1c, and had further improvements in metabolic markers. Tirzepatide treatment was well tolerated irrespective of the HbA1c level achieved, with a low incidence of hypoglycemic events. CONCLUSIONS: These findings may help to inform clinical decisions in Asia-Pacific patients with type 2 diabetes.

Tirzepatide 5, 10 and 15 mg versus injectable semaglutide 0.5 mg for the treatment of type 2 diabetes: An adjusted indirect treatment comparison.

AIMS: To compare the efficacy and safety of tirzepatide 5, 10 and 15 mg with subcutaneous semaglutide 0.5 mg as second-line treatment for adults with type 2 diabetes mellitus, after metformin monotherapy, using adjusted indirect treatment comparisons (aITCs). METHODS: The aITCs were performed using the Bucher method to compare the relative efficacy and safety of tirzepatide 5, 10 and 15 mg versus semaglutide 0.5 mg via a common comparator (subcutaneous semaglutide 1.0 mg) based on trial results from SURPASS-2 (NCT03987919) and SUSTAIN7 (NCT02648204). RESULTS: All tirzepatide doses showed statistically significantly greater reductions in glycated haemoglobin, body weight and body mass index from baseline to week 40, with a comparable adverse event (AE) profile and no statistically significant differences in the odds of gastrointestinal AEs versus semaglutide 0.5 mg. Furthermore, all tirzepatide doses showed greater odds of patients achieving HbA1c targets of ≤ 6.5 % (≤48 mmol/mol) and < 7.0 % (<53 mmol/mol) and weight loss targets of ≥ 5 % and ≥ 10 %, versus semaglutide 0.5 mg. CONCLUSIONS: In these aITCs, glycated haemoglobin and weight reductions were significantly greater for all tirzepatide doses versus semaglutide 0.5 mg with a comparable AE profile. These findings provide comparative effectiveness insights in the absence of a head-to-head clinical trial.