Pramlintide

Long-acting amylin-related peptides as therapies for obesity and type 2 diabetes.

Clifford J Bailey, Peter R Flatt, J Michael Conlon

The first therapeutically useful amylin receptor (AMYR) agonist, pramlintide was based upon the structure of non-aggregating rat amylin and found limited application as an adjunct to insulin therapy. It acts centrally to induce satiety, promote weight loss, suppress prandial glucagon release and reduce prandial hyperglycaemia. Recent understanding of the heterodimeric structure of amylin-calcitonin receptor complexes and of amylin structure-function properties has assisted the design of a second generation of non-aggregating, long-acting amylin analogues. These are now advancing in clinical development and promise to provide an effective additional resource for the management of obesity and type 2 diabetes. Amongst these agents is the dual AMYR/ calcitonin-receptor (CTR) agonist, cagrilintide that has also been co-formulated into a once weekly subcutaneous injection with the long-acting glucagon-like peptide-1receptor (GLP-1R) agonist, semaglutide (CagriSema). In clinical trials, CagriSema has achieved greater effects than either component alone. A unimolecular AMYR/CTR/GLP-1R multi-agonist peptide, amycretin has been developed for weekly injection and as a once-daily tablet. Several recently developed long-acting amylin analogues have shown strong efficacy as monotherapy in clinical trials: these include eloralintide, petrelintide, Met-233 and AZD6234. Other analogues with marked efficacy in preclinical studies, including non-peptide AMYR agonists are under development. Gastrointestinal side effects, especially nausea, similar to those reported for GLP-1R agonists are commonplace during initiation and up-titration of amylin analogues but mostly resolve during continued use. Evidence is emerging that long-acting AMYR agonists may show potential therapeutic benefits in treatment of patients with fatty liver disease, diabetes-associated kidney complications and resistant hypertension.

From the pancreas to the amygdala: New brain area critical for ingestive and motivated behavior control exerted by amylin.

Suyeun Byun, Ivana Maric, Stina Börchers +4 more

Amylin, a pancreatic peptide, has a well-established role in feeding behavior control. Amylin analogues are clinically utilized in patients with diabetes and are under investigation as potential anti-obesity pharmacotherapies. The neural circuits underlying actions of amylin on behavior are not well understood. While amylin was found to bind to the central amygdala (CeA) of rodents and primates and we found that all components of amylin receptors are present in the CeA, their potential role in physiology or behavior remains unknown. Here, we investigated the impact of this potential pancreas - CeA amylin-mediated communication - on ingestive and motivated behaviors. Activation of CeA amylin receptors resulted in a robust hypophagia, reduced food-motivated behavior, and altered macronutrient preference in male and female rats. Clinically used amylin analogue, pramlintide, reduced meal size and frequency by acting on the CeA. Disruption of CeA amylin signaling led to hyperphagia and body weight gain in a sex divergent manner. Importantly, CeA amylin signaling was required for appetite suppression induced by peripherally applied amylin, highlighting translational relevance of this brain site. Our data indicate the CeA is a critical neural substrate for amylin signaling.

The story of amylin: from physiology to therapy.

Anna Secher, Thomas A Lutz, Kirsten Raun

Amylin is a glucoregulatory peptide hormone discovered in 1986. Almost 20 years later, pramlintide, a human amylin analogue, emerged as the first amylin-based drug, approved as an adjunct treatment to insulin for type 1 diabetes (T1D) and type 2 diabetes (T2D). Despite its effects on multiple organ systems, the therapeutic potential of amylin has remained relatively underexplored until recently, when growing interest in amylin has prompted advancement of several amylin-based therapies towards clinical use. This Review contextualizes the evolving therapeutic potential of amylin, focusing on recent preclinical and clinical data, amylin receptor pharmacology and its broader biological effects. We discuss the potential and challenges of developing amylin-based treatments for cardiometabolic disease, including milestones in drug development of amylin, and its combination with additional molecules as part of the future landscape of therapies for patients with diabetes or obesity.

In vitro metabolic profiling of weight-loss-inducing amylin receptor agonists in the context of preventive doping research.

Hana Alhalabi, Lisa Borschel, Christelle Le Foll +3 more

Peptide hormone-based weight-loss therapeutics have gained increasing attention, driven amongst other reasons, by the clinical and commercial success of semaglutide. Their increasing accessibility raises concerns about their potential misuse in sports, especially in disciplines where weight management is decisive for athletic performance. Semaglutide has been included in the World Anti-Doping Agency's monitoring program since 2024. Given that amylin signalling is a key therapeutic target for next-generation weight-loss drugs, amylin receptor agonists such as pramlintide, cagrilintide and KBP-066 also warrant consideration as to metabolism and detection strategies in sports drug testing programs. This study aimed to characterize the metabolic profiles of pramlintide, cagrilintide and KBP-066, identify analytically suitable metabolites and develop and validate a LC-MS/MS-based detection approach. Comprehensive in vitro models, including human skin S9 fraction, kidney S9 fraction and biological fluids, were used to investigate metabolic pathways. HRMS/MS was employed to characterize metabolites and evaluate their suitability as analytical targets. For comparison, authentic post-administration rat samples were analysed for cagrilintide and respective biotransformation products. All three peptides underwent N-terminal and C-terminal degradation, yielding multiple stable metabolic products suitable as detection targets. Cagrilintide metabolites predicted from in vitro experiments were observed in authentic post administration rat plasma samples, confirming in vivo relevance. Finally, suitable preparation and detection methods were established and validated. This study provides the first systematic metabolic characterization of pramlintide, cagrilintide and KBP-066. The identified metabolites and LC-MS/MS detection approach offer a foundation for future monitoring of emerging weight-loss peptide hormone analogues in anti-doping contexts.

Amylin Revisited: A 5-Year Perspective on Its Emerging Role in the Treatment of Diabesity.

Chae Won Chung, Jaetaek Kim

Amylin is a pancreatic peptide hormone that regulates blood glucose levels and appetite. This review outlines the physiological role of amylin and highlights recent clinical studies exploring its therapeutic potential in diabetes and obesity. Amylin lowers postprandial glucose levels by delaying gastric emptying and suppressing glucagon secretion, while promoting satiety via central nervous system pathways. Preclinical research has driven the development of long-acting amylin analogs with enhanced pharmacokinetics and reduced aggregation, resulting in significant weight loss and metabolic benefits in animal models. Clinically, the synthetic analog pramlintide has been shown to modestly improve glycemic control and induce weight loss in patients with diabetes. More recently, cagrilintide, a long-acting analog, has produced substantial weight reduction in individuals with obesity. Combination therapy with glucagon like peptide-1 receptor agonists has achieved synergistic effects, with weight loss exceeding 15%, positioning amylin analogs as a promising approach for treatment of diabesity-the co-existence of diabetes and obesity. This review summarizes recent advancements and discusses their implications for future therapeutic applications in diabesity management.

Incretin impact on gastric function in obesity: physiology, and pharmacological, surgical and endoscopic treatments.

Michael Camilleri

The aims of this review are to appraise the role of the stomach in satiation, the effects of incretin and other hormone agonists on weight loss and the role of altered gastric functions in their effects on obesity or glycaemic control. In addition to the gut in its role in enzymatic digestion and hormonal responses to nutrient ingestion, gastric motor functions include accommodation, trituration and emptying [gastric emptying (GE)] of food and elicitation of postprandial satiation and satiety. The postprandially released hormones most extensively studied and utilized therapeutically are glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP). Their mechanisms of action include stimulation of pancreatic β cells to produce insulin. However, GLP-1 reduces glucagon and slows GE, whereas GIP increases glucagon and does not alter GE. Molecular modifications of GLP-1 (which has a T1/2 of 3 min) led to the development of long-acting subcutaneous or oral pharmacological agents that have been approved for the treatment of obesity, and their effects on gastric function are documented. Other medications in development target other molecular mechanisms, including glucagon and amylin. Small-molecule GLP-1 receptor agonists are promising for the treatment of obesity and may also slow GE. Bariatric surgery and endoscopy increase satiation by restricting gastric size; in addition Roux-en-Y gastric bypass and to a lesser extent sleeve gastrectomy (but not endoscopic gastroplasty) increase postprandial circulating incretins, reducing appetite. In conclusion the stomach's function is integral to the impact of the most effective pharmacological and procedural reversal of obesity related to the incretin revolution.

Noninsulin Therapies in Management of Type 1 Diabetes.

Zeb I Saeed, Jayachidambaram Ambalavanan, Melanie Natasha Rayan +2 more

With the increasing prevalence of double diabetes (features of type 2 diabetes in people with type 1 diabetes (T1D)), there is a growing interest in using noninsulin therapies to improve glycemic outcomes, promote weight loss, and reduce cardiovascular risk in T1D. In this narrative review, we summarize current literature and provide practical guidance for clinicians when considering these therapies.

A Pilot Outpatient Assessment of a Fully Closed-Loop Insulin and Pramlintide System.

Madison Odabassian, Michael A Tsoukas, Elisa Cohen +3 more

Type 1 diabetes is treated with exogenous insulin using multiple daily injections or insulin pumps. However, both strategies require carbohydrate counting for prandial insulin dosing, which is both burdensome and error prone.

Central pramlintide administration potently suppresses operant responding for sucrose and locomotor activity in male rats.

Katherine A Kern, Adrianne M DiBrog, Emily Demieri +3 more

Amylin is a feeding-suppressive hormone which acts centrally in the control of energy balance. Some evidence suggests it reduces motivation for food rewards. Pramlintide is a synthetic amylin analog that is used clinically in the treatment of diabetes, and it also reduces feeding and weight gain. However, the mechanisms behind these pramlintide-induced reductions in feeding are unclear. Here we tested the hypothesis that pramlintide would decrease motivation for a palatable food, sucrose pellets. Results show that peripheral (IP) pramlintide had no effect on progressive ratio responding for sucrose pellets. In contrast, intracerebroventricular (ICV) pramlintide reduced active lever pressing, reinforcers earned, and breakpoint for sucrose, even at lower doses subthreshold for effects on 24 h chow intake and body weight change. However, lever pressing behavior was completely abolished for many rats, raising concern for unexpected motor effects. To test whether central pramlintide impacted locomotor activity, we conducted an open field study and found that ICV pramlintide significantly reduced distance traveled at several timepoints, suggesting suppressed locomotor activity. Overall, our results suggest that peripheral pramlintide does not affect motivation for sucrose, and that although central pramlintide does reduce outcomes assessing motivation, this may be confounded by a concurrent reduction in locomotor activity.

Amylin: emergent therapeutic opportunities in overweight, obesity and diabetes mellitus.

Christopher S Walker, Jacqueline F Aitken, Greeshma Vazhoor Amarsingh +2 more

The identification of amylin as a glucoregulatory peptide hormone with roles in meal-ending satiation sparked a surge of experimental development, which culminated in the amylin mimetic drug pramlintide. Pramlintide was approved by the FDA in 2005 for the treatment of type 1 diabetes mellitus and insulin-requiring type 2 diabetes, and was also explored as a novel anti-obesity treatment. Despite this exciting potential, efforts to develop an amylin-based anti-obesity therapeutic stalled owing to challenges around dosage frequency, safety and formulation. Generally, anti-obesity therapies have displayed modest efficacy and mixed safety profiles, leaving a clear unmet clinical need that requires addressing. Advances in peptide chemistry have reinvigorated the amylin field by enabling the manufacture of effective new amylin-based molecules, resulting in therapeutics that are now on the cusp of approval. At present, there are growing concerns around GLP1 receptor agonist-based therapeutics, in particular their association with loss of lean body mass. Additionally, treatment of patients with overweight or obesity without associated comorbidities is increasingly common. The widespread pharmacotherapy of otherwise healthy populations with overweight or obesity with the goal of improving future health requires further regulatory and ethical consideration. This Review describes how amylin controls energy homeostasis and provides a current overview of amylin-based therapeutic development.

Intranasal pramlintide matches intraperitoneal effects on food intake and gastric emptying in mice.

Milena S Almeida, Mariele P Sanches, Natália S Tonet +5 more

Pramlintide is an amylin analog developed as a complementary treatment for diabetes. However, it requires several subcutaneous injections, reducing patients' adherence. Since the intranasal route might be an alternative for drug administration, we evaluated whether intranasal pramlintide treatment exerts comparable actions with intraperitoneal administration.

In silico evaluation of pramlintide dosing algorithms in artificial pancreas systems.

Borja Pons Torres, Iván Sala-Mira, Clara Furió-Novejarque +4 more

Pramlintide's capability to delay gastric emptying has motivated its use in artificial pancreas systems, accompanying insulin as a control action. Due to the scarcity of pramlintide simulation models in the literature, in silico testing of insulin-plus-pramlintide strategies is not widely used. This work incorporates a recent pramlintide pharmacokinetics/pharmacodynamics model into the T1DM UVA/Padova simulator to adjust and validate four insulin-plus-pramlintide control algorithms. The proposals are based on an existing insulin controller and administer pramlintide either as independent boluses or as a ratio of the insulin infusion. The results of the insulin-pramlintide algorithms are compared against their insulin-alone counterparts, showing an improvement in the time in range between 3.00% and 10.53%, consistent with results reported in clinical trials in the literature. Future work will focus on individualizing the pramlintide model to the patients' characteristics and evaluating the implemented strategies under more challenging scenarios.

Amylin: From Mode of Action to Future Clinical Potential in Diabetes and Obesity.

Špela Volčanšek, Andrijana Koceva, Mojca Jensterle +2 more

Precision diabetology is increasingly becoming diabetes phenotype-driven, whereby the specific hormonal imbalances involved are taken into consideration. Concomitantly, body weight-favorable therapeutic approaches are being dictated by the obesity pandemic, which extends to all diabetes subpopulations. Amylin, an anorexic neuroendocrine hormone co-secreted with insulin, is deficient in individuals with diabetes and plays an important role in postprandial glucose homeostasis, with additional potential cardiovascular and neuroprotective functions. Its actions include suppressing glucagon secretion, delaying gastric emptying, increasing energy expenditure and promoting satiety. While amylin holds promise as a therapeutic agent, its translation into clinical practice is hampered by complex receptor biology, the limitations of animal models, its amyloidogenic properties and pharmacokinetic challenges. In individuals with advanced β-cell dysfunction, supplementing insulin therapy with pramlintide, the first and currently only approved injectable short-acting selective analog of amylin, has demonstrated efficacy in enhancing both postprandial and overall glycemic control in both type 2 diabetes (T2D) and type 1 diabetes (T1D) without increasing the risk of hypoglycemia or weight gain. Current research focuses on several key strategies, from enhancing amylin stability by attaching polyethylene glycol or carbohydrate molecules to amylin, to developing oral amylin formulations to improve patients' convenience, as well as developing various combination therapies to enhance weight loss and glucose regulation by targeting multiple receptors in metabolic pathways. The novel synergistically acting glucagon-like peptide-1 (GLP-1) receptor agonist combined with the amylin agonist, CagriSema, shows promising results in both glucose regulation and weight management. As such, amylin agonists (combined with other members of the incretin class) could represent the elusive drug candidate to address the multi-hormonal dysregulations of diabetes subtypes and qualify as a precision medicine approach that surpasses the long overdue division into T1DM and T2DM. Further development of amylin-based therapies or delivery systems is crucial to fully unlock the therapeutic potential of this intriguing hormone.Graphical abstract available for this article.

Amylin is incorporated into extracellular vesicles in an ESCRT-dependent manner and regulates senescence.

S Iglesias-Fortes, A C Lockwood, C González-Blanco +7 more

Type 2 diabetes mellitus is a disease which initiates with insulin resistance. Then, pancreatic β cells start to counteract this situation by increasing insulin secretion, which is known as pre-diabetic state. Amylin protein or islet amyloid polypeptide (IAPP), has multiple physiological roles such as the regulation of satiety and avoiding gastric emptying. However, amylin is able to aggregate, forming insoluble structures that affects pancreatic β cell survival. Interestingly, not all the amylin from the different species has this aggregate-prone capacity. There are species, which possesses non-amyloidogenic capacity and does not aggregate such as the rodents. However, there are versions of the protein, for instance from humans and primates, which can aggregate. Previously, we observed that small oligomers could be found in extracellular vesicles (EVs). Now, we have used a pancreatic β cell which overexpresses human amylin (hIAPP) (INS1E-hIAPP) and we have explored the capacity of amylin to be incorporated into EVs and how amylin could affect to different essential signaling pathways such as the mammalian target of rapamycin complex 1, endoplasmic-reticulum stress and senescence. Here, we report that amylin can be incorporated into EVs in an endosomal sorting complexes required for transport (ESCRT)-dependent manner. When we treated the cells with the neutral sphingomyelinase inhibitor, GW4869, one of the pathways for EV biogenesis and under high glucose conditions, there was an increased incorporation of soluble amylin into vesicles. Interestingly in this condition, when we isolated the EVs, we clearly observed that the size of the vesicles was higher, compatible with microvesicles (MVs). Resveratrol increased a pro-senescent phenotype but, it was able to revert either the high glucose or GW4869-associated senescent. In summary, these results indicate that amylin can be recruited in an ESCRT-dependent manner into EVs and, resveratrol presents an important role in inducing senescence in INS1E-hIAPP pancreatic β cells.

A temperature-responsive dual-hormone foam nanoengine improves rectal absorptivity of insulin-pramlintide for diabetes treatment.

Shujun Feng, Yu Zhang, Chunyuan Hou +4 more

Despite the therapeutic benefits of insulin-pramlintide dual-hormone therapy in diabetes, its application potential has been limited due to a lack of efficient delivery routes. Here, we developed a temperature-responsive dual-hormone foam nanoengine (HormFoam) and combined it with a customized spraying device to further construct an in situ foam-generating system for improving the rectal bioavailability of dual-hormone therapy. To support rapid clinical translation, a continuous microfluidic preparation for HormFoam was proposed, including the power unit of perfluorocarbon nanodroplets and the pharmaceutical components Pluronic F127-functionalized liposomal insulin and pramlintide. We found that HormFoam could consistently generate foams to drive drugs forward after rectal administration, which enhanced intestinal distribution and mucosa absorption, leading to systemic codelivery of insulin-pramlintide. HormFoam reproduced the physiology of endocrine pancreas for glycemic control and induced body weight loss while reversing metabolic disorders in diabetic mice with good biosafety. Therefore, HormFoam represents a state-of-the-art dual-hormone regimen with the potential to address unmet needs in diabetes management.

Does Incretin Agonism Have Sustainable Efficacy?

Sok-Ja Janket, Miyo K Chatanaka, Dorsa Sohaei +3 more

Recent clinical trials using synthetic incretin hormones, glucagon-like peptide 1 (GLP-1), and glucose-dependent insulinotropic polypeptide (GIP) receptor agonists have demonstrated that these treatments ameliorated many complications related to obesity, emphasizing the significant impact of body weight on overall health. Incretins are enteroendocrine hormones secreted by gut endothelial cells triggered by nutrient ingestion. The phenomenon that oral ingestion of glucose elicits a much higher insulin secretion than intra-venous injection of equimolar glucose is known as the incretin effect. This also alludes to the thesis that food intake is the root cause of insulin resistance. Synthetic GLP-1 and GIP agonists have demonstrated unprecedented glucoregulation and body weight reduction. Also, randomized trials have shown their ability to prevent complications of obesity, including development of diabetes from prediabetes, reducing cardiovascular disease risks and renal complications in diabetic patients. Moreover, the benefits of these agonists persist among the patients who are already on metformin or insulin. The ultimate question is "Are these benefits of incretin agonism sustainable?" Chronic agonism of pancreatic β-cells may decrease the number of receptors and cause β-cell exhaustion, leading to β-cell failure. Unfortunately, the long-term effects of these drugs are unknown at the present because the longest duration in randomized trials is 3 years. Additionally, manipulation of the neurohormonal axis to control satiety and food intake may hinder the long-term sustainability of these treatments. In this review, we will discuss the incretins' mechanism of action, challenges, and future directions. We will briefly review other molecules involved in glucose homeostasis such as amylin and glucagon. Amylin is co-expressed with insulin from the pancreas β-cells but does not have insulinotropic function. Amylin suppresses glucagon secretion, slowing gastric emptying and suppressing the reward center in the central nervous system, leading to weight loss. However, amylin can self-aggregate and cause serious cytotoxicity and may cause β-cell apoptosis. Glucagon is secreted by pancreatic α-cells and participates in glucose homeostasis in a glucose-dependent manner. In hypoglycemia, glucagon increases the blood glucose level by glycogenolysis and gluconeogenesis and inhibits glycogenesis in the liver. Several triple agonists, in combination with dual incretins and glucagon, are being developed.

Weight-centric treatment of type 2 diabetes mellitus.

Wissam Ghusn, Maria Daniela Hurtado, Andres Acosta

Chronic non-communicable diseases (CNCD) represent a major cause of morbidity and mortality. Type 2 diabetes mellitus (T2DM) is one of the most prevalent CNCD that is associated with a significant medical and economic burden. One of the main modifiable risk factors of T2DM is obesity. Many medications used for T2DM can lead to weight gain, worsening one of the root causes of this disease.

Amylin analogs for the treatment of obesity without diabetes: present and future.

Theodoros Panou, Evanthia Gouveri, Djordje S Popovic +1 more

Obesity is a pandemic, linked with increased morbidity including diabetes mellitus (DM) and certain cancer types. Amylin is a major regulatory hormone for satiation and food intake perception in humans. Amylin analogs (pramlintide and cagrilintide) are emerging as promising anti-obesity agents in non-DM subjects.

ADO09, a co-formulation of pramlintide and insulin A21G, lowers body weight versus insulin lispro in type 1 diabetes.

Grit Andersen, Rosy Eloy, Tim Heise +7 more

To study safety, efficacy and weight loss with ADO09, a co-formulation of insulin A21G and pramlintide, in type 1 diabetes.

Exploring the central region of amylin and its analogs aggregation: the influence of metal ions and residue substitutions.

Mawadda Alghrably, Giulia Bennici, Gabriela Szczupaj +7 more

Human amylin (hIAPP) is found in the form of amyloid deposits within the pancreatic cells of nearly all patients diagnosed with type 2 diabetes mellitus (T2DM). However, rat amylin (rIAPP) and pramlintide - hIAPP analogs - are both non-toxic and non-amyloidogenic. Their primary sequences exhibit only slight variations in a few amino acid residues, primarily concentrated in the central region, spanning residues 20 to 29. This inspired us to study this fragment and investigate the impact on the aggregation properties of substituting residues within the central region of amylin and its analogs. Six fragments derived from amylin have undergone comprehensive testing against various metal ions by implementing a range of analytical techniques, including Nuclear Magnetic Resonance (NMR) spectroscopy, Thioflavin T (ThT) assays, Atomic Force Microscopy (AFM), and cytotoxicity assays. These methodologies serve to provide a thorough understanding of how the substitutions and interactions with metal ions impact the aggregation behavior of amylin and its analogs.

Simple meal announcements and pramlintide delivery versus carbohydrate counting in type 1 diabetes with automated fast-acting insulin aspart delivery: a randomised crossover trial in Montreal, Canada.

Elisa Cohen, Michael A Tsoukas, Laurent Legault +11 more

In type 1 diabetes, carbohydrate counting is the standard of care to determine prandial insulin needs, but it can negatively affect quality of life. We developed a novel insulin-and-pramlintide closed-loop system that replaces carbohydrate counting with simple meal announcements.

Are insulin sensitizers the new strategy to treat Type 1 diabetes? A long-acting dual amylin and calcitonin receptor agonist improves insulin-mediated glycaemic control and controls body weight.

Simone Anna Melander, Anna Thorsø Larsen, Morten Asser Karsdal +1 more

Insulin therapies for Type 1 diabetes (T1D) have limitations, such as glucose fluctuations, hypoglycaemia, and weight gain. Only pramlintide is approved with insulin. However, its short half-life limits efficacy, requiring multiple daily injections and increasing hypoglycaemia risk. New strategies are needed to improve glycaemic control. Dual amylin and calcitonin receptor agonists are potent insulin sensitizers developed for Type 2 diabetes (T2D) as they improve glucose control, reduce body weight, and attenuate hyperglucagonemia. However, it is uncertain if they could be used to treat T1D.

Chronic pramlintide decreases feeding via a reduction in meal size in male rats.

Katherine A Kern, Adrianne M DiBrog, Kiran Kaur +2 more

Amylin, a pancreatic hormone, is well-established to suppress feeding by enhancing satiation. Pramlintide, an amylin analog that is FDA-approved for the treatment of diabetes, has also been shown to produce hypophagia. However, the behavioral mechanisms underlying the ability of pramlintide to suppress feeding are unresolved. We hypothesized that systemic pramlintide administration in rats would reduce energy intake, specifically by reducing meal size. Male rats were given b.i.d. administration of intraperitoneal pramlintide or vehicle for 1 week, and chow intake, meal patterns, and body weight were monitored throughout the test period. Consistent with our hypothesis, pramlintide decreased chow intake mainly via suppression of meal size, with corresponding reductions in meal duration on several days. Fewer effects on meal number or feeding rate were detected. Pramlintide also reduced weight gain over the 1-week study. These results highlight that the behavioral mechanisms by which pramlintide produces hypophagia are similar to those driven by amylin itself, and provide important insight into the ability of this pharmacotherapy to promote negative energy balance over a period of chronic administration.

Liraglutide versus pramlintide in protecting against cognitive function impairment through affecting PI3K/AKT/GSK-3β/TTBK1 pathway and decreasing Tau hyperphosphorylation in high-fat diet- streptozocin rat model.

Hoda M Moghazy, Nesreen G Abdelhaliem, Sherine Ahmed Mohammed +2 more

The American Diabetes Association guidelines (2021) confirmed the importance of raising public awareness of diabetes-induced cognitive impairment, highlighting the links between poor glycemic control and cognitive impairment. The characteristic brain lesions of cognitive dysfunction are neurofibrillary tangles (NFT) and senile plaques formed of amyloid-β deposition, glycogen synthase kinase 3 beta (GSK3β), and highly homologous kinase tau tubulin kinase 1 (TTBK1) can phosphorylate Tau proteins at different sites, overexpression of these enzymes produces extensive phosphorylation of Tau proteins making them insoluble and enhance NFT formation, which impairs cognitive functions. The current study aimed to investigate the potential contribution of liraglutide and pramlintide in the prevention of diabetes-induced cognitive dysfunction and their effect on the PI3K/AKT/GSK-3β/TTBK1 pathway in type 2 diabetic (T2D) rat model. T2D was induced by administration of a high-fat diet for 10 weeks, then injection of a single dose of streptozotocin (STZ); treatment was started with either pramlintide (200 μg/kg/day sc) or liraglutide (0.6 mg/kg/day sc) for 6 weeks in addition to the HFD. At the end of the study, cognitive functions were assessed by novel object recognition and T-maze tests. Then, rats were sacrificed for biochemical and histological assessment of the hippocampal tissue. Both pramlintide and liraglutide treatment revealed equally adequate control of diabetes, prevented the decline in memory function, and increased PI3K/AKT expression while decreasing GSK-3β/TTBK1 expression; however, liraglutide significantly decreased the number of Tau positive cells better than pramlintide did. This study confirmed that pramlintide and liraglutide are promising antidiabetic medications that could prevent associated cognitive disorders in different mechanisms.

Newer pharmacological interventions directed at gut hormones for obesity.

Michael Camilleri, Andres Acosta

The objective is to review the newer pharmacological interventions for obesity, specifically single, dual and triple incretin receptor agonists that are either available or in the pipeline for treatment of obesity. The three incretin receptor targets are glucagon like peptide-1 (GLP-1), glucose-dependent insulinotropic peptide (GIP) and glucagon. There are several approved single or dual incretin agonists which can be administered subcutaneously daily (e.g., liraglutide) or weekly (e.g., semaglutide, dulaglutide, and exenatide QW), and other experimental dual or triple incretin agonists. Analogues of amylin, peptide YY and oxyntomodulin, as well as the combination of a GLP1R agonist and GIPR antagonist also are in development. Oral semaglutide (administered daily) is approved for type 2 diabetes mellitus and is on track for regulatory review for obesity. The review includes specifically perspectives on the effects of these mechanisms and pharmacological agents on gastric emptying, which contribute to satiation and weight loss, in addition to the established evidence on effects on central mechanisms controlling appetite. In the future, it is anticipated that small molecule GLP-1 receptor agonists (e.g., oral danuglipron) will be developed for treating obesity. These pharmacological agents are having significant impact on glycaemic control and obesity and on their co-morbidities.

Amylin, Another Important Neuroendocrine Hormone for the Treatment of Diabesity.

Stjepan Eržen, Gašper Tonin, Dubravka Jurišić Eržen +1 more

Diabetes mellitus is a devastating chronic metabolic disease. Since the majority of type 2 diabetes mellitus patients are overweight or obese, a novel term-diabesity-has emerged. The gut-brain axis plays a critical function in maintaining glucose and energy homeostasis and involves a variety of peptides. Amylin is a neuroendocrine anorexigenic polypeptide hormone, which is co-secreted with insulin from β-cells of the pancreas in response to food consumption. Aside from its effect on glucose homeostasis, amylin inhibits homeostatic and hedonic feeding, induces satiety, and decreases body weight. In this narrative review, we summarized the current evidence and ongoing studies on the mechanism of action, clinical pharmacology, and applications of amylin and its analogs, pramlintide and cagrilintide, in the field of diabetology, endocrinology, and metabolism disorders, such as obesity.

A model of subcutaneous pramlintide pharmacokinetics and its effect on gastric emptying: Proof-of-concept based on populational data.

Clara Furió-Novejarque, Iván Sala-Mira, José-Luis Díez +1 more

Pramlintide, an amylin analog, has been coming up as an agent in type 1 diabetes dual-hormone therapies (insulin/pramlintide). Since pramlintide slows down gastric emptying, it allows for easing glucose control and reducing the burden of meal announcements. Pre-clinical in silico evaluations are a key step in the development of any closed-loop strategy. However, mathematical models are needed, and pramlintide models in the literature are scarce. This work proposes a proof-of-concept pramlintide model, describing its subcutaneous pharmacokinetics (PK) and its effect on gastric emptying (PD). The model is validated with published populational (clinical) data. The model development is divided into three stages: intravenous PK, subcutaneous PK, and PD modeling. In each stage, a set of model structures are proposed, and their performance is assessed using the Akaike Information Criterion (AIC) and the Bayesian Information Criterion (BIC). In order to evaluate the modulation of the rate of gastric emptying, a literature meal model was used. The final pramlintide model comprises four compartments and a function that modulates gastric emptying depending on plasma pramlintide. Results show an appropriate fit for the data. Some aspects are left as open questions due to the lack of specific data (e.g., the influence of meal composition on the pramlintide effect). Moreover, further validation with individual data is necessary to propose a virtual cohort of patients.

Combined GLP-1 Receptor Agonist and Amylin Analogue Pharmacotherapy to Treat Obesity Comorbid With Type 1 Diabetes.

Gunther Wong, Erica M Garner, Gitanjali Srivastava

Type 1 diabetes mellitus (T1DM) with obesity is increasingly common, prompting effective clinical interventions to induce weight loss in this population. We present 3 patients with T1DM and obesity prescribed a glucagon-like peptide 1 receptor agonist (GLP-1RA) and pramlintide. Case 1: A 32-year-old male with obstructive sleep apnea (OSA) who lost -20.9 kg (-16.1% of total body weight [TBW]) over 10 months on semaglutide and pramlintide. Case 2: A 68-year-old female with diabetic retinopathy, coronary artery disease, hypertension, hypothyroidism, and depression/anxiety initially treated with topiramate, losing -8.4 kg, but experiencing weight plateau. After adding dulaglutide and pramlintide, she lost an additional -12.8 kg (-14.0% TBW) over 7 months, with total weight loss of -21.2 kg (-23.1% TBW). Case 3: A 49-year-old female with hypertension, hypothyroidism, and depression who lost -14.6 kg (-17.9% TBW) over 6 months on semaglutide and pramlintide. No significant side effects were experienced. All patients reported decreased insulin requirements on pramlintide, and hemoglobin A1c levels remained constant or decreased throughout the treatment period. Pramlintide and GLP-1RA resulted in excellent weight loss in our patients with obesity and T1DM. This combination may have a synergistic effect on the gut-brain axis. More research is required to substantiate these findings.