Amylin Adventure

Understanding the Role of Amylin in Obesity
as an Emerging Therapeutic Target

This educational resource is provided by Vindico Medical Education Logo  and supported by an educational grant from Novo Nordisk, Inc.

Explore cutting-edge knowledge of amylin biology and its therapeutic implications. Review this resource to learn about amylin as well as 3 other hormones—glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP), and glucagon—and their various actions throughout the body.

Disclaimer: This educational content is for educational purposes only. It has been developed using a combination of peer-reviewed references, insights from OpenEvidence (www.openevidence.com), and expert opinion from 2 independent faculty members. The information presented is current as of June 2025. Ongoing research and clinical developments may influence future recommendations. Healthcare providers should exercise their own clinical judgment when applying the information in practice.

Amylin

Amylin is a 37-amino-acid, neuroendocrine peptide hormone co-secreted with insulin by pancreatic beta-cells in response to nutrient intake. Though it has a short half-life, amylin is a multifunctional hormone that may play a significant role in metabolic regulation.

There are at least 3 amylin receptors—AMY1, AMY2, and AMY3—each of which is composed of the calcitonin receptor bound to 1 of 3 corresponding receptor activity-modifying proteins. Amylin receptors are considered proven drug targets, and amylin mimetics are emerging as novel treatments for overweight, obesity, and diabetes mellitus.

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Click to watch the video Amylin Adventure: Biology and Modes of Action

Amylin is a multifunctional hormone through its actions on various organs:

  • Appetite;
    Food intake

  • Satiety; Responsiveness to leptin

Its proposed human mechanism is extrapolated from animal models.

Its actions are located centrally and mediated through specific amylin receptors, which are multi-subunit G protein-coupled receptors.

  • Gastric emptying

Its effects lead to a more gradual release of nutrients like glucose.

This helps to reduce postprandial glucose spikes—an effect that may be especially helpful for individuals with obesity and type 2 diabetes.

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  • Adipose tissue inflammation
  • Promotes lipolysis (preclinical only)

Only rodent and cell culture data is currently available to support these effects.

There are no human biopsy or metabolic tracer studies to show an anti‑inflammatory or direct lipolytic action.

  • Pancreatic glucagon release

Amylin can promote glucose homeostasis and reduce hyperglycemia.

  • Bone resorption

  • Bone formation

Amylin may influence bone health by regulating both the formation and breakdown of bone, highlighting its wide-ranging effects throughout the body.
  • Glucose production
  • Glucose surge postprandial

Indirect effects

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Glucagon-like peptide-1 (GLP-1)

GLP-1 is a 30-amino-acid, incretin hormone secreted by intestinal L-cells in response to nutrient intake. It enhances glucose-dependent insulin secretion, inhibits glucagon release, delays gastric emptying, and promotes satiety.

Many professional organization and medical societies recognize approved GLP‑1 receptor agonist-based obesity medications, including as semaglutide and tirzepatide, as highly-effective for treating excess adiposity in adults with obesity or overweight and related complications.

Guidance from the American Diabetes Association (ADA), American Association of Clinical Endocrinology/The Obesity Society (AACE/TOS), American Gastroenterological Association (AGA), Endocrine Society, and the American Heart Association (AHA) notes that large‑scale trials of these agents have shown sustained weight loss (roughly 10% to 20%), as well as improvements in glycemic control, blood pressure, lipid profiles, and other cardiometabolic risk factors.

Reflecting this evidence, clinical guidelines increasingly support GLP-1 receptor agonists as an appropriate first-line or add-on treatment option when obesity pharmacotherapy is indicated, in conjunction with comprehensive lifestyle interventions.

GLP-1 exerts a broad range of physiological effects due to the widespread expression of GLP-1 receptors in various organs:

  • Appetite; Neuronal inflammation (preclinical only)

  • Satiety

GLP-1 influences brain regions involved in hunger regulation, such as the hypothalamus.

It may have neuroprotective effects in models of neurodegenerative diseases.

  • Gastric emptying

GLP-1 promotes a prolonged feeling of fullness after meals and reduces overall food intake.

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  • Pancreatic glucagon release
  • Glucose-dependent insulin secretion

GLP-1 acts as an incretin that enhances insulin release from pancreatic beta-cells only when blood glucose is elevated, thereby reducing the risk of hypoglycemia.

It also inhibits glucagon secretion from pancreatic alpha-cells—further contributing to glucose control.

  • Bone resorption
  • Bone formation

Mechanistically, preclinical and translational studies suggest that GLP-1 may promote bone formation and inhibit bone resorption via direct effects on osteoblasts and osteoclasts.

In human studies, GLP-1 receptor agonists may slightly increase bone formation markers (eg, osteocalcin, bone alkaline phosphatase) and acutely reduce bone resorption markers, but these effects are modest and inconsistent. There are no strong data showing increased bone formation or fracture risk reduction.

  • Glucose production;
    Liver fat content

Indirect effects

Hepatocytes do not express GLP-1 receptors.

A study shows indirect effects on liver fat reduction for metabolic dysfunction-associated steatotic liver disease (MASLD).

  • Adipose tissue inflammation
  • Promotes lipolysis (preclinical only)

These indirect effects contribute to decreased fat mass and improved metabolic health.

However, no direct lipolytic or anti inflammatory action is proven in humans; these effects are currently hypothetical.

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Glucose-dependent insulinotropic polypeptide (GIP)

GIP is a 42-amino-acid incretin hormone secreted by enteroendocrine K-cells in the upper small intestine in response to nutrient intake. GIP potentiates glucose-dependent insulin secretion and plays a role in postprandial glucose and lipid metabolism.

GIP affects weight and obesity through its insulinotropic effects on several organs:

  • Insulin secretion; Glucagon secretion

Insulinotropic action is strictly glucose-dependent, meaning it enhances insulin secretion only when blood glucose levels are elevated, thus minimizing the risk of hypoglycemia.

In addition to its primary effect on beta-cells, GIP also exerts actions on alpha-cells to stimulate glucagon secretion (particularly at lower glucose concentrations).

  • Triglyceride clearance from the circulation

Increased fat clearance from the bloodstream via activation of lipoprotein lipase, which promotes fat storage in adipocytes, especially in the postprandial state.

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  • Hypothalamic inflammation (preclinical only)

In animal models of the CNS, GIP may decrease neuronal inflammation and oxidative stress and may have neuroprotective effects in models of neurodegenerative diseases.

  • Bone resorption

Human studies demonstrate that GIP administration acutely reduces CTX levels (a marker of bone resorption) by about 20% to 50%.

Some observational data suggest possible protective effects on bone, but no trial has shown improved bone mineral density or fracture reduction.

Long-term effects remain uncertain.

  • Hepatic steatosis
  • Insulin resistance

Indirect effects

GIP may worsen insulin resistance in the context of obesity and T2D, but improve insulin sensitivity when used pharmacologically in dual agonist therapies. Its effects are highly dependent on metabolic context, receptor engagement patterns, and duration of exposure.

It does not significantly impact gastric motility or emptying.

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Glucagon

Glucagon is a 29-amino-acid peptide hormone that is secreted by pancreatic alpha-cells.

It primarily functions to increase blood glucose levels by stimulating glycogenolysis and gluconeogenesis in the liver. It reduces hepatic lipogenesis and promotes fat oxidation, which can help reduce hepatic steatosis.

Glucagon is a counter-regulatory hormone to insulin, thus playing a crucial role in glucose homeostasis and metabolism. Glucagon’s primary actions are through the liver and pancreas.

  • Gluconeogenesis; Glycogenolysis; Hepatic lipid metabolism; Uptake of amino acids

Its primary actions lead to increasing blood glucose levels, as well as promoting lipolysis and fatty acid oxidation—which can reduce hepatic steatosis.

  • Insulin secretion

This interplay between glucagon and insulin is essential for regulating blood glucose levels.

High‑dose IV glucagon suppresses acid secretion and slows emptying. However, this effect is not seen at physiological levels or with chronic use.

Intravenous or subcutaneous glucagon at physiological or supraphysiological levels has inconsistent effects on hunger and subsequent food intake.

Several placebo controlled studies report no significant reduction in ad libitum meal size; any anorectic effect seen at high doses is confounded by nausea.

Because native glucagon does not readily cross the blood–brain barrier, a hypothalamic mechanism has not been demonstrated in humans.

Human adipocyte studies conflict; whole body tracer studies show no additional lipolysis at physiological concentrations.

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Little information regarding the presence of a functional glucagon receptor in bone is available. Glucagon may influence bone resorption through RANKL signaling in preclinical studies, but this has not been demonstrated in humans. Conflicting preclinical and clinical data have shown that glucagon may exert small and variable inhibitory effects on bone turnover markers.

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Abraham MA, Lam TKT. Diabetologia. 2016;59(7):1367-1371.

Al-Massadi O, et al. Int J Mol Sci. 2019;20(16):E3905.

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Galsgaard KD, et al. Front Physiol. 2019;10:413.

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Kajani S, et al. Physiol Rev. 2024;104(3):1021-1060.

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Winther JB, Holst JJ. Diabetes Obes Metab. 2024;26(9):3501-3512.

These 4 hormones—amylin, GLP-1, GIP, and glucagon—interact in complex ways to regulate body weight and impact obesity through their actions on the brain, stomach, adipose tissue, pancreas, bone, and liver.

In the context of obesity, amylin’s ability to enhance satiety and reduce food intake works synergistically with the other hormones.

  • Like GLP-1, amylin also promotes satiety and reduces food intake.
  • Amylin inhibits glucagon postprandially to prevent excessive hepatic glucose production.
  • GIP primarily promotes insulin secretion and fat storage. However, amylin’s satiety effects can counteract GIP’s adipogenic actions, thus aiding in weight management.

In summary, these hormones interact to regulate weight and obesity by modulating insulin and glucagon secretion, influencing gastric emptying, and acting on the central nervous system to control appetite and energy expenditure.

Their combined effects on various organs contribute to their overall impact on weight regulation and metabolic homeostasis.

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