GLP-1: Appetite, Insulin, and Genetics

If you are someone who struggles with your weight or with diabetes, the GLP-1 hormone may be at the heart of your issues. The body has several amazing ways of controlling appetite and managing blood glucose levels. GLP-1 is a small peptide that tells your pancreas that you’ve just eaten and need insulin and signals your brain to stop eating.

Glucagon-like Peptide-1(GLP-1) signals that you’ve just eaten

Food reaching your intestines for absorption triggers the release of certain hormones. These signals can tell your brain that you’re no longer hungry and tell the pancreas to release insulin.

One of these hormones is called GLP-1, a glucagon-like peptide-1.

GLP-1 is a peptide hormone (a small protein molecule) that is released in the upper part of the intestinal tract when you eat carbohydrates or certain proteins. It is classified as an incretin, which helps regulate blood glucose levels.

The GLP-1 peptide hormone signals the body when food consumption occurs. The GLP-1 receptor (GLP1R), found in pancreatic beta cells, receives the signal triggering the release of insulin. It also targets other cells in the pancreas to stop the glucagon signal for generating glucose in the liver.[ref]

Additionally, GLP-1 is created in the brain and acts as a neuropeptide. More on this in a minute…

Let’s back up a sec and talk about proglucagon…

Proglucagon is a big molecule that can be chopped apart to form other molecules — including GLP-1. Preproglucagon is encoded by the GCG gene and cleaved into proglucagon.

Both the pancreas (alpha cells) and the intestines can make proglucagon.

Controlling glucose levels: In the pancreas, the proglucagon can convert into glucagon, which in turn signals the liver to release glucose. The alpha cells in the pancreas secrete proglucagon when blood glucose levels are low. The release of proglucagon causes the liver to make glucose (gluconeogenesis – converting protein to glucose) as well as to convert fatty acids into ketone bodies.

Intestinal proglucagon cleaves (breaks up) into several different molecules:

  • GLP-1
  • GLP-2
  • GRPP
  • Oxyntomodulin

The enzyme PCSK1 converts proglucagon to GLP-1 in the central nervous system. (We’ll come back to this in the genetics section)

Here’s a diagram of the possible cleaving of proglucagon:

Schematic of proglucagon cleavage into GLP-1 and more. CC image from PMC68812410

GLP-1 signal to the pancreas:

The GLP-1 hormone doesn’t stick around long. With a half-life of around 2 minutes, this quick signal is rapidly degraded by the protein DPP-4 (dipeptidyl peptidase 4).

Thus, only about 10-15% of released GLP-1 reaches the pancreas as a signal.

The GLP-1 that does reach the pancreas calls for the release of more insulin when food is being broken down and absorbed. Plus, it stops the production of glucagon, thus decreasing glucose from the liver.

The effects of GLP-1 are completed through its binding to the GLP-1 receptor (GLP1R).

Are GLP-1 levels genetic?

The heritability of GLP-1 release is around 50%.[ref] Thus, while there is a fairly important genetic component, diet is also really important.

Common genetic variants in the GLP1R (GLP-1 receptor) gene impact weight and type 2 diabetes risk.

GLP-1 and appetite suppression:

I mentioned above that the intestines and the brain make GLP-1.

Certain areas of the hypothalamus can make GLP-1, as well as regions of the brain stem. Plus, GLP-1 is involved in stress response and the HPA axis.[ref]

Different regions in the brain control your desire to eat, and GLP-1 comes into play here in specific ways.

Specific neurons in the brain stem control swallowing, intestinal movements — and stress-induced loss of appetite. (The brain stem also controls other involuntary functions such as heartbeat and breathing.)

GLP-1 in the brain stem activates due to stress and causes a loss of appetite. Researchers have figured this out by using transgenic mice in which they can turn off the GLP-1 in the brain to see what happens. The researchers found that turning off GLP-1 in the brain didn’t affect the normal daily intake of food, but instead was important in several specific situations: prolonged fasting, large feedings, and stress-induced appetite loss.[ref]

Essentially, the neurons activated by GLP-1 help to limit binging after a fast – they keep you from massively overeating after not eating for a while.

The GLP-1-activated neurons in the brain also limit appetite for a while after a large meal (e.g., the thought of eating is unappealing for many hours after pigging out on pizza).[ref]

Additionally, the GLP-1 neurons activate during times of acute stress to suppress appetite. We all have experienced that loss of appetite during stressful situations – when the thought of eating food just doesn’t cross the mind.

The GLP-1 produced in the intestines after a meal also plays a role in suppressing eating, likely through different circuits than those GLP-1-expressing neurons found in the brain stem. Researchers think that this involves the vagus nerve.[ref]

GLP-1 receptor agonist drugs:

Recent clinical trials show that drugs that activate GLP-1 receptors, such as liraglutide or semaglutide (diabetes drugs), cause gradual weight loss in obese people. This may be due to decreasing the amount eaten after fasting – limiting a binge – or increasing the appetite suppression longer after eating a big meal.

The drawback to these drugs is that they are administered as weekly injections, and it isn’t known if the weight loss is permanent.

GLP-1 and immune response:

In addition to their role in pancreatic insulin secretion, GLP-1 receptors are found in certain types of immune cells, including T cells and macrophages.[ref] This is an interesting link between metabolic health and immune health.

The receptor for GLP-1 is found on the cell membrane of macrophages, regulatory T cells, and natural killer T cells. GLP-1 plays an immunomodulatory role. A GLP-1 receptor agonist medication may help patients with psoriasis.[ref]

Asthma exacerbations also decreased in patients on GLP-1 receptor agonist medications.[ref]

GLP-1 and Alzheimer’s disease:

In animal studies, infusions of GLP-1 decrease amyloid-beta levels and prevent neuronal cell death.[ref]

Dysregulation of glucose entry into the brain is one hallmark of Alzheimer’s disease, tying together insulin resistance, GLP-1, and dementia.[ref][ref] GLP-1 receptor agonist drugs, such as liraglutide, are being studied for Alzheimer’s disease.[ref]

Role of Circadian Rhythm in GLP-1:

Circadian rhythm is the 24-hour rhythm of your body’s functions. It controls when hormones are released, the production of enzymes at different times of the day, immune response during the day vs. night, sleep-wake timing, and much more.

Like many hormones, there is a circadian aspect to GLP-1. Research points to GLP-1 as having a role in entraining the circadian rhythm of insulin release in the pancreas. While GLP-1 will be released from intestinal cells upon consumption of food, the amount of insulin release caused by GLP-1 varies due to the time of day.[ref]

A ‘Western Diet’, high in fat and sugar, is used in research studies to make animals fat. This type of diet actually alters the rhythm of GLP-1 secretion in animal studies and in people with type 2 diabetes.[ref]

What is the role of DPP-4?

Again, the half-life of GLP-1 is really short – about 2 minutes – because a ubiquitous protein-degrading enzyme called DPP-4 breaks it down quickly.

Blocking the degradation of GLP-1 by inhibiting DPP-4 is one way certain types of diabetes medicine work.


GLP-1 Genotype Report

Members: Be sure to select your data file to see your genotype
Not a member? Join now to see your genes below.

GLP1R variants: GLP-1 receptor

Check your genetic data for rs10305492 A316T (23andMe v5):

  • A/A: low fasting glucose, decreased risk of type 2 diabetes[ref], less of a response to GLP-1 receptor agonist for weight loss[ref]
  • A/G: lower fasting glucose, decreased risk of type 2 diabetes
  • G/G: typical

Members: Your genotype for rs10305492 is .

Check your genetic data for rs6923761 Gly168Ser (23andMe v4, AncestryDNA):

  • A/A: DPP-4-inhibitors may not be as effective for diabetics[ref], slower gastric emptying with liraglutide (possibly better for weight loss)[ref], better response to GLP-1 receptor agonist for weight loss in women with PCOS[ref]
  • A/G: typical response to DPP-2, slower gastric emptying with liraglutide (possibly better for weight loss); better response to GLP-1 receptor agonist for weight loss in women with PCOS
  • G/G: typical

Members: Your genotype for rs6923761 is .

Check your genetic data for rs1042044 (23andMe v4; AncestryDNA):

  • A/A: higher anhedonia (inability to feel pleasure) scores in depression[ref]
  • A/C: most common genotype
  • C/C: higher morning cortisol levels (children)[ref]

Members: Your genotype for rs1042044 is .

PCSK1 gene: encodes the enzyme that converts proglucagon into GLP1. Rare mutations in PCSK1 cause early childhood obesity (not listed here). More common variants, such as those below, have links to an increase in the relative risk of weight gain.

Check your genetic data for rs6232 N221D(23andMe v4, v5; AncestryDNA):

  • T/T: typical
  • C/T: higher risk of obesity and insulin sensitivity; decreased PCSK1 activity; increased risk of childhood obesity
  • C/C: higher risk of obesity and insulin sensitivity; decreased PCSK1 activity[ref] increased risk of childhood obesity[ref]

Members: Your genotype for rs6232 is .

Check your genetic data for rs6234 (23andMe v4, v5):

  • G/G: typical
  • C/G: slightly increased risk of obesity[ref]
  • C/C: increased risk of obesity[ref][ref][ref]

Members: Your genotype for rs6234 is .

GCG gene: encodes the proglucagon molecule that is cleaved into GLP-1

Check your genetic data for rs4664447 (23andMe v5):

  • C/C: lower fasting plasma glucose, lower fasting serum insulin[ref]
  • C/T: typical glucose
  • T/T: typical

Members: Your genotype for rs4664447 is .


Lifehacks:

Increasing GLP1 through binding to the GLP-1 receptor has been shown to slowly reduce weight in people who are obese.[ref]

Supplements that increase GLP-1:

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About the Author:
Debbie Moon is the founder of Genetic Lifehacks. Fascinated by the connections between genes, diet, and health, her goal is to help you understand how to apply genetics to your diet and lifestyle decisions. Debbie has a BS in engineering and also an MSc in biological sciences from Clemson University. Debbie combines an engineering mindset with a biological systems approach to help you understand how genetic differences impact your optimal health.