If there is one disease I ask my patients to have on their minds, it’s type 2 diabetes. According to the 2017 report from the U.S. Center for Disease Control and Prevention, more than 100 million Americans have diabetes (30.3 million) or prediabetes (84.1 million).1 This means that nearly half of Americans have the disease or its precursor.
And while there has been much progress in the prevention and management of diabetes, the disease can come with serious complications that cause significant health, financial, mental, and emotional burden for patients. To make matters worse, the cost of many diabetes medications are soaring, forcing patients to put themselves in danger by rationing their medications.
Fortunately, recent research shows that a class of medications called glucagon-like peptide 1 (GLP-1) receptor agonists may have more benefits than initially thought. Although it is currently not regarded as first-line diabetes drugs, there is growing evidence that GLP-1 receptor agonists may have the potential to be a “one-stop shop” for the management of type 2 diabetes and its complications.
A Review of Insulin and Glucagon
Both insulin and glucagon are hormones secreted by pancreatic cells. Together, they help keep your blood glucose levels within a very narrow range.
Briefly, the release of insulin is triggered by elevated blood glucose levels, amino acid and fatty acid levels, release of acetylcholine, and secretion of hyperglycemic hormones like glucagon. Once triggered, insulin enhances the transport of glucose from the blood to body cells, namely muscle, and fat cells. It also inhibits the breakdown of glycogen, the stored form of sugar in your body. Once glucose enters target cells, it can be used for:
- Energy production
- Formation of glycogen
- Conversion into fat (especially in adipose tissue, or fat)
Conversely, glucagon raises blood glucose levels by inducing conversion of glucagon into glucose, which is then released into the bloodstream. Glucagon also promotes the production of glucose from lactic acid and amino acids, and it reduces blood levels of amino acids so liver cells can use them to make new glucose molecules.
Glucagon-like peptide 1 (GLP-1) is similar to glucagon in that they are both products of preproglucagon. However, as you’ll see, the function of GLP-1 is opposite that of glucagon.
What is Glucagon-like Peptide 1?
Glucagon-like peptide 1 (GLP-1) is a 30 or 31 amino acid long hormone produced primarily (though not entirely) by L-cells in the small intestine. It belongs to a family of hormones called incretins, so-called because they stimulate the secretion of insulin (think incretin = increase) from pancreatic beta cells. Beyond insulin secretion, GLP-1:
- Stimulates insulin production and gene expression23
- Inhibits glucagon secretion
- Delays emptying of the stomach (also known as gastric emptying), thereby increasing the feeling of fullness and controlling the rate at which nutrients are absorbed into the intestine after a meal
- Influence pathways that regulate blood pressure
- Contributes to weight control
For these reasons, GLP-1 research has received increasing attention for its possible involvement in the development of diabetes. And because of its wide range of coordinated actions, some scientists believe that GLP-1 receptor agonists could be used to significantly reduce the number of medications diabetic patients need to take.
GLP-1 and Metabolic Syndrome
GLP-1 receptor agonists have the potential to be used to treat metabolic syndrome. The term metabolic syndrome refers to a group of risk factors that raise your risk for health problems such as heart disease, type 2 diabetes, and stroke. These risk factors include:4
- High blood pressure
- High blood sugar
- Excess body fat, especially around your waist
- High “bad” cholesterol levels
- High triglyceride levels (a type of fat in your blood)
- High fasting blood sugar
The risk for metabolic syndrome also increases with insulin resistance, a condition in which your body’s cells don’t respond well to insulin. When your pancreas senses that blood sugar levels aren’t going down, it works harder to release enough insulin to overcome this resistance. However, your pancreas is unable to keep this up for too long, and over time, its ability to release insulin decreases. This leads to the development of type 2 diabetes.
GLP-1 and the “One-Stop Shop” Approach for Diabetes Treatment
Older diabetic patients have higher risks of hypoglycemia (low blood sugar) and adverse drug events due to diabetic complications. Furthermore, mortality rates and coexistence of other chronic diseases also increase the longer a patient has diabetes.5 The coexistence of multiple chronic diseases such as Alzheimer’s, nonalcoholic fatty liver disease, and pain creates a big concern for patients and physicians alike because of factors such as:
- Increased risk of serious hypoglycemia due to multiple medications
- Age-associated changes in drug clearance from body
- Age-related changes in sensory function
- Suboptimal compliance to diet and medical advice and regimen
Serious hypoglycemic events could result in injuries from falls, depression, heart problems, dementia, and other incidences or illnesses that reduce the quality of a patient’s life.6 This is where GLP-1 receptor agonists can come in — they would effectively allow for a “one-stop shop” approach for physicians to care for patients with clinically complex diabetes.
Effects of GLP-1 Based Therapies in the Human Body
GLP-1 Effects on Skeletal Muscle
Skeletal muscle is a major target of insulin action and is responsible for 80–90% of insulin-stimulated total body glucose disposal.7 However, to exert its effects, insulin first has to be delivered to the microvasculature, tiny blood vessels that nourish the muscle cells and transport insulin into the muscle interstitium. The recruitment of muscle microvasculature has been proven to be pivotal for insulin delivery, contributing up to 40% of insulin-mediated glucose disposal.8 The expansion of muscle microvascular exchange surface area and improvement of microvascular insulin sensitivity may increase the uptake of insulin by muscle cells, thereby improving blood sugar control.910
As such, microvascular endothelium has become an attractive potential therapeutic target for diabetes prevention and management.
Recent studies have found that GLP-1 and its analogs actively recruit muscle microvasculature, increasing muscle delivery of insulin and increasing muscle use of glucose. This is done by:
- Increasing glycogen synthesis
- Increasing glycogen synthase ɑ activity
- Enhancing glucose metabolism
- Inhibiting glycogen phosphorylase ɑ activity
Additionally, one study found that GLP-1 enhances muscle oxygenation. Tissue hypoxia has been shown to contribute to insulin resistance; thus, the muscle oxygenation effect of incretin-based therapies are of particular clinical interest.
GLP-1 Effects on Smooth Muscle and Vascular Tissue
In smooth muscle, GLP-1 and its analogs can relax conduit arteries, which contain large amounts of collagen and elastin filaments to expand with each pulse of the heart. They can also recruit and relax microvessels, resulting in effects similar to those seen in skeletal muscle.
Animal and human studies have presented conflicting results for the effects of GLP-1 analogs on blood pressure. In one human study, administration of GLP-1 resulted in an increase of blood pressure over 2 hours in healthy subjects,11 while another reported that GLP-1 reduced blood pressure when administered to patients with metabolic syndrome.121314 These conflicting results may come from the fact that GLP-1 and its analogs have a complex multi-tissue effect by acting on vascular smooth muscle and cardiac tissue as well as the autonomic nervous system. Still, it’s clear that further research is warranted to fully understand the activities and effects of GLP-1 and its analogs on smooth muscle and vascular tissue.
Another way by which incretin-based therapies may help reduce the development of metabolic syndrome is through their actions on the gastrointestinal (GI) tract and satiety. Specifically, the activation of GLP-1 receptors in the GI tract reduces the rate of gastric emptying. This is an effect that not only increases the feeling of fullness, but one that also delays the entry and therefore absorption of nutrients into the small intestine. In turn, the post-meal glucose metabolism and hormonal responses are affected, ultimately enhancing the anti-diabetes effects of GLP-1 receptor agonists.1516 Simply put, prolonging the sensation of fullness can lead to weight loss by limiting how much a person eats.
GLP-1 Effects on the Kidneys
GLP-1 therapies also have a broad range of renoprotective properties. Although kidneys may not be at the top of the list when you think of metabolic syndrome, researchers have noticed increasing evidence of a link between metabolic syndrome and kidney disease.1718
Although researchers don’t agree on exactly where GLP-1 receptors are located on the kidneys, there is agreement that GLP-1 analogs are beneficial to kidney function through:19
- Increasing the renal blood flow
- Increasing the urinary flow rate
- Preventing the rise of the waste product creatinine
- Reducing acute kidney injuries (tubular necrosis)
- Increasing fluid around cells
- Increasing the glomerular filtration rate
These activities are also important for the prevention of diabetic nephropathy, a long-term kidney disease that occurs when high blood glucose levels impair kidney functions. Protecting the kidneys is a critical target in the management of type 2 diabetes, so further investigation into the renal outcomes of GLP-1 based therapy will be required.
GLP-1 Effects on the Heart
People with type 2 diabetes and obesity tend to also develop heart disease. This is further complicated by indications that some medications used to control blood sugar, while effective, increase the risk of cardiovascular events.2021 These findings prompted changes in the regulatory approval processes for new anti-diabetes treatments, which were previously not required to produce robust cardiovascular-outcome data.
Researchers believe GLP-1 receptor agonists may have multiple effects on the cardiovascular system. This is particularly important for patients with type 2 diabetes, who not only have a higher risk of developing heart disease, but also are less likely to fully recover from cardiovascular events compared to patients without diabetes. Type 2 diabetes is frequently associated with risk factors that promote arterial buildup of fatty substances, such as:22
- High blood pressure
- Overweight or obesity
- Abnormal amounts of cholesterol or other fats in the blood (dyslipidemia)
- Impaired widening of blood vessels (vasodilation), which restricts blood flow to a region
- Small artery disease (also known as coronary microvascular disease)
- Increased stiffness of the arteries
- Enlargement and thickening of the heart’s left ventricle, the main pumping chamber
- Abnormal thickening of the heart valves
A large analysis of 35 trials showed that GLP-1 agonist therapy was associated with modest decreases in:23
- Low-density lipoprotein cholesterol (LDL-C, also known as “bad” cholesterol)
- Triglycerides (a type of fat in your blood)
- Total cholesterol
However, it did not have a significant impact on high-density lipoprotein cholesterol (HDL-C), commonly referred to as the “good” cholesterol. Lowering the level of total cholesterol can theoretically improve the risk of heart disease. Additionally, there is evidence that GLP-1 receptor agonists can also benefit the cardiac tissue and blood vessels, leading to outcomes such as:
- Have a long-term effect on reducing high blood pressure24
- Help with weight loss24
- Lower blood sugar24
- Improvements in heart function
A number of large clinical trials have shown GLP-1 receptor agonists may reduce the rates of death from cardiovascular causes, non-fatal heart attack, and non-fatal stroke among patients with type 2 diabetes.252627 While we still don’t fully understand the mechanisms behind the cardioprotective effects of GLP-1 receptor agonists, the evidence so far suggests that GLP-1 receptor agonists may help reduce rates of serious heart disease among type 2 diabetics.
GLP-1 Effects on the Liver
GLP-1 is transported from the GI tract, gallbladder, pancreas, and spleen to the liver by a blood vessel called the hepatic portal vein. This means that the highest levels of GLP-1 are found in your liver.
This is significant for various reasons. Nonalcoholic fatty liver disease (NAFLD) is common in type 2 diabetics. In 2015, the review in the Journal of the American Medical Association stated that approximately ⅔ of overweight diabetics over the age of 50 had a subtype of NAFLD called nonalcoholic steatohepatitis with advanced fibrosis.28 This close correlation exists because NAFLD increases the risk of type 2 diabetes, while type 2 diabetes contributes to the progression of NAFLD.29 Because NAFLD and diabetes together worsen liver function and accelerate the development of diabetes complications, there is an urgent need for the development of pharmacological therapies.
Several laboratory and animal studies have shown that GLP-1 and its analogs may restore function to damaged liver. The changes induced can regulate several processes in the liver, including:
- Hepatic gluconeogenesis, the generation of glucose in the liver from non-glucose precursors
- Synthesis of glycogen, the multibranched form of glucose that serves as a major form of energy
- Glycolysis, the breakdown of glucose to produce energy
Simply put, this means that GLP-1 and its analogs lower glucose output by your liver, which helps to lower blood sugars. As the stimulation of gluconeogenesis — the synthesis of glucose in your body — occurs, glucagon receptors in the liver are reduced, blocking glucose formation. This encourages uptake of glucose by muscle cells, thus decreasing the amount of glucose in the blood.
GLP-1 Effects on the Brain
Although the primary source of GLP-1 is the small intestine, a small amount of the peptide is secreted in the brain. In addition to the benefits already discussed, one effect of GLP-1 that has been gaining particular interest among scientists is neuroprotection. Stimulation of the GLP-1 receptor promotes neuroprotection in certain neurodegenerative disorders, such as Alzheimer’s disease and Parkinson’s disease. While the mechanisms for these effects remain unclear,
While gut-derived GLP-1 is able to cross the blood-brain barrier to bind its receptors in the brainstem, it has a short half-life. A half-life refers to the amount of time 50% of a material takes to decay. And because GLP-1 has a short half-life, scientists believe that direct effects on the brain are unlikely. Rather, it is believed that GLP-1 transmits metabolic information through nerve fibers in the enteric nervous system, a massive network of neurons in your gut that is also known as the body’s “second brain.”
Are GLP-1 Based Therapies the Future of Type 2 Diabetes Management?
As we’ve discussed, GLP-1 and its analogs favorably address all factors of metabolic syndrome. They can induce weight loss, stimulate insulin secretion, and improve insulin sensitivity, all of which make GLP-1 receptor agonists attractive therapeutic agents for not only type 2 diabetes, but for other disorders involving the heart, liver, lungs, kidneys, and brain.
Side Effects of GLP-1 Based Therapies
Still, it’s important to remember that GLP-1 receptor agonists are still a relatively new class of drugs. They appear to have a favorable safety profile, but there have been concerns regarding an association of these drugs with pancreatitis, pancreatic cancer, and thyroid cancer. Several studies have reported acute kidney injuries.30 Other common adverse effects of GLP-1 receptor agonists include:
- Itching at the injection site
- Raised bumps near injection site
- Pounding heart
- Nausea, vomiting
- Increase in heart rate
- Allergic reactions, anaphylaxis
- Low blood sugar
- Increased risk of bone fractures
- Upper respiratory infection
- Urinary tract infection
If you have or are at risk of developing metabolic syndrome, I recommend using natural alternatives to help control your blood sugar levels. Numerous human trials have found cinnamon extracts and omega-3 fatty acids to be effective at controlling blood sugar as well as other contributing factors of metabolic syndrome.31323334 The supplements I recommend are Metabolic Synergy, a concentrated water-soluble cinnamon extract, and CoQ10 Plus Omega Essentials, which contains highly absorbable fish oil and CoQ10 for dual-action cardiovascular support.
Now it’s your turn. Have you been diagnosed with type 2 diabetes or prediabetes? If yes, did your doctor recommend using a GLP-1 receptor agonist as part of your treatment strategy? Share your experience in the comments below!