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Type 2 Diabetes is a worldwide growing pandemic. Globally, around 425 million people have type 2 diabetes; that’s more than the entire US population. Almost 10% of Americans have type 2 diabetes, which is characterized by the body’s inability to regulate blood sugar (glucose). Uncontrolled high blood glucose levels can have severe long-term effects, impacting the cardiovascular system, brain function, and overall mortality. Because of the increased dangers associated with diabetes, there are a myriad of medications that target this disease. Unfortunately, these can be difficult to adhere to and usually require a daily activity like a pill, blood strip testing, and/or exercise. The more intensive and difficult these steps are (for instance, taking three pills a day vs one), the less likely people will be able to follow through. Additionally, though the medications can effectively reduce blood sugar levels and the risk of complications, they do not target the underlying disease. Medications may need to be increased or changed if the disease progresses. So, what is the underlying disease profile?

The big picture causes of type 2 diabetes include genetics, diet, exercise, and overall weight. Inside the body, these risk factors and habits manifest as cellular changes. The most significant change that takes place is called insulin resistance. Insulin is an important hormone that helps your body manage blood sugar; when cells are resistant to insulin, they can’t adequately respond to high blood sugar. This is the key indicator of type 2 diabetes. Many medications attempt to correct insulin resistance by replicating or replacing chemicals involved in the insulin pathway – including insulin itself in advanced cases. These have been a significant boon to many patients, but what if we could go deeper?

One of the changes many people see is in the intestines. The part of the intestines connected to the stomach is called the duodenum. The duodenum is short but important. It regulates the release of  hormones like glucagon-like peptide-1 (GLP-1) and gastric inhibitory peptide (GIP), both disrupted in insulin resistance. Scientists have found evidence that people with type 2 diabetes have increased duodenum tissue; a process called hypertrophy. Tissue removal in these patients may positively affect type 2 diabetes.

One of the most successful therapies for type 2 diabetes is bariatric (weight loss) surgery that bypasses some or all of the duodenum. These surgeries have been shown to have an immediate and long-lasting effect on people with diabetes. Studies have found that A1C levels, which measure blood sugar, are completely back to normal range in patients who have had these surgeries at a rate five times higher than people on medication alone. It is thought that by bypassing or removing the duodenum, the hypertrophic cells stop interfering with the insulin process, and insulin resistance decreases or is outright reversed! Also, since surgery is a one-time deal, the adherence problems of pills and other daily activities are reduced or eliminated.

Unfortunately, surgery is invasive, intensive, painful, and somewhat risky (10-20% have complications). Additionally, removing parts of the duodenum can result in malabsorption of nutrients. To solve this, researchers have devised a new investigative procedure for tackling type 2 diabetes. Instead of cutting the body open and removing, adding, or rearranging the intestinal tract, a new approach called the Revita system is being tested. This system revolves around a catheter that moves into the duodenum and ablates, or removes, the top layer of hypertrophic duodenum tissue. Early studies have shown that by targeting just the hypertrophic tissue, the duodenum will heal and retain its function while blood sugar normalizes. This is an exciting potential alternative to normal bariatric surgery for people with type 2 diabetes.

Staff Writer / Editor Benton Lowey-Ball, BS, BFA

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References:

Cummings, D. E., Overduin, J., & Foster-Schubert, K. E. (2004). Gastric bypass for obesity: mechanisms of weight loss and diabetes resolution. The Journal of Clinical Endocrinology & Metabolism, 89(6), 2608-2615. https://academic.oup.com/jcem/article/89/6/2608/2870294

Jacobsen, S. H., Olesen, S. C., Dirksen, C., Jørgensen, N. B., Bojsen-Møller, K. N., Kielgast, U., … & Madsbad, S. (2012). Changes in gastrointestinal hormone responses, insulin sensitivity, and beta-cell function within 2 weeks after gastric bypass in non-diabetic subjects. Obesity surgery, 22, 1084-1096. https://link.springer.com/article/10.1007/s11695-012-0621-4

Rubino, F., Forgione, A., Cummings, D. E., Vix, M., Gnuli, D., Mingrone, G., … & Marescaux, J. (2006). The mechanism of diabetes control after gastrointestinal bypass surgery reveals a role of the proximal small intestine in the pathophysiology of type 2 diabetes. Annals of surgery, 244(5), 741. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1856597/

Rubino, F. (2008). Is type 2 diabetes an operable intestinal disease? A provocative yet reasonable hypothesis. Diabetes care, 31(Supplement_2), S290-S296. https://doi.org/10.2337/dc08-s271

Schauer, P. R., Bhatt, D. L., Kirwan, J. P., Wolski, K., Aminian, A., Brethauer, S. A., … & Kashyap, S. R. (2017). Bariatric surgery versus intensive medical therapy for diabetes—5-year outcomes. New England Journal of Medicine, 376(7), 641-651. https://www.nejm.org/doi/full/10.1056/nejmoa1600869

Theodorakis, M. J., Carlson, O., Michopoulos, S., Doyle, M. E., Juhaszova, M., Petraki, K., & Egan, J. M. (2006). Human duodenal enteroendocrine cells: source of both incretin peptides, GLP-1 and GIP. American Journal of Physiology-Endocrinology and Metabolism, 290(3), E550-E559. https://journals.physiology.org/doi/full/10.1152/ajpendo.00326.2004

Wickremesekera, K., Miller, G., Naotunne, T. D., Knowles, G., & Stubbs, R. S. (2005). Loss of insulin resistance after Roux-en-Y gastric bypass surgery: a time course study. Obesity surgery, 15(4), 474-481. https://link.springer.com/article/10.1381/0960892053723402

van Baar, A. C., Holleman, F., Crenier, L., Haidry, R., Magee, C., Hopkins, D., … & Bergman, J. J. (2020). Endoscopic duodenal mucosal resurfacing for the treatment of type 2 diabetes mellitus: one year results from the first international, open-label, prospective, multicentre study. Gut, 69(2), 295-303. https://gut.bmj.com/content/69/2/295.abstract

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Sugars are sweet, tasty, and disastrous for your health in large quantities. They are also ubiquitous in modern society. We find them added to everything from salad dressings, drinks, bread, even peanut butter! Sugars and other carbohydrates make up over half of the calories consumed by Americans. Carbohydrates are broken down into a simple sugar called glucose and delivered around the body after eating. This can be surprisingly tricky. Too little glucose and cells can’t function. Too much and it gets converted to fat and damages the metabolic system, heart, and bloodstream. Type 1 Diabetes is a condition where the body doesn’t produce enough insulin. Type 2 Diabetes is more complicated; the body doesn’t respond to raised glucose in the bloodstream properly. A big culprit for failure is when insulin isn’t released well. To remedy this a class of drugs called glucagon-like peptide-1 (GLP-1) agonists have been developed.  Agonist in this case means the medication has a similar function to the natural hormone. The opposite is an antagonist, which acts in opposition to them. GLP-1 medicines include Trulicity, Mounjaro, and semaglutide / Ozempic. In this article, we will review how insulin works, how GLP-1 works on the cellular level, and what GLP-1 medicines do to the body.

Insulin is the main hormone that tells your body how to process sugar. Before we can understand how GLP-1 works, we need to understand the healthy release of insulin. This starts in the pancreas, an organ near our gut. The pancreas is filled with many types of cells called islet cells. These are responsible for regulating the balance of glucose in our bloodstream. Two major types are alpha and beta islet cells. Alpha islet cells produce glucagon and GLP-1. Glucagon tells the liver to increase blood sugar when you need energy. Beta cells make insulin and amylin, which help lower blood sugar. Alpha and beta islet cells work in opposition. They keep each other in check and our blood sugar levels just right. In Type 1 Diabetes, alpha cells may be dysfunctional and beta cells don’t exist or get destroyed. WIth Type 2 Diabetes, problems can occur when beta cells don’t function properly. Beta cells make insulin and release it in two stages. When these cells detect high blood glucose, they “trigger” and release insulin right away. This short response lasts 10-20 minutes, but is still several steps long. After triggering, a complicated “amplifying” pathway turns on to produce and release more insulin. Together this is powerful, slow, complex and has many potential points of failure. Beta cells are vital, and when they fail it often signals the transition from obesity to Type 2 Diabetes.

GLP-1 is like a shortcut for beta cells. When it is detected the triggering response is primed and the cells are ready to release insulin as soon as glucose is detected. This pathway bypasses a lot of the complicated cellular machinery that is damaged in diabetic patients. The upshot is that GLP-1 stimulates insulin release from islet cells. An added benefit is that the insulin is only released in the presence of elevated glucose. This is good because you don’t release too much insulin, which can be dangerous. GLP-1 medications also last much longer in the body than natural GLP-1, giving longer-term effects which can last for up to a day!

Now we know a little of how GLP-1 acts inside our cells, but what effects does this have on the body? Many, and widespread, it turns out! GLP-1 affects cells all over the body. The three biggest effects are decreased blood glucose, appetite suppression, and weight loss.

Insulin decreases blood glucose, and GLP-1 increases the response to glucose. But GLP-1 medications have a secret extra benefit. Remember that alpha and beta cells work opposite each other. Normally when blood sugar is low, we release GLP-1 from our pancreas along with glucagon. Glucagon is very useful, and one of its uses is to stimulate the liver into producing more blood sugar. GLP-1 medications suppress glucagon production and the liver stays quiet. The pancreas still releases insulin, but the liver produces 45% less glucose!

GLP-1 affects two of the biggest portions our appetite: our stomach and our brain. It slows the absorption of nutrients from the stomach, a process called gastroparesis. Food – and the glucose inside – is retained in the stomach and gut instead of the bloodstream. GLP-1 can also affect the brain. It can cross from the bloodstream into the brain, but also affect the vagus nerve – the major nerve connecting the brain and gut. Here it acts on the hypothalamus, suppressing the appetite and giving you feelings of being full. With the stomach slowing down and the brain signaling that it’s full, we tend to eat less.

Combined, lower blood sugar and appetite can have serious effects on weight. This can be a big benefit of GLP-1 medications. Weight loss is linked with better outcomes for Type 2 Diabetes patients. Getting to a healthy weight is also good for the heart, joints, liver, and so on. Significant weight loss has been seen with GLP-1. Let’s not sugar-coat this though; not all weight loss is created equal. Ideally we’d cut our body fat while maintaining – or building – our muscle. This is especially true with diabetes, as skeletal muscle uses up extra glucose. Unfortunately, when we lose weight through diet restriction we lose more than just fat. This is true of gastric surgery, diet-induced weight loss, and GLP-1 medications. In GLP-1 medication studies, 20-50% of the weight lost is things other than fat – including muscle. Studies vary widely. The type of GLP-1 medication and other medications patients are taking may affect this. The best way to offset this is through building muscle with exercise!

GLP-1 medications are truly amazing. They increase insulin response, lower blood glucose, suppress appetite, and lead to weight loss. It’s not all sugar and spice, however. Side effects can be rough, including vomiting and diarrhea. Additionally, meds can’t do it alone. When taking GLP-1 medications, the goal should still be to create an environment conducive to healthy living. Limiting carbohydrate intake is one critical step. Exercising is another. When fighting weight loss, victory is very sweet, but our diets shouldn’t be!

Written By Benton Lowey-Ball, BS Behavioral Neuroscience

Sources:

Campbell, J. E., & Newgard, C. B. (2021). Mechanisms controlling pancreatic islet cell function in insulin secretion. Nature reviews Molecular cell biology, 22(2), 142-158. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8115730/

Cervera, A., Wajcberg, E., Sriwijitkamol, A., Fernandez, M., Zuo, P., Triplitt, C., … & Cersosimo, E. (2008). Mechanism of action of exenatide to reduce postprandial hyperglycemia in type 2 diabetes. American Journal of Physiology-Endocrinology and Metabolism, 294(5), E846-E852.https://journals.physiology.org/doi/full/10.1152/ajpendo.00030.2008

Cohen, E., Cragg, M., deFonseka, J., Hite, A., Rosenberg, M., & Zhou, B. (2015). Statistical review of US macronutrient consumption data, 1965–2011: Americans have been following dietary guidelines, coincident with the rise in obesity. Nutrition, 31(5), 727-732. https://pubmed.ncbi.nlm.nih.gov/25837220/

Drucker, D. J. (2018). Mechanisms of action and therapeutic application of glucagon-like peptide-1. Cell metabolism, 27(4), 740-756. https://www.sciencedirect.com/science/article/pii/S1550413118301797

Dungan, K., & DeSantis, A. (2013). Glucagon-like peptide-1-based therapies for the treatment of type 2 diabetes mellitus. https://www.uptodate.com/contents/glucagon-like-peptide-1-based-therapies-for-the-treatment-of-type-2-diabetes-mellitus#H1

Baggio, L. L., & Drucker, D. J. (2014). Glucagon-like peptide-1 receptors in the brain: controlling food intake and body weight. The Journal of clinical investigation, 124(10), 4223-4226.https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4191040/

Sargeant, J. A., Henson, J., King, J. A., Yates, T., Khunti, K., & Davies, M. J. (2019). A review of the effects of glucagon-like peptide-1 receptor agonists and sodium-glucose cotransporter 2 inhibitors on lean body mass in humans. Endocrinology and Metabolism, 34(3), 247-262. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6769337/

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In fifth grade, I learned that mitochondria are the powerhouses of the cell. But what’s the fuel? The answer is carbohydrates. Big carbohydrates are broken down by digestion and converted into a couple of simple sugars. The most abundant of these simple sugars in our bodies is glucose. 

Glucose is small, simple, and packed with energy. We transport it through our bloodstream to cells in our body. Glucose levels are regulated by the liver and pancreas. Unfortunately, conditions like diabetes can result in the dysregulation of blood glucose levels. Having too much sugar in the blood is very bad over time. It can result in damage to the eyes, kidneys, nerves, and heart. On the flip side, having low blood sugar can get dangerous right away. Glucose is the fuel that powers our cells, without it the brain and other organs can’t function.

We know that glucose is critical to body function. We also know that glucose levels can get out of control. What can we do to make sure glucose levels stay safe? The most important piece of the puzzle is information. Good information on what our blood glucose levels are is critical to know what to do. We get this information by testing our blood glucose levels. There are three major ways of testing blood glucose; chemical redox reactions, color change, and enzyme-based reactions.

• Chemical redox reaction testing works because glucose reacts with metals. By measuring how the metals react to blood, we can indirectly measure the amount of glucose. Unfortunately, other chemicals in the blood react to metal as well and can complicate the results. This method is rarely used these days.
• The second method is through color change. This method combines blood and a special chemical called o-Toluidine. The o-Toluidine reacts to a specific part of the glucose molecule and changes it to be bright green (normally it is white or colorless). We can measure the color change visually, using test strips or with a digital glucose meter. Color change is cheap and effective, but the o-Toluidine can react to other sugars and give distorted results.
• The industry standard for the last few decades has been enzyme-based reactions. A special enzyme, usually glucose oxidase or glucose dehydrogenase reacts with blood. This enzyme is very specific and only reacts to glucose. A result of this reaction is the production of H2O2, hydrogen peroxide. This is easily measured by digital devices. This method is inexpensive and specific, giving good results.

Now we know the chemical methods of measuring glucose, but how do we actually test our glucose level? Three broad testing types exist: oral, self-test, and continuous glucose monitors. These are differentiated mainly by the frequency and invasiveness of the test. 

• Oral tests are a lengthy and (frankly) pretty gross affair. You fast for several hours, then drink an offensively sweet beverage and wait another hour. Blood is drawn and tested to determine how well your body can break down and clear the glucose from the bloodstream.
• Self-tests involve drawing blood and putting it on a strip or in a digital detector. This is quick and can be done many times a day if needed. Unfortunately, repeated pricks can be annoying and you can’t test overnight unless you wake up. 
• Continuous glucose monitors (CGMs) are worn like a patch and have a tiny sensor that goes just under the skin into the interstitial space and sends results to an external monitor. This tests blood glucose constantly, typically reporting every 1-5 minutes. CGMs can let people know their glucose via a phone app or external device. 

As the old saying goes, knowledge is power! With the help of the latest CGM technology, we are able to see information in real-time such as how food, exercise, and stress impact glucose levels. This helps us take immediate action to manage our glucose levels. So, take action to keep your blood glucose in the healthy range with your new knowledge, a good diet, and consistent exercise. Make sure it stays there by monitoring your blood glucose levels regularly. Keep your eyes open to look for new studies looking at ways to monitor your blood glucose and keep your cells powered up!

Sources:

American Diabetes Association (n.d.). Understanding A1C diagnosis. American Diabetes Association. https://diabetes.org/diabetes/a1c/diagnosis

McMILLIN, J. M. (1990). Blood glucose. Clinical Methods: The History, Physical, and Laboratory Examinations. 3rd edition. Chapter 141. https://www.ncbi.nlm.nih.gov/books/NBK248/

Wang, H. C., & Lee, A. R. (2015). Recent developments in blood glucose sensors. Journal of food and drug analysis, 23(2), 191-200. https://doi.org/10.1016/j.jfda.2014.12.001

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How does the body use energy? After we eat, most food is broken down into parts that cells can use for energy. The bloodstream carries these pieces through the bloodstream to our cells, which let them in and convert food to energy. In some cases, the cells don’t let food particles in. In these cases, the problem may be diabetes.

Cells need to separate their insides from the environment around them. Cells only let in specific molecules at specific times. Insulin is the molecule that tells cells to let in sugars in the form of glucose. It is produced by the pancreas and is released when the pancreas detects high levels of sugars in the blood. In some cases, such as with obesity, fatty acids can disrupt how cells absorb and use sugar in the blood. When this happens, cells are less sensitive to insulin and absorb less blood sugar per unit of insulin in the blood. Since blood sugar stays high, the pancreas produces more and more insulin, which has less and less effect. Cells can’t respond to all the excess insulin and are increasingly resistant to its effects.

Insulin is also the hormone the pancreas uses to communicate with the liver about blood sugar. When the liver detects insulin it converts blood glucose into glycogen, a short term storage molecule. When high levels of insulin persist, the liver sends extra energy to fat cells.

After long periods of insulin resistance, the pancreas itself stops working properly. Pancreatic cells become damaged and unable to produce insulin. This is called Type 2 Diabetes (T2D). With T2Ds, blood sugar stays high, insulin stops being produced, any produced insulin is less effective, and cells stop metabolizing properly. On top of this, the body gains excess weight which can stress the pancreas further. Other symptoms include cardiovascular disease, nerve dysfunction in the extremities (called neuropathy), and increased chance of death.

Diabetes is very common in the United States. Tens of millions of Americans have T2D. Type 1 diabetes is an autoimmune disorder which results in pancreatic damage. Type 2 diabetes is an insulin resistance disorder and can have a slow onset.  Major risk factors are obesity and lack of exercise. These should be the first steps to managing T2D as well.

When a healthy diet and exercise aren’t enough to manage healthy blood sugars, or aren’t an option, several key medications exist to help with type 2 diabetes:

• Insulin: By injecting insulin with meals, the effects of a compromised pancreas can be reduced. Synthetic insulin, such as glargine, is in wide use.
• Glucagon-like peptide-1 receptor agonists (GLP-1 RA): These stimulate the pancreas and coerce it into properly releasing the correct amounts of insulin. It slows some pancreatic cells and helps restore the pancreas-liver communication lines. One generic name for GLP-1 RA drugs is semaglutide, often branded as Ozempic and Rybelsus. A benefit of these drugs is that a common side effect is weight loss, one of the drivers of type 2 diabetes.
• Metformin: Originally inspired by the French Lilac plant, metformin lowers blood sugar levels by acting on the liver, bloodstream, intestinal tract, and even the gut microbiome! The complex action on different areas of the body results in overall lower blood sugar levels.
• SGLT2 Inhibitors: These act on the kidneys, changing the threshold of reabsorption of sugar so they excrete more than usual removing blood sugar through the urine. 

Altogether, there are several medications which may be helpful for controlling type 2 diabetes. Discovering how these medications interact, lowering side effects,  and finding treatments that are easy and straightforward is key. If you have type 2 diabetes, look for enrolling studies soon and improve your diet and exercise if possible!

Written by Benton Lowey-Ball, BS Behavioral Neuroscience

Sources:

Berg, J. M., Tymoczko, J. L., & Stryer, L. (2012). Biochemistry (7th Ed., pp 798-803). New York: W. H. Freeman and Company

DeFronzo, R. A., Ferrannini, E., Groop, L., Henry, R. R., Herman, W. H., Holst, J. J., … & Weiss, R. (2015). Type 2 diabetes mellitus. Nature reviews Disease primers, 1(1), 1-22. https://www.nature.com/articles/nrdp201519

Olokoba, A. B., Obateru, O. A., & Olokoba, L. B. (2012). Type 2 diabetes mellitus: a review of current trends. Oman medical journal, 27(4), 269. http://doi.org/10.5001/omj.2012.68

Rena, G., Hardie, D. G., & Pearson, E. R. (2017). The mechanisms of action of metformin. Diabetologia, 60(9), 1577-1585. https://doi.org/10.1007%2Fs00125-017-4342-z

U.S. Department of Health & Human Services/Centers for Disease Control and Prevention (August 10, 2021). Insulin Resistance and Diabetes https://www.cdc.gov/diabetes/basics/insulin-resistance.html

U.S. Department of Health & Human Services/Centers for Disease Control and Prevention (December 16, 2021). Type 2 Diabetes https://www.cdc.gov/diabetes/basics/type2.html

Witters, L. A. (2001). The blooming of the French lilac. The Journal of clinical investigation, 108(8), 1105-1107.https://doi.org/10.1172%2FJCI14178