by Lara Roach
figures by Rebecca Senft

In Greek, macrophage means “big eater,” and that is exactly their job. Like a growing teenager or athlete after a big game, macrophages are activated immune cells whose primary focus is to “eat.” But instead of, say, a plate of pasta, macrophages take in and digest pathogenic microbes, unhealthy molecules, and even other cells in the body when they become damaged. Macrophages are present throughout the body, armed and ready to lend their protection when called upon. Recently, researchers from the University of California, San Diego (UCSD) learned more about how macrophages are influenced by obesity. They discovered that obesity can alter the function of macrophages in the pancreas, preventing the pancreas from functioning properly and contributing to the development of Type 2 diabetes.

The Pancreas and the Blood Sugar Balancing Act

The pancreas, located in the back of the abdomen behind the stomach, is important for proper food digestion and maintaining the balance of sugar levels in the blood (Figure 1). Specialized cells in the pancreas, called beta cells, are responsible for lowering blood sugar levels by making the molecule insulin. Insulin is a signal to other cells in the body, such as fat cells, to take up sugar from the blood, leading to lower blood sugar levels. The insulin signal is balanced by another molecule made in the pancreas, called glucagon. Glucagon is a signal for the liver to release sugar into the bloodstream, leading to higher blood sugar levels. This blood sugar balancing act is important because glucose is one of the body’s main energy sources, so its uptake from the blood fuels healthy cellular function. If blood sugar becomes either too high or too low, a host of health problems can occur, from kidney malfunction and nerve damage to heart disease and stroke.

Figure 1: The pancreas is responsible for controlling the levels of sugar in the blood. Two important cell types, alpha and beta cells, send signals to increase or decrease blood sugar. Alpha cells make glucagon, which signals the liver to increase sugar in the blood. Beta cells make insulin to let body cells know they need to take up sugar from the blood, leading to decreased blood sugar. Maintaining balance in blood sugar levels is necessary for a healthy body and to avoid medical problems.

One condition that can  have severe negative impacts on this glucose regulation process is obesity. During obesity, accumulation of excess body fat from poor nutrition and physical activity puts a strain on many organs, including the pancreas. Over time, beta cells no longer make enough insulin, even when blood sugar levels are high. Without a change in diet or activity, high blood sugar leads to the development of Type 2 diabetes.

The Trouble with Type 2 Diabetes

Over 30 million adults in the United States are currently diagnosed with Type 2 diabetes, a disease marked by improper sensitivity to insulin and dysfunctional blood sugar regulation.  Notably, people with this disease are at risk for medical complications like heart and kidney disease, nerve damage, and stroke. A major risk factor for the development of Type 2 diabetes is obesity. In non-obese individuals, blood sugar is typically at its lowest right when waking up or before having a meal. However, with a sugary diet and lack of exercise over time, blood sugar levels can remain extremely high even after fasting. This causes two major problems in the pancreas, namely insulin resistance and beta cell dysfunction, which contribute to the development of Type 2 diabetes (Figure 2).

Figure 2: Obesity can contribute to insulin resistance and type II diabetes. Increased body fat and consistently high blood sugar lead to an increased demand of insulin from the pancreas. However, the insulin signal is less powerful the more it is used. Over time, body cells respond less and less to the insulin, and blood sugar remains high. At the same time, the pancreas becomes inflamed. Macrophages become active, inhibit beta cells from functioning properly, and take in the insulin the beta cells are trying to release to lower blood sugar.

When blood sugar levels are persistently high over time, the insulin signal becomes less powerful because it is being used too often, and cells no longer use or store sugar in response to the insulin signal. This phenomenon is known as insulin resistance. In addition to this resistance, the beta cells in the pancreas begin to function improperly, causing beta cell dysfunction. For example, with consistently high blood sugar levels, beta cells can lose their ability to sense changes in how much sugar is in the blood, which in turn impacts their insulin production.

There are many processes that can lead to beta cell dysfunction and overall lowered insulin levels, some of which are not known or fully understood by researchers. For example, obesity has long been associated with the development of type 2 diabetes, but it was not until recently that researchers began to understand why. Near the end of 2018, scientists at UCSD identified specific immune cells in the pancreas, the macrophages, that may provide a missing link between obesity and the dysfunctional beta cells that contribute to type 2 diabetes.

What’s the Immune System Got to Do with It?

The immune system is like the body’s army. It is in charge of fighting foreign invaders like bacteria and viruses and clearing out anything else that’s not supposed to be present in a healthy body. Many different cells make up the immune system, and, like in an army, each cell has its own role.

The immune system not only responds to a foreign attack, but it has also been shown to become active in response to chronic diseases such as autoimmune diseases, heart disease, and cancer. In fact, Type 1 diabetes is an example of an autoimmune disease where the immune system mistakenly targets healthy cells for destruction. Unlike Type 2 diabetes, which occurs due to changes in sensing and responding to insulin, Type 1 diabetes is a chronic condition caused by immune cells mistakenly destroying beta cells, leaving the pancreas unable to make any insulin at all.

In recent years, research has also shown that obesity can affect the immune system. Obesity is known to cause inflammation – the immune system response that increases blood flow, immune cells, and immune communication molecules in a specific area of the body. Inflammation is meant to be a short-term response, but when it becomes chronic, it can cause more harm than good.

Obesity can drive inflammation in body fat and the pancreas, among other organs. But the impact of this inflammation on pancreatic cells is not well-understood. The research team from UCSD used obese mice to test the relationship between the immune system and the pancreas during obesity. They show that obesity causes macrophages, the “big eaters” already present in the pancreas, to grow in number and impact the function of beta cells.

In the pancreas during obesity, the macrophages begin to interact with beta cells, those all-important insulin-producing cells. The researchers found that this direct cell-to-cell contact from the macrophages impairs beta cell function. They also found that the macrophages were taking in or “eating” the insulin the beta cells were producing, contributing to overall lower insulin levels in the mouse. These changes in insulin levels could be detrimental to maintaining normal blood sugar levels over time and could contribute to the development of diabetes. 

So why does this matter?

The recent findings about the interactions between the immune system and the pancreas are important for answering some of the previously unanswered questions about how beta cell dysfunction happens and what cells and molecules are involved. By understanding more about how things go wrong in the pancreas during obesity and diabetes, researchers and clinicians can work toward developing better ways of preventing and treating patients with these diseases.

Lara Roach is a third year PhD candidate in the Biological and Biomedical Sciences program at Harvard University

Rebecca Senft is a fourth-year Program in Neuroscience PhD student at Harvard University who studies the circuitry and function of serotonin neurons in the mouse

For more information:

  • To read the original study from UCSD, see this article 
  • To see some facts and figures about obesity, see this page from the CDC
  • To learn more about type 2 diabetes, see this article from the American Diabetes Association
  • For more information about this link between obesity and type 2 diabetes, check out this article from the Obesity Action Coalition
  • To learn more about how obesity can impact the immune system, see this piece from the Obesity Action Coalition
  • To learn more about blood sugar regulation, see this page on insulin and glucagon

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