Blog post Author: Arianna McDaniels
December 2024
Diabetes: A Growing Global Concern
Diabetes mellitus affects over 530 million adults globally and this number is expected to soar to 783 million by 2045.1 Diabetes occurs when the body either doesn’t produce enough insulin, completely stops producing insulin, or can’t use it effectively.
The pancreas is an organ that helps control blood sugar. Pancreatic islets are small groups of cells inside the pancreas that act like tiny managers, they help maintain your blood sugar levels. Beta cells are special cells inside of these islets that produce insulin. Insulin is a hormone that helps your body use sugar from the food you eat. After you eat, your body breaks down food into glucose (sugar), which enters your bloodstream. Insulin moves this sugar from your bloodstream into your cells, where it’s used for energy or storage. Without insulin, your body would run like a car without fuel, unable to function. Without enough insulin, sugar builds up in the bloodstream. The buildup of sugar creates an imbalance and can lead to diabetes and other serious health issues.
Figure 1. Schematic of body highlighting pancreas, pancreatic islet, and beta cell. Image from National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health.2
There are two main types of diabetes3:
Type 1 Diabetes
- Primarily diagnosed in children and young adults, though it can also develop in adults.
- Symptoms are usually rapid, appearing within a few weeks to months.
- An autoimmune condition where the body attacks insulin-producing cells in the pancreas.
- People with type 1 diabetes rely on insulin therapy for life.
Treatment: Patients must rely on insulin for life because their pancreas no longer produces insulin. Insulin can be administered via injections or insulin pumps.
Type 2 Diabetes
- Often diagnosed in adults, particularly those who are obese, it can be diagnosed at any age.
- A more common form where the body becomes resistant to insulin.
- Often linked to lifestyle factors like aging, inactivity, and limited access to nutritious food or healthcare.
Treatment: Many people with type 2 diabetes can manage their blood glucose levels through lifestyle changes such as diet and exercise. As the condition progresses, medications such as *metformin, **GLP-1 receptor agonists, or insulin may be required.
*Metformin: helps the body use insulin better.4
**GLP-1 receptor agonists: help control blood sugar after meals and can aid in weight loss.4
Zinc: A Vital Trace Element for Health and Metabolism
Zinc is an important mineral that supports a wide range of bodily functions. It helps over 300 enzymes and thousands of transport proteins perform essential tasks such as maintaining healthy metabolism and protecting cells from damage.5 Around 10% of human proteins depend on zinc, making it vital for activities like cell growth, repair, and energy production. Zinc also plays a key role in neutralizing harmful molecules called reactive oxygen species (ROS). These molecules can damage cells when in excess. A deficiency in zinc reduces the body’s ability to fight this oxidative stress, potentially leading to severe issues in conditions like diabetes.
Zinc 101: Zinc Needed and Selected food sources
Table 1. Amounts of Zinc Needed: Information derived from NIH Zinc Data6
| Age | Male | Female | Pregnancy | Lactation |
| Birth to 6 months* | 2 mg | 2 mg | ||
| 7 – 12 months | 3 mg | 3 mg | ||
| 1 – 3 years | 5 mg | 5 mg | ||
| 4 – 8 years | 5 mg | 5 mg | ||
| 9-13 years | 8 mg | 8 mg | ||
| 14-18 years | 11 mg | 9 mg | 12 mg | 13 mg |
| 19+ years | 11 mg | 8 mg | 11 mg | 12 mg |
*Adequate Intake (AI), equivalent to the mean intake of zinc in healthy, breastfed infants.
Common Foods Highlighted from U.S. Department of Agriculture (USDA)’s FoodData Central7: FoodData Central
| Zinc Content of Selected Foods | Milligram (mg) per serving | % Daily Value (DV) Male 11mg | % Daily Value (DV) Female 8mg | % Daily Value (DV) Lactating Adults 12mg |
| Oysters, Eastern, cooked, dry heat (3oz) | 38 mg | 345% | 475% | |
| Oysters, Eastern, farmed, raw, (3 oz) | 32 mg | 291% | 400% | |
| Beef, chuck eye roast (3 oz) | 8 mg | 73% | 100% | 67% |
| Chickpeas (1 cup) | 5.5 mg | 50% | 69% | 46% |
| Crustaceans, crab, blue, crab cakes (2 cakes) | 5 mg | 46% | 63% | |
| Cereals, ready-to-eat, granola, homemade | 4 mg | 36% | 50% | 33% |
| Lamb (4oz) | 3 mg | 27% | 37.5% | 25% |
| Breakfast cereals, fortified with 25% of the DV zinc (1 serving) | 2.8 mg | 25% | 35% | 23% |
| Lentils (1 cup) | 2.5 mg | 23% | 31% | 21% |
| Pumpkin seeds (1 oz) | 2.2 mg | 20% | 28% | 18% |
| Quinoa (1 cup) | 2 mg | 18% | 25% | 16% |
| Cashews (1oz) | 1.6 mg | 15% | 20% | 13% |
| Oats, regular and quick, not fortified (0.5 cup) | 1.5 mg | 14% | 19% | 12% |
| Greek yogurt, plain, lowfat (1 container) | 1.26 mg | 12% | 16% | 11% |
| Egg, 2 large | 1.2 mg | 11% | 15% | 10% |
| Sardines, 1 can | 1.2 mg | 11% | 15% | 10% |
| Cheddar Cheese 1 slice (1 oz) | 1.05 mg | 10% | 13% | 9% |
| Tofu (1 oz) | 0.6 mg | 6% | 8% | 5% |
Zinc and Diabetes: Link Between an Essential Trace Mineral and a Global Health Challenge8
When we think about diabetes, our minds jump to sugar and insulin. Did you know that zinc, a tiny trace element, plays a significant role in the disease? In diabetes, zinc deficiency contributes to harmful effects like inflammation, *oxidative stress, and cell damage. This can potentially lead to complications such as blood vessel issues, nerve damage, and insulin dysfunction.
*oxidative stress: occurs when there are too many unstable molecules (free radicals: molecules that can damage cells) in the body, which can lead to health problems.
Figure 2. How our cells manage zinc levels. Image from Ahmad et al. 8 “Zinc and Diabetes: A Connection between Micronutrient and Metabolism,”Cells, vol. 13, no. 16, 2024, p. 1359, https://doi.org/10.3390/cells13161359. ZIP proteins let zinc into the cell. ZnT proteins help move zinc out of the cell and keep levels balanced. Metallothioneins (MTs) are proteins that store zinc, holding onto extra zinc for when it’s needed, and preventing the cell from getting overloaded. The teamwork of these proteins ensures that your body has the right amount of zinc essential for energy, growth, and protection from zinc imbalance.
The Role of ZnT8: Insulin Storage and Release
As seen in figure 2, ZnT proteins play a critical role transporting zinc out of cells and maintaining zinc levels. One key member of this family, ZnT8 (zinc transporter 8), an essential protein that helps move zinc into small storage areas inside of insulin-producing beta cells in the pancreas.9 Zinc helps insulin to form stable crystals, once formed, it is safely stored and released when needed.9
Imagine ZnT8 as a librarian organizing books (insulin molecules) on shelves (insulin granules). Without proper organization, searching for the right book (insulin) would be chaos! If there is not enough zinc available, or if ZnT8 isn’t working properly, the process breaks down. This leads to difficulties in regulating blood blood sugar levels.
The Role of ZnT8 in Diabetes9
In Type 1 diabetes, the immune system, which usually protects us from harmful invaders like bacteria and viruses, gets confused and starts attacking healthy cells in the pancreas that make insulin. One of the targets of this attack is ZnT8. As the immune system damages the insulin-producing cells, there’s less ZnT8 in the pancreas. This means the storage and release of insulin get even worse over time, making it harder for the body to regulate blood sugar.
In Type 2 diabetes, changes in ZnT8 can affect insulin production and glucose control. Some mutations in the ZnT8 gene reduce insulin secretion, Other mutations may cause excess insulin release, which doesn’t always work effectively in high blood sugar conditions.
Current research is focused on understanding ZnT8’s role in both types of diabetes and developing alternative treatments.
Surprising Findings From Mouse Studies10 (All figures in this section are from the paper)
In 2019, researchers at Southeast University in Nanjing, China, studied mice that they altered to lack the ZnT8 gene, which helps produce the ZnT8 protein. These mice had no functioning version of the gene at all. The results were surprising and revealed ZnT8’s unexpected role in fat storage and energy metabolism.
Body weight and fat mass measured of female and male groups.
WT: wild-type, normal mice
Slc30a8-/-: mice lacking ZnT8 gene
Increased Fat Storage: Mice without the ZnT8 gene stored more fat even though they didn’t gain extra weight.
Seen on the right: They observed the body weight changes over time. They saw no extra weight gain despite increased fat storage
Seen on the left: Here we see the body composition differences between wild-type and ZnT8-deficient mice. Mice lacking the gene were observed to have significantly higher accumulation of fat compared to those with the gene.
Lipid Imbalances: The researchers found that mice lacking the ZnT8 gene had higher levels of fat in their liver. This led to changes in how the liver processed and stored fat. Measuring triglycerides is important because they are a type of fat found in your blood, high levels can signal problems with metabolism or liver. The liver is responsible for processing and storing fats, by measuring triglyceride levels, scientists can get a sense of how well the liver is functioning. When levels are too high, this can result in liver damage or increase the risk of heart disease, diabetes, and other health issues.
Liver triglyceride levels measured in WT (normal mice) and Slc30a8-/- (ZnT8-deficient mice)
WT: wild-type, normal mice
Slc30a8-/-: mice lacking Znt8 gene
TG: triglyceride levels measured
Differences observed in colon structure: Hematoxylin-eosin staining of the proximal colon (top), revealing structural changes in the intestines of ZnT8-deficient mice. This form of staining is a method that uses two dyes to stain tissue samples, highlighting the main parts in pink and the other showing the cell centers (nuclei) in blue. Here, thicker walls are observed on the colon. (Bottom) Thickness of the colon (diameter) in WT (control) and ZnT8-deficient mice. ZnT8-deficient mice have significantly thicker colon walls.
Staining of mouse colon tissue wild-type (normal) and Slc30a8-/-, ZnT8-deficient mice
Colon diameter measured of WT and ZnT8-deficient mice.
WT: wild-type, normal mice
Slc30a8-/-: mice lacking ZnT8 gene
Image (top): Staining of colon tissue from both mouse groups
Gut Changes: Mice lacking the ZnT8 gene had intestines that were thicker than usual. On the top image, they stained a section of the colon tissue. This may indicate that the enzymes that help break down food and process nutrients weren’t working properly, affecting their digestion and metabolism.
Role of ZnT8 and Serotonin in Fat Storage and Blood Sugar Control
Serotonin (5-HT) is a chemical in the body that helps regulate mood, sleep, and appetite. It also plays a role in controlling how the body stores fat and manages energy. Think of serotonin as a messenger that helps different parts of the body communicate. Serotonin influenced by how we feel or how our bodies process food.
In the mice missing the ZnT8 gene, serotonin levels in the gut rose, leading to more fat buildup and worse blood sugar control. When serotonin production was blocked, these negative effects were reversed. This suggests that targeting ZnT8 can potentially provide insights for treatments for diabetes management.
The serum serotonin levels in wild-type and ZnT8-deficient mice, demonstrating how serotonin levels are elevated in the latter.
5-HT: Serotonin
WT: wild-type, normal mice
Slc30a8-/-: mice lacking ZnT8 gene
Next, they looked at using a serotonin inhibitor to determine if it’s possible to reverse the fat storage issues seen in ZnT8-deficient mice.
This figure shows the effects of inhibiting serotonin synthesis (via PCPA injection) in ZnT8-deficient mice, which could reverse the fat storage and blood glucose problems. This finding supports their hypothesis of the role of serotonin in regulating fat storage.
PCPA: inhibitor of serotonin
WT-ND-PCPA: normal mice, normal diet, serotonin inhibitor
KO-ND-PCPA: ZnT8 deficient mice, normal diet, serotonin inhibitor
Hope From Research: Exploring alternatives for Diabetes management11 (All figures from this section are from the paper)
In 2019, researchers from Stanford University discovered a novel way to use zinc’s unique properties to potentially improve diabetes treatment. The researchers focused on pancreatic beta cells, which produce insulin and store large amounts of zinc.
The scientists attached a zinc-binding molecule to a drug that has been observed to help beta cells grow. This design ensured the drug was delivered directly to beta cells, improving its effectiveness. This technique is still in the early stages and needs refining to examine the side effects. It has the potential for future techniques for diabetes management. If perfected, this technique can lead to treatments that help the body produce more insulin. The body’s production would occur naturally with latent effects of reducing the burden of diabetes and expensive costs for insulin therapy.
In this study, scientists used a special stain (TSQ) that lights up when it finds zinc (seen on the left). Looking at beta cells from the pancreas, normal cells were stained and brightly lit up (zinc is present). In the other group TSQ+TPEN (on the right), cells were treated with a chemical (TPEN) removing zinc and the stain did not light up. The staining of zinc supports their hypothesis that zinc can be targeted for drug delivery.
TPEN: a chemical that works like a “zinc remover”. It binds tightly to zinc in cells, pulling it away from where it’s normally stored or used. The use of TPEN in this experiment is to see how important zinc is in the process.
TSQ: is a special dye that glows when it finds zinc. Researchers utilize it to understand how much zinc is in a cell and where it is stored and used.
4877-EXT-DBA & 4877-EXT-DPA: Drugs tested for zinc binding and cell growth
PDX-1: marker for a pancreatic protein.
INS: marker for insulin-producing cells.
Ki-67: marker protein found in cells that are actively growing and dividing.
Merge: overlap of these markers, indicating which beta cells are producing insulin & how many of them are actively dividing.
The researchers tested two different drugs (4877-EXT-DBA & 4877-EXT-DPA) on the islet cells to see if they can stimulate the cells to grow and divide, an essential function needed to help individuals with diabetes. These drugs were designed in collaboration Dr. Annes team and Dr. Smith, a medicinal chemist at Stanford University.12 The molecules were modified versions of existing drugs, with some designed to bind zinc tightly and others not (others tested, not shown in this post), to observe how they affect specific pancreatic cells involved in diabetes. The yellow arrows in the figure above point to cells that are actively dividing. This finding indicates that these drugs can help beta cells in the pancreas multiply. A major breakthrough, more beta cells can help blood sugar control for people who have diabetes!
By attaching a zinc-targeting component to a drug that encourages beta cells to grow, scientists were able to direct the drug specifically to the islets. Selective accumulation is an essential step towards understanding targets to promote beta cell replication. Replication is vital for treating diabetes. This focus on the zinc-dependence of drug accumulation provides a strong case for the potential of alternative methods for diabetes management.
Why This Research Matters
Emerging research can lead to innovative therapies that target the root causes of diabetes, offering hope for millions worldwide. Unlocking the secrets of zinc can enable scientists to develop treatments that enhance insulin production, restore metabolic balance, and prevent diabetes-associated complications.
The relationship between zinc and diabetes highlights how even the smallest of elements can play a major role in our lives. Advancing research in the field of metals is crucial for uncovering innovative solutions to global health challenges. Hopefully, we can move towards a future where diabetes becomes more manageable, less expensive, and potentially preventable!
Works Cited:
- Hossain, Md Jamal et al. “Diabetes mellitus, the fastest growing global public health concern: Early detection should be focused.” Health science reports vol. 7,3 e2004. 22 Mar. 2024, doi:10.1002/hsr2.2004
- National Institute of Diabetes and Digestive and Kidney Diseases. Media Library. U.S. Department of Health and Human Services, https://www.niddk.nih.gov/news/media-library/18115. Accessed 6 Dec. 2024.
- “Diagnosis of Diabetes.” Johns Hopkins Diabetes Information, Johns Hopkins Medicine, https://hopkinsdiabetesinfo.org/diagnosis-of-diabetes/.
- Cuthbertson, Joy et al. “Addition of metformin to exogenous glucagon-like peptide-1 results in increased serum glucagon-like peptide-1 concentrations and greater glucose lowering in type 2 diabetes mellitus.” Metabolism: clinical and experimental vol. 60,1 (2011): 52-6. doi:10.1016/j.metabol.2010.01.001
- MacKenzie, Stephanie, and Andreas Bergdahl. “Zinc Homeostasis in Diabetes Mellitus and Vascular Complications.” Biomedicines vol. 10,1 139. 9 Jan. 2022, doi:10.3390/biomedicines10010139
- “Zinc.” Office of Dietary Supplements, U.S. National Institutes of Health, 1 Sept. 2023, https://ods.od.nih.gov/factsheets/Zinc-Consumer/. Accessed 5 Dec. 2024.
- U.S. Department of Agriculture, Agricultural Research Service. FoodData Central. 2024, https://fdc.nal.usda.gov. Accessed 5 Dec. 2024.
- Ahmad, R., Shaju, R., Atfi, A., and Razzaque, M. S. “Zinc and Diabetes: A Connection between Micronutrient and Metabolism.” Cells, vol. 13, no. 16, 2024, p. 1359, https://doi.org/10.3390/cells13161359.
- Olechnowicz, J et al. “Zinc status is associated with inflammation, oxidative stress, lipid, and glucose metabolism.” The journal of physiological sciences : JPS vol. 68,1 (2018): 19-31. doi:10.1007/s12576-017-0571-7
- Mao, Zhuo et al. “Deficiency of ZnT8 Promotes Adiposity and Metabolic Dysfunction by Increasing Peripheral Serotonin Production.” Diabetes vol. 68,6 (2019): 1197-1209. doi:10.2337/db18-1321
- Horton, Timothy M et al. “Zinc-Chelating Small Molecules Preferentially Accumulate and Function within Pancreatic β Cells.” Cell chemical biology vol. 26,2 (2019): 213-222.e6. doi:10.1016/j.chembiol.2018.10.019
- Stanford Diabetes Research Center. “Zinc Chelation: A Siren Song to Draw Regenerative Drugs to the Beta Cell.” Stanford Diabetes Research Center, 22 Feb. 2019, https://sdrc.stanford.edu/news/2019/2/22/zinc-chelation-a-siren-song-to-draw-regenerative-drugs-to-the-beta-cell. Accessed 10 Dec. 2024.