Open access peer-reviewed chapter
Abstract
This book chapter provides an overview of Type 1 diabetes, focusing on the role of beta cells, autoimmunity, genetics, environmental factors, and beta cell health. While genetic factors are also important, environmental factors such as viral infections and dietary factors may trigger or accelerate the development of Type 1 diabetes. Maintaining beta cell health is essential for the prevention and management of Type 1 diabetes. Factors such as glucose toxicity, oxidative stress, and inflammation can contribute to beta cell dysfunction and death. The chapter discusses transplantation of islet cells both primary and stem cell-derived to treat diabetes. The chapter also outlines the stages of Type 1 diabetes development, starting with the pre-symptomatic stage and progressing to the onset of symptoms, the clinical diagnosis, and the eventual need for insulin therapy. Supporting hormones, such as insulin, glucagon, amylin, somatostatin, and incretin hormones, play critical roles in maintaining glucose homeostasis. Finally, the chapter highlights the effect of food on beta cell health and the effect of various drugs and medications used to manage diabetes.
Keywords
- beta cells
- diabetes
- insulin
- autoimmunity
- diabetes medications
1. Introduction
Type 1 diabetes (T1D) is a chronic condition in which the body’s immune system attacks and destroys the insulin-producing cells in the pancreas, called beta cells. Insulin is a hormone that regulates the amount of glucose (sugar) in the bloodstream and allows the body to use it for energy. Without enough insulin, glucose builds up in the blood and can lead to a range of health problems.
T1D is usually diagnosed in children and young adults, although it can occur at any age. The exact cause of T1D is not known, but genetic and environmental factors are thought to play a role. Symptoms of T1D can include frequent urination, increased thirst, extreme hunger, unexplained weight loss, fatigue, and blurred vision.
There is no cure for T1D, but with proper treatment and management, people with the condition can live long and healthy lives. Ongoing research is focused on improving treatments and finding a cure for this chronic disease. This book chapter aims to highlight key aspects of diabetes and beta cells.
2. Autoimmunity and diabetes
Genetics can play a role in the development of type 1 and type 2 diabetes [1, 2, 3, 4]. In the case of T1D, genetic factors can contribute to the destruction of beta cells in the pancreas, which leads to a lack of insulin production. This destruction is often caused by an autoimmune response, where the body’s immune system attacks and destroys the beta cells. The exact cause of this autoimmune response is not fully understood, but both genetic and environmental factors are thought to play a role.
Several genetic factors have been identified that can contribute to the destruction of beta cells in the pancreas and the development of T1D [2]. Some of these factors include:
2.1 Genetic factors
Certain genetic variations have been associated with an increased risk of developing T1D. These variations affect the immune system and can make individuals more susceptible to autoimmune diseases.
Certain variations in the human leukocyte antigen (HLA) genes have been associated with an increased risk of developing T1D [5]. These genes play a key role in regulating the immune system and can affect how the body recognizes and attacks foreign invaders, including beta cells.
Variations in the insulin gene (INS) have also been associated with an increased risk of developing T1D [6]. This gene plays a role in the production of insulin, and variations can affect the development and function of beta cells [7, 8, 9, 10].
The protein tyrosine phosphatase non-receptor type 22 (PTPN22) gene is involved in regulating the immune system and has been associated with an increased risk of developing T1D [11, 12, 13]. The Trp620 variant of PTPN22 gene is also associated with other autoimmune disorders [14, 15, 16].
The cytotoxic T-lymphocyte antigen 4 (CTLA4) gene encodes a molecule that functions as a negative regulator of T-cell activation. Polymorphisms in this gene are involved in regulating the immune system and has been associated with an increased risk of developing T1D [17, 18, 19, 20].
Other genes involved in immune system regulation, such as IL2RA/CD25 [21, 22], IL7RA, SUMO4 [23, 24] and IFIH1 [25, 26], have also been associated with an increased risk of developing T1D.
Given the autoimmune basis of T1D autologous hematopoietic stem cell transplantation (auto-HSCT), a type of auto-transplantation where hematopoietic stem cells are removed from a patient, enriched and introduced back into the patient [27, 28, 29, 30] could regenerate immune tolerance against auto-antigens and be associated with lasting and complete remission of T1D.
2.2 Environmental factors
Environmental factors such as viral infections, toxins, and diet have also been linked to the development of T1D [31]. Some researchers believe that viral infections can trigger the immune system to attack the beta cells, leading to the development of T1D. In particular, enteroviruses have been linked to an increased risk of developing T1D [32, 33]. Exposure to toxins such as nitrosamines [34] and bisphenol A (BPA) [35] has also been associated with an increased risk of developing T1D.
2.3 Other factors
Other factors that may play a role in the development of autoimmune diabetes include the gut microbiome [36, 37], stress [38], and low levels of vitamin D [39].
Overall, the development of autoimmune diabetes is likely due to a combination of genetic and environmental factors. In the case of type 2 diabetes, genetics can also play a role in the development of the condition [40, 41]. Certain genes can affect how the body processes insulin, leading to insulin resistance and an increased risk of developing type 2 diabetes. However, lifestyle factors such as diet, exercise [42] and stress [38] also play a significant role in the development of type 2 diabetes.
3. Beta cell health
The classic view of immune response gone wrong in T1D is that autoreactive T cells mistakenly destroy healthy β-cells. There is an alternative view that in response to cell stress an unhealthy β-cell provokes an immune attack that negatively effects the source of insulin [43, 44]. Restoring β-cell health therefore is proposed as an important component of treating T1D. Beta cell health can be affected by a variety of factors, including:
3.1 Glucose and lipid levels
Chronic exposure to high levels of glucose and lipids in the blood can lead to beta cell dysfunction and damage, impairing their ability to produce and release insulin effectively. The beta cell workload hypothesis [45] is a theory that suggests that chronic exposure of beta cells in the pancreas to high levels of glucose and lipids (fatty acids) can lead to beta cell dysfunction and the development of type 2 diabetes.
3.2 Oxidative stress
Beta cells are known to express lower levels of antioxidant enzymes like catalase and glutathione peroxidase that are required to protect against reactive oxygen species (ROS), thus making them have higher susceptibility to ROS damage [46]. This oxidative stress can damage cell membranes, DNA, and other cellular components, impairing beta cell function [47, 48]. Oxidative stress leads to loss of β-cell identity by downregulation of maturity genes like MAFA and PDX1, and upregulation of progenitor genes like SOX9 and HES1 [49, 50]. This makes beta cells less beta-cell like and leads to further decrease in insulin secretion.
3.3 Age
Beta cell function tends to decline with age, contributing to an increased risk of developing diabetes in older individuals [51, 52]. This decline in beta cell function may be due to a combination of factors, including increased oxidative stress, inflammation, and mitochondrial dysfunction, which can accumulate over time and impair beta cell survival and function.
In addition to these cellular changes, aging is also associated with changes in hormonal and metabolic regulation, which can further contribute to beta cell dysfunction. For example, age-related changes in insulin sensitivity and glucose metabolism can increase the demand on beta cells, leading to increased oxidative stress and cellular damage. Furthermore, changes in hormones such as growth hormone and cortisol, which occur with aging, can impair beta cell function and contribute to the development of diabetes.
3.4 Other factors
Inflammation and genetic factors: Chronic inflammation can also contribute to beta cell dysfunction, damage [53] and dedifferentiation [54], as well as impairing insulin sensitivity [55]. Certain genetic variations can affect beta cell function and increase the risk of developing diabetes. These factors have been discussed in detail in Section 2.1.
Obesity and physical activity: Excess body fat, particularly abdominal fat, can contribute to beta cell dysfunction and insulin resistance, increasing the risk of developing diabetes [56, 57]. Regular physical activity can improve beta cell function and insulin sensitivity, reducing the risk of developing diabetes [58].
Medications and environmental toxins: Certain medications, such as corticosteroids, can impair beta cell function and increase the risk of developing diabetes. These effects have been discussed elsewhere in this chapter. Exposure to environmental toxins, such as bisphenol A (BPA) and phthalates, can also impair beta cell function and increase the risk of developing diabetes. These effects have been discussed in Section 2.2.
Overall, maintaining beta cell health is important for preventing and managing diabetes, and a healthy lifestyle that includes regular physical activity, a balanced diet, and avoidance of environmental toxins can help support beta cell function.
4. Islet cell transplants
4.1 Islet cell auto-transplantation
Auto-transplantation is a type of islet transplantation where the islet cells are taken from the patient’s own pancreas and transplanted back into the patient’s liver [59]. This procedure is typically used in cases where the patient’s pancreas has been removed or damaged due to disease or injury. Auto transplantation may also be used to treat chronic pancreatitis [60], a condition that causes inflammation and scarring of the pancreas, which can lead to diabetes.
Stem Cell Derived Beta Cell (SC-β cell) transplantation is a special type of auto-transplantation where β cells derived from a patient’s stem cells can be transplanted into the patient [61, 62]. SC-β cell therapy is still in its early stage where work is being done to understand how to prevent cell death post engraftment [63, 64].
4.2 Islet cell allo-transplantation
Allotransplantation is a type of islet transplantation where the islet cells are taken from a donor pancreas and transplanted into the recipient’s liver [59]. This procedure is typically used in patients with T1D who have severe hypoglycemia unawareness or difficult-to-control blood sugar levels despite optimal medical therapy. Allotransplantation can provide long-term insulin independence for some patients, but it requires immunosuppressive medications to prevent rejection of the transplanted cells.
Both auto-transplantation and allotransplantation have advantages and disadvantages. Auto-transplantation avoids the need for immunosuppressive medications, as the transplanted cells are from the patient’s own body, but it may not be effective for all patients with diabetes. Allo-transplantation can provide long-term insulin independence, but it requires immunosuppressive medications, which can have side effects and increase the risk of infections and other complications.
In summary, both auto-transplantation and allo-transplantation of islet cells are potential strategies to treat diabetes. However, their use depends on the individual patient’s medical history and condition.
5. Stages of type 1 diabetes development
JDRF (formerly known as the Juvenile Diabetes Research Foundation) has identified several stages of T1D development, based on the progression of autoimmunity and beta cell destruction [65]. These stages are:
Stage 1—Autoimmunity: During this stage, the immune system begins to attack the beta cells in the pancreas, but there are no symptoms of diabetes yet. This stage can last for months or even years.
Stage 2—Abnormal blood sugar levels: During this stage, the destruction of beta cells has progressed to the point where blood sugar levels begin to rise, but there are still no symptoms of diabetes. This stage is also known as preclinical T1D.
Stage 3—Clinical onset of diabetes: During this stage, the destruction of beta cells has reached a critical threshold, and the individual begins to experience symptoms of diabetes, such as frequent urination, excessive thirst, and weight loss. At this point, the individual is diagnosed with T1D.
6. Supporting hormones for glucose homeostasis
There are supporting hormones that complement insulin’s role in regulating glucose levels in the body. Glucagon, amylin, somatostatin, and incretin hormones are all involved in regulating glucose homeostasis in the body [66]. Here are brief summaries of their roles:
Glucagon is produced by the alpha cells of the pancreas in response to low blood glucose levels. Its main function is to stimulate the production and release of glucose from the liver, increasing blood glucose levels [67].
Amylin is co-secreted with insulin from the beta cells of the pancreas. Its main function is to slow down gastric emptying and suppress glucagon secretion, which helps to regulate blood glucose levels [68].
Somatostatin is produced by the delta cells of the pancreas and inhibits the release of insulin, glucagon, and other hormones that affect glucose metabolism [69].
Incretin hormones, such as glucagon-like peptide-1 (GLP-1) and gastric inhibitory polypeptide (GIP), are produced by the intestines in response to food intake. They stimulate insulin secretion from the pancreas, inhibit glucagon secretion, and slow down gastric emptying, all of which help to regulate blood glucose levels [70].
Overall, the actions of these hormones work together to maintain glucose homeostasis in the body. Insulin and amylin work to lower blood glucose levels, while glucagon and incretin hormones work to increase or decrease blood glucose levels depending on the body’s needs. Somatostatin plays a regulatory role by inhibiting the secretion of other hormones to maintain balance. Dysfunction in any of these hormones can lead to impaired glucose regulation, which can contribute to the development of diabetes.
7. Infections associated with diabetes
People with diabetes are generally more susceptible to infections due to a weakened immune system [71]. Some infections that are particularly associated with diabetes include:
7.1 Urinary tract infections (UTIs)
There are several reasons why people with diabetes are more susceptible to urinary tract infections (UTIs). High blood glucose levels can cause bacteria to grow in the urinary tract, leading to UTIs [72]. Diabetes can damage nerves that control bladder function, leading to incomplete bladder emptying and increased urine retention, which can also increase the risk of UTIs [73, 74]. Diabetic patients also tend to have increased adherence of bacteria to uroepithelial cells [75]. There is a downregulation of the antimicrobial peptide psoriasin and this increases bacterial burden in the urinary bladder [76]. This too may play a role in the pathogenesis of UTIs in diabetics.
7.2 Skin infections
High blood glucose levels can lead to dry, cracked skin, making it easier for bacteria to enter and cause infections. High blood glucose levels can also promote the growth of certain types of bacteria, leading to an overgrowth of harmful bacteria on the skin. Poor wound healing and decreased immunity can also contribute to the development and persistence of skin infections in people with diabetes. Common skin infections in people with diabetes include cellulitis, styes, and boils [77].
7.3 Fungal infections
High blood glucose levels can also create a favorable environment for fungal infections, particularly in the mouth, genital area, and feet. Yeasts like Candida spp. can utilize glucose as a viable nutrient [78]. Since diabetics with uncontrolled hyperglycemia have increased glucose in their secretions, they are at a higher risk for fungal infection. Diabetes can create an imbalance in the body’s natural microbiota, which can promote fungal growth [79]. Common fungal infections in people with diabetes include oral thrush, vaginal yeast infections, and athlete’s foot [80].
7.4 Respiratory infections
People with diabetes may be more susceptible to respiratory infections, such as pneumonia and bronchitis, due to a weakened immune system [81]. Diabetes can damage the small blood vessels and nerves in the lungs [82], making it more difficult to clear mucus and other secretions from the airways. This can create an environment that is more conducive to bacterial growth and increase the risk of respiratory infections.
7.5 Tuberculosis (TB)
People with diabetes are at increased risk of developing TB, a bacterial infection that mainly affects the lungs [83] due to several factors. The weakening of the immune system makes it harder for the body to fight off infections such as TB. This can allow the TB bacteria to take hold and multiply, leading to an active TB infection. Diabetes can also increase the risk of latent TB infection (LTBI), which occurs when a person is infected with TB bacteria but does not develop active TB disease [84, 85]. People with diabetes are more likely to progress from LTBI to active TB disease, as diabetes weakens the immune system’s ability to control the TB bacteria. Finally, people with diabetes may have other risk factors for TB, such as malnutrition, poverty, and overcrowding, which can increase their risk of exposure to TB bacteria [86].
It’s important for people with diabetes to practice good hygiene and take steps to prevent infections, such as keeping blood glucose levels under control, washing hands frequently, and getting vaccinated against preventable infections like the flu and pneumonia.
8. Foods affecting β-cells
In this section we will cover vitamins, supplements, and foods that improve or impair β-cell function and ultimate blood glucose control [87]. Consuming too much carbohydrates, especially those with a high glycemic index increases stresses on β-cells and risk of diabetes. The key to preventing insulin resistance and protecting β-cells is to increase intake of foods that allow blood sugar to rise slowly. Dietary fiber slows digestion and release of sugars and that is key to reduce blood sugar spikes. Simple carbohydrates like the sugars found in candy, syrups, etc. are easily digestible causing rapid increase in blood sugar levels and stressing the β-cells to rapidly produce large amounts of insulin.
Vitamin deficiencies have been linked with increased risk for diabetes mellitus.
8.1 Vitamin A (VA)
Vitamin A (VA) is the name of a group of fat-soluble retinoids [88]. In animal models, VA deficiency has been linked with β-cell death, insulin insufficiency, and hyperglycemia [89]. While incorporation of VA in the diet has been shown to improve hyperglycemia and glucose tolerance [90]. Islet stellate cells (ISCs) are VA-storing cells in pancreatic islets. ISCs when activated are implicated in islet fibrosis which reduces β-cell mass and glucose tolerance [91]. VA deficiency reduces islet function by activating ISCs, while reintroduction of dietary VA can restore pancreatic VA levels, endocrine hormone profiles, and inhibit ISCs activation [92].
8.2 Vitamin B6 (VB6)
Vitamin B6 is a cofactor in various metabolic reactions that regulate glucose, lipids, and amino acids [93]. Because of this VB6 deficiency impairs glucose and lipid metabolism. Mutations in genes involved in vitamin B6 metabolism cause diabetes [94, 95]. Reduced VB6 availability affects T-cell composition [96], which may contribute to pancreatic islet autoimmunity in T1D.
8.3 Vitamin B9 or folate (VB9)
Depletion of VB9 causes oxidative stress, abnormal glucose and lipid metabolism, insulin resistance, and endothelial disruption [97]. Folate supplementation lowers insulin resistance and improves glucose metabolism [98, 99]. While the exact mechanisms linking folate deficiency and beta cell health are not yet fully understood, it is thought that folate may play a role in regulating the expression of genes involved in beta cell function and survival [100].
8.4 Vitamin B12 (VB12)
Vitamin B12 is a cobalt containing vitamin and is therefore also called as cobalamin [101]. VB12 has many physiological functions but its effect on diabetes comes from its role as a cofactor for methionine synthase which catalyzes the conversion of homocysteine to the essential amino acid methionine [102]. Homocysteine promotes oxidative stress, autoimmunity, insulin resistance, β-cell dysfunction, systemic inflammation, obesity, and endothelial dysfunction. Reduced VB12 availability affects homocysteine levels and through that route promote β-cell dysfunction [103, 104, 105].
8.5 Vitamin C or ascorbic acid (VC)
Vitamin C cannot be synthesized by humans and has to be obtained from diet [106]. Ascorbic acid acts as a cofactor for 15 mammalian enzymes [107]. Some studies suggest that VC deficiency predisposes to T2DM [108] and VC supplementation reduced fasting glucose levels in patients with T2DM [109]. VC administration has been shown to reduce blood glucose and increase superoxide dismutase and glutathione levels, resulting in reduced insulin resistance by lowering oxidative stress [110]. VC prevents sorbitol accumulation and glycosylation of proteins and thus reduces the microvascular complications of diabetes [111]. Overall, while the relationship between ascorbic acid deficiency and beta cell health is still not fully understood, there is evidence to suggest that optimizing ascorbic acid status through a healthy diet or supplementation may be beneficial for preserving beta cell function and reducing the risk of diabetes or its progression [112].
8.6 Vitamin D or calciferol (VD)
Vitamin D is a fat soluble vitamin that is obtained through diet and endogenously when ultraviolet (UV) rays from sunlight strike the skin and trigger VD synthesis [113]. VD deficiency may promote β-cell autoimmunity [97, 114], cause insulin resistance, insulin insensitivity, and impaired insulin secretion through β-cell dysfunction [115, 116, 117, 118, 119]. VD has been shown to prevent epigenetic alterations associated with insulin resistance and diabetes [120]. Some clinical studies [121, 122, 123, 124] have shown that calciferol supplementation was associated with the improvement of insulin secretion while others have not shown a statistically significant benefit [125, 126, 127]. Overall, while the relationship between VD deficiency and beta cell health is still not fully understood, optimizing calciferol status through a healthy diet or supplementation may be beneficial for preserving beta cell function and reducing the risk of T1D.
8.7 Vitamin E (VE)
Vitamin E is the collective name for a group of eight fat-soluble compounds that have distinctive antioxidant activities [128]. As a dietary anti-oxidant VE inhibits lipid per oxidation [129]. Significant correlation has been observed between the increased blood sugar levels and the depletion of the antioxidants [130] and higher dietary anti-oxidant capacity is inversely associated with prediabetes [131]. VE deficiency is associated with prediabetes in apparently healthy individuals [132]. In clinical trials VE supplementation has been shown to protect residual beta-cell function in insulin-dependent diabetes mellitus [133, 134].
8.8 Vitamin K (VK)
Vitamin K (VK) is the generic name for a group of fat-soluble vitamins with a common structure that includes phylloquinones (VK1) and menaquinones (VK2) [135] and can regulate glycemic status [136, 137, 138]. Menaquinone-4 is the predominant form of VK2, which is present in large amounts in the pancreas [139]. Human studies indicate that VK-dependent protein osteocalcin [140], anti-inflammatory properties, and lipid-lowering effects may mediate the beneficial function of vitamin K in insulin sensitivity and glucose tolerance [140]. Glucose-stimulated insulin secretion is higher in pancreatic islet cells that have been treated with VK2 [139]. Vitamin K supplementation has been found to be associated with significant reductions in blood glucose, increased fasting serum insulin, reduced hemoglobin A1c and increased ß-cell function in diabetic animal studies [137].
9. Drugs and medications for diabetes
There are several classes of drugs and medications used to treat or manage diabetes [141, 142]. Here is a summary of the most common types:
Metformin is a biguanide medication that is often prescribed as the first-line treatment for type 2 diabetes [143]. It helps to lower blood glucose levels by reducing glucose production in the liver and improving insulin sensitivity [144].
Sulfonylureas are a class of medications that stimulate insulin secretion from the pancreas, helping to lower blood glucose levels. They close ATP-sensitive K-channels in the beta-cell plasma membrane. This closure causes depolarization of the cell membrane, which triggers the release of insulin into the bloodstream [145]. Examples of sulfonylureas include glyburide, glipizide, and glimepiride [146].
Dipeptidyl Peptidase-4 (DPP-4) inhibitors, also known as gliptins, are a class of medications that increase insulin secretion and decrease glucagon secretion, helping to lower blood glucose levels. They work by blocking the action of the enzyme DPP-4, which is responsible for breaking down incretin hormones such as GLP-1 (glucagon-like peptide 1) and GIP (glucose-dependent insulinotropic peptide) [147]. By blocking DPP-4, gliptins increase the levels of these hormones in the body. GLP-1 and GIP stimulate the secretion of insulin from the beta cells in the pancreas, reduce the production of glucose by the liver, and slow the emptying of food from the stomach. Examples of gliptins include sitagliptin, saxagliptin, and linagliptin [148].
GLP-1 receptor agonists are a class of medications that mimic the action of incretin hormones, stimulating insulin secretion, suppressing glucagon secretion, and slowing down gastric emptying. Examples include exenatide, liraglutide, and dulaglutide [149].
SGLT2 inhibitors are a class of medications that work by blocking the reabsorption of glucose in the kidneys, leading to increased urinary glucose excretion and lower blood glucose levels. Examples include canagliflozin, dapagliflozin, and empagliflozin.
Insulin is a hormone that is essential for the regulation of blood glucose levels. People with T1D and some with type 2 diabetes may require insulin therapy to manage their condition. Insulin can be administered through injections or an insulin pump [150].
It’s important to note that diabetes treatment is highly individualized, and the choice of medication depends on a variety of factors, such as the type and severity of diabetes, other medical conditions, and the patient’s preferences and lifestyle. A healthcare provider can help determine the most appropriate treatment plan for each individual.
10. Conclusion
Beta cell health is critical for the development and management of T1D, as these cells produce insulin, the hormone that regulates blood glucose levels. Current approaches to preserving and promoting beta cell health in T1D include optimizing blood glucose control, reducing inflammation, and minimizing exposure to environmental toxins that can damage beta cells. Scientists are also exploring the use of targeted immunotherapies to prevent or reverse the autoimmune destruction of beta cells.
Future directions in beta cell health and T1D treatment include the development of regenerative therapies aimed at restoring beta cell function. These therapies may involve the use of stem cells, gene editing techniques, or biomaterials that promote beta cell growth and survival.
In addition to these approaches, precision medicine and personalized care are also gaining momentum in the T1D field. This involves tailoring treatment plans to the specific needs and characteristics of individual patients, such as their genetic profile, immune system status, and environmental exposures.
Advances in technology are also transforming the landscape of T1D care and management. For example, continuous glucose monitoring systems and closed-loop insulin delivery systems are becoming increasingly sophisticated and may improve outcomes for individuals with T1D.
Overall, a multifaceted approach that includes a focus on preserving and promoting beta cell health, precision medicine, and technological advancements offers promise for improving outcomes and quality of life for individuals with T1D.
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