Diabetes & Obesity

Diabetes and its molecular basis

Diabetes mellitus is a group of metabolic disorders characterized by high blood sugar levels. There are two main types of diabetes: Type 1 (also known as T1D) is an autoimmune disease in which the immune system attacks and destroys insulin-producing beta cells in the pancreas, resulting in an insulin deficiency. Type 2 (also known as T2D) is the most common form, and it involves insulin resistance and reduced glucose uptake. Unless they are effectively managed, both types can lead to long-term complications, including cardiovascular disease, kidney problems, nerve damage and vision issues. (1, 2)

Insulin (INS) is a hormone produced by pancreatic beta cells that plays an essential role in glucose metabolism. In healthy individuals, insulin binds to the insulin receptor (INSR) and triggers a cascade of intracellular signals that ultimately result in the translocation of glucose transporter proteins, such as GLUT4, to the cell membrane. This translocation allows glucose to enter the cells, where it is used for energy production or stored for later use. In both type 1 and type 2 diabetes, there are abnormalities in this process, although the underlying mechanisms differ. (1)

In type 1 diabetes, the immune system mistakenly targets and destroys the pancreatic beta cells, resulting in the production of little or no insulin. Without sufficient insulin, glucose cannot enter cells effectively, and this leads to elevated blood sugar levels. Individuals with type 1 diabetes require lifelong insulin replacement therapy to manage the condition. The exact cause of this autoimmune response is still under investigation, but it is believed to be triggered by a combination of genetic susceptibility and environmental factors, such as diet, exposure to certain enteroviruses, vitamin D availability and gut microbiome health. (2)

Type 2 diabetes, on the other hand, is characterized by a combination of insulin resistance and inadequate insulin secretion. Insulin resistance occurs when the body's cells become less responsive to the effects of insulin, impairing their ability to take in glucose. This can be influenced by genetic factors and is strongly associated with obesity and a sedentary lifestyle. Over time, the pancreas struggles to produce enough insulin to compensate for the resistance, leading to relative insulin deficiency. While insulin resistance is a hallmark of type 2 diabetes, the exact mechanisms responsible for its development are complex and not fully understood. (1)

Initially, the pancreatic beta cells try to compensate for insulin resistance and maintain normal blood sugar levels by increasing insulin production and secretion. But over time, the beta cells become exhausted and unable to sustain the increased insulin requirements, resulting in inadequate insulin secretion. (1)

Two major regulators of insulin sensitivity are the peroxisome proliferators-activated receptor γ (PPARγ) along with the mechanistic target of rapamycin (mTOR). PPARγ is a nuclear hormone receptor and is a master regulator of adipogenesis, making it a major therapeutic target in insulin resistance. mTOR is a Ser/Thr protein that can form two complexes, mTORC1 and mTORC2. mTORC1 inhibits insulin signaling via its substrate S6K1. mTORC2 exhibits a positive effect on glucose uptake and tolerance. (3)

Maturity onset diabetes of the young (MODY) is a less common type of diabetes that is characterized by early onset (typically before the age of 25) and a family history of diabetes. MODY is caused by genetic mutations that affect the function of pancreatic beta cells and lead to impaired insulin production. Unlike type 1 and type 2 diabetes, MODY is not typically associated with insulin resistance or autoimmune processes. Instead, the molecular basis of MODY primarily involves defects in the genes responsible for beta cell function and insulin secretion. (4)

Around 70% of MODY cases can be attributed to variations in the glucokinase (GCK) and hepatocyte nuclear factor 1-alpha (HNF1A) genes, giving rise to MODY2 and MODY3, respectively. The GCK enzyme is critical to glucose metabolism, and it regulates blood sugar levels by controlling the rate at which glucose is converted to glucose-6-phosphate, an early step in glucose utilization within the cells. In MODY2, GCK mutations result in a malfunctioning form of the glucokinase enzyme, which requires higher levels of glucose to become fully active. As a result, people with this condition cannot respond to typical fluctuations in blood glucose levels and experience mild hyperglycemia, even if they have not eaten. (4)

HNF1A is a transcription factor involved in the normal development and function of the pancreas and liver, particularly in the regulation of insulin production in the beta cells of the pancreas. In MODY3, mutations in the HNF1A gene lead to a dysfunctional transcription factor, which in turn disrupts the regulation of genes involved in insulin secretion and glucose metabolism. For example, HNF1A mutations can impact the expression of the INS gene, leading to reduced insulin production by pancreatic beta cells. These mutations can also dysregulate glucose transporter proteins, such as GLUT2 and GLUT4, resulting in impaired glucose uptake by cells and contributing to hyperglycemia. HNF1A mutations can also affect GCK expression, further disrupting glucose sensing and insulin secretion. (4)

Obesity and its molecular mechanisms

Obesity involves an excessive accumulation of body fat and is defined as a body mass index above 30 kg/m². While genetic predisposition can play a role in the development of obesity, environmental and lifestyle factors also contribute. Obesity increases the risk of various health conditions, including diabetes, cardiovascular diseases, certain cancers and musculoskeletal problems. (5)

Several molecular mechanisms contribute to the development and progression of obesity. One key mechanism is the regulation of appetite and energy balance. Leptin is a hormone produced by fat cells that plays a vital role in communicating feelings of fullness and regulating energy storage to the brain. In obesity, there is often a dysregulation of leptin signaling, leading to a reduced sensitivity to its effects. This can result in increased food intake and reduced energy expenditure, contributing to weight gain. (5)

Insulin resistance is another important molecular mechanism associated with obesity. In obesity, adipose tissue releases inflammatory molecules called adipokines, which interfere with insulin signaling. This leads to reduced insulin sensitivity in tissues such as muscle and liver, resulting in elevated blood glucose levels and further weight gain. (6)

Chronic low-grade inflammation is also seen in obesity and contributes to its metabolic complications. Adipose tissue releases pro-inflammatory cytokines, such as tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6), which disrupt insulin signaling and promote insulin resistance. Inflammation in obesity is thought to be triggered by an increased influx of immune cells into adipose tissue and is linked to the activation of inflammatory signaling pathways, such as the nuclear factor-kappa B (NF-κB) pathway. (6)

The obesity–diabetes connection

There is a strong association between obesity and the development of type 2 diabetes. Obesity contributes to insulin resistance and to compensate, the body produces more insulin. But eventually, the pancreas can no longer keep up with this demand, resulting in insufficient insulin production. This imbalance between insulin resistance and inadequate insulin secretion contributes to the development of type 2 diabetes. (7) Type 1 diabetes is not directly linked to obesity, but individuals can develop obesity and insulin resistance over time due to prolonged insulin therapy. (5)

References

1. Rachdaoui N. Insulin: The Friend and the Foe in the Development of Type 2 Diabetes Mellitus. Int J Mol Sci. 2020 Mar 5;21(5):1770. doi: 10.3390/ijms21051770.

2. DiMeglio LA, Evans-Molina C, Oram RA. Type 1 diabetes. Lancet. 2018 Jun 16;391(10138):2449-2462. doi: 10.1016/S0140-6736(18)31320-5.

3. Petersen MC, Shulman GI. Mechanisms of Insulin Action and Insulin Resistance. Physiol Rev. 2018 Oct 1;98(4):2133-2223. doi: 10.1152/physrev.00063.2017.

4. Sousa M, Rego T, Armas JB. Insights into the Genetics and Signaling Pathways in Maturity-Onset Diabetes of the Young. Int J Mol Sci. 2022 Oct 26;23(21):12910. doi: 10.3390/ijms232112910.

5. Obradovic M, et al. Leptin and Obesity: Role and Clinical Implication. Front Endocrinol (Lausanne). 2021 May 18;12:585887. doi: 10.3389/fendo.2021.585887.

6. Wu H, Ballantyne CM. Metabolic Inflammation and Insulin Resistance in Obesity. Circ Res. 2020 May 22;126(11):1549-1564. doi: 10.1161/CIRCRESAHA.119.315896.

7. Chobot A, Górowska-Kowolik K, Sokołowska M, Jarosz-Chobot P. Obesity and diabetes-Not only a simple link between two epidemics. Diabetes Metab Res Rev. 2018 Oct;34(7):e3042. doi: 10.1002/dmrr.3042.