Diabetes

diabetes

Two types of Diabetes

Diabetes is described by the body’s inability to produce insulin, type 1 diabetes, or to respond to insulin, type 2 diabetes. Type 2 diabetes represents 90% of all diabetes patients and is characterized by defects in insulin sensitivity leading to hyperglycaemia and the disruption of normal glucose metabolism.

Insulin

The major function of insulin is to take care of nutrients entering into the blood circulation during feeding. One of these components, glucose, is rapidly being taken care of after feeding and transported into different cells for immediate or later use. It is very important to maintain a very precise blood glucose level. High levels will damage cells (organs) and to low level will disable normal cell and body function.

Type 2 diabetes

Type 2 diabetes is a complex multi-factorial disorder. Understanding of how the disease develops increases, and environmental factors like over-consumption of food and lack of exercise leading to obesity, is found to be a major risk factor. Glucose, or sugar, enters the bloodstream after a meal and the body’s normal response is to release insulin from the pancreas in response to rising blood glucose levels. Insulin then acts as a key, opening cells to allow glucose in from the bloodstream and to be stored in the form of “harmless” glycogen. The efficiency of the insulin to remove excess glucose from outside and inside the cells is crucial for not inflicting oxidative stress causing cellular damage. Once inside the cells, the glucose can additionally be turned into energy that the body needs to function normally.

Type 2 diabetes develops when muscle, fat and liver cells fail to respond normally to insulin. This failure to respond is called insulin resistance. The pancreas initially compensate for this insulin resistance by increasing insulin output. Over time, pancreatic cells ”burn out” and become unable to produce enough insulin to maintain normal glucose levels. Eventually, type 2 diabetes may thus develop into a type 1 like state.

Diabetes complications

High blood glucose levels causes tissue damage by increased glycation of proteins and elevated ROS production, in particular through increased NAD(P)H-oxidase activity. Initially this may lead to micro-vascular impairment as in the kidneys (nephropathy), eye (retinopathy) and nerves (neuropathies). On prolonged poorly controlled hyperglycaemia macro-vascular damage may develop resulting in severe cardiovascular problems like infarctions.

Background of target mechanism of NOX4 in Diabetic Retinopathy

Reactive oxygen species (ROS), including hydrogen peroxide and superoxide, are known to play a dual role in physiology. They are essential for normal physiological processes, such as cell signaling and immune response.

However, excessive production of ROS or impaired antioxidant defense mechanisms can lead to oxidative stress and damage to cells and tissues.

NADPH oxidase (NOX) enzymes, including the isoform NOX4, are a major source of ROS generation in various cells and tissues. NOX enzymes are membrane-bound proteins that transfer electrons across the membrane, leading to the production of superoxide. NOX4, in particular, has unique characteristics compared to other isoforms. It is regulated primarily by gene expression rather than the assembly of subunits, and it can generate hydrogen peroxide directly within the enzyme.

The major hazard to public health are the quick growth of diabetes that is expected to increase from 451 million cases in 2017 (age 18-99 years) to 693 million in 2045 (Cho et al., Diabetes Research and clinical Practice 138, 2018, 271-281). Both type 1 and type 2, individuals face challenges in maintaining normal glucose levels in the blood. This chronic exposure to hyperglycemia, along with other metabolic abnormalities like dyslipidemia and hypertension, contributes to the development of oxidative stress in several organs. The increased activity of NOX enzymes, including NOX4, plays a significant role in this process. Elevated levels of ROS generated by NOX4 can lead to damage in various organs.

Glucox Biotech AB have generated several NOX4 specific and selective inhibitors.

To develop safe and efficient pharmaceuticals targeting NOX activity – it is highly important with surgically precision inhibit the specific isoform. To use general quenching antioxidants may contra productive. This is the reason for several of the contradictive results that has been published in this area of research.

Diabetic Retinopathy

Diabetic retinopathy (DR) is one of the most frequent chronic complications of diabetes. In the context of the retina, NADPH oxidase 4 (NOX4) is a major isoform expressed in retinal endothelial cells. In DR, which is characterized by pathological changes in retinal blood vessels, NOX4-mediated ROS production plays a crucial role in the development and progression of the disease. The abnormal growth of blood vessels, leakage of fluid, and subsequent damage to retinal tissue contribute to vision loss and, in severe cases, blindness.

Managing oxidative stress and inhibiting excessive NOX activity, including NOX4, are potential therapeutic targets for preventing or treating diabetic complications such as DR. By reducing ROS levels and maintaining a healthier redox balance, it may be possible to mitigate the harmful impact on various organs and improve patient outcomes.

GLX7013114 as promising therapeutic candidate in DR treatment.

In the latest GB publication “Topically Administered NOX4 Inhibitor, GLX7013114 Is Efficacious in Treating the Early Pathological Events of Diabetic Retinopathy”, Diabetes Volume 72 May 2023. The impact of elevated NOX4 activity was clearly stated. GB believe that the therapeutic efficacy using GLX7013114 is based on NOX4 inhibition acting on several pathological mechanisms causing the DR development.