Impact of Altered Metabolic Interorgan Crosstalk in Type 2 Diabetes

Pathophysiology of type 2 diabetes and the impact of altered metabolic interorgan crossrtalk presented by R. M. Sparjan Samuvel 1

HERO vs VILLAIN Fate of Glucose Co-actors of Glucose Mechanism

Diabetes Mellitus: Diabetes melilotus is a devastating chronic metabolic disorder characterized by dysregulated insulin secretion leading to altered metabolism (hyperglycemia, dyslipidemia). Metabolic interorgan crosstalk: Metabolic interorgan crosstalk refers to how organs communicate with each other through secreted factors, affecting health and disease. Secreted factors are metabolites (substances produced during metabolism). The pancreas, liver, adipose tissue, and muscles are major organs involved in glucose and lipid metabolism, and they communicate through metabolites.

Organokines: Organokines are signaling molecules released by organs like the liver, adipose tissue, and muscles. They can influence how the body uses insulin and glucose, and are involved in developing diseases like type 2 diabetes.

Challenges in studying metabolite levels: Researchers use metabolomics to analyze these metabolites, but prior studies have shown conflicting results. For example, some studies showed increased levels of certain amino acids (building blocks of proteins) in people with T2D, while others showed a decrease. This inconsistency might be due to factors like the type of sample used (blood, urine etc.) and limitations in the technology. Specific metabolites and their potential link to T2D: Amino acids: Isoleucine, leucine, tyrosine, phenylalanine, alanine, and glutamate are some amino acids that appear to be elevated in T2D. However, it's unclear whether these changes cause or are consequences of the disease. Carbohydrates: High blood sugar (glucose) is a hallmark of T2D. Other sugars like mannose and fructose may also be elevated. Nucleotides: These molecules are involved in various cellular processes. Uridine, trimethylamine, and glyoxylic acid are some examples of nucleotides with increased levels in T2D. Interestingly, similar changes are observed in type 1 diabetes as well. Lipids: Molecules like fats and cholesterol are crucial for energy storage. Studies suggest that imbalances in certain fats (like palmitic acid) and fat transporters (carnitine) might be linked to T2D.

1. Free-Fatty acid: FFAs can come from the diet or be made in the body through a process called de novo lipogenesis, which mainly happens in the liver and fat tissue. FFAs can contribute to insulin resistance, which is when cells don't respond properly to insulin. FFAs can damage pancreatic islet cells, which are responsible for producing insulin. FFAs can also cause inflammation in various tissues. This experiment investigated the role of the liver in fatty acid metabolism and how it affects insulin sensitivity using a special type of mouse. Consequences of these issues Long-term effects on the mice The mouse model Cdk1 knockout (cKO) Hyperinsulinemia High blood free fatty acids (FFAs) Impaired fat burning (FAO) Initial boost in insulin secretion Insulin resistance Increased fat breakdown (lipolysis) Fatty liver disease (steatosis)

2. Diacylglycerol (DAG): DAG and its role in insulin resistance: DAG buildup in muscles and the liver is linked to insulin resistance, a hallmark of metabolic diseases and inflammation. DAG activates an enzyme called protein kinase C (PKC), which disrupts insulin receptor signaling, leading to insulin resistance. Interestingly, insulin resistance itself might also trigger more fat storage, creating a vicious cycle. How DAG levels are regulated: Elevated free fatty acids (FFAs) in the blood can lead to more DAG production. DAG is a building block for triglycerides (TAG), the main form of fat storage. DAG can be synthesized in multiple ways: From monoacylglycerol by an enzyme called monoacylglycerol acyltransferase. o From breaking down triglycerides and phospholipids by specific enzymes. o From phosphatidic acid through the action of proteins called LPIN1 and LPIN3. o

3. Ceramides: Ceramides and Insulin Resistance: Ceramides are lipids linked to both T1D and T2D, but not all ceramide types contribute equally. They may affect insulin signaling in muscles by inhibiting the activation of a protein called Akt, leading to insulin resistance. Studies suggest higher ceramide levels in muscles might be a risk factor for T2D in men. Ceramides might also reduce glucose uptake and storage in muscle cells. Animal studies show a connection between increased ceramides, decreased insulin sensitivity, and high fat intake. Ceramides and Inflammation: High ceramide levels may be linked to inflammation, which can further worsen insulin resistance. This inflammation might be caused by decreased adiponectin (a beneficial hormone) and increased ceramide precursors.

4.Alanine: Alanine production and T2D: Alanine can be produced in various organs, with muscles and liver being major contributors in T2D patients. Elevated alanine levels are observed in these individuals. Alanine and gluconeogenesis: Alanine can be converted into pyruvate, a key player in gluconeogenesis (glucose production) in both muscles and the liver. This suggests alanine might be a biomarker for glucose synthesis in T2D. Liver-pancreas communication: Studies suggest alanine, along with other amino acids, might stimulate glucagon production in pancreatic alpha cells and potentially contribute to alpha cell proliferation. However, inhibiting glucagon signaling might be observed under certain conditions. Muscle-liver crosstalk: Alanine metabolism in the liver seems to be connected to muscle health in T2D. Breaking down alanine in the liver might contribute to muscle wasting observed in diabetic conditions. Alanine and sphingolipids: Alanine can be used to create harmful sphingolipids, which have been linked to T2D and neurological problems.

Metabolites and the Inflammatory Response: High levels of metabolites like FFAs (free fatty acids), DAG (diacylglycerol), ceramides, and glutamate can trigger inflammation in T2D. These metabolites collaborate with free radicals to worsen the inflammatory response. The proinflammatory response can be caused by the activation of pathways like NF- B and NLRP3 inflammasome. This inflammation disrupts insulin signaling, leading to insulin resistance - a hallmark of T2D. Cytokines released during inflammation further damage tissues and contribute to T2D complications. Chronic inflammation can damage tissues, including pancreatic beta cells responsible for insulin production. This damage can worsen T2D progression and lead to complications.

Challenges in Studying Crosstalk: Limited biopsy samples from multiple organs in human studies. Differences in metabolism between humans and animal models used in research. Difficulty in establishing cause-and-effect relationships between metabolites and disease. Identifying target tissues for a specific signaling molecule is complex. Future Directions: Develop better research models to investigate communication between organs. Improved understanding of crosstalk may lead to better treatments and prognosis for T2D patients.