Diabetes/Metabolism

Metabolism consists of a series of reactions that occur within cells of living organisms to sustain life. The process of metabolism is organised into distinct metabolic pathways that ultimately provide cells with the energy required to carry out their function. Metabolic changes can lead to a huge range of outcomes in different disease areas, from cancer or neurodegeneration to obesity and diabetes.

The insulin signalling pathway plays a pivotal role in maintaining glucose homeostasis and regulating various metabolic processes within the body. This technically detailed brief aims to provide a comprehensive understanding of glucose storage and uptake, protein synthesis, regulation of lipid synthesis, and mitogenic responses, along with the involvement of specific biomarkers, cytokines, and molecules.

• Glucose Storage and Uptake

Insulin signaling primarily involves the regulation of glucose transporters (GLUTs) to facilitate glucose uptake into cells. In response to insulin, GLUT4 translocation from intracellular vesicles to the plasma membrane occurs, increasing glucose uptake. Additionally, insulin promotes glycogen synthesis through glycogen synthase activation and inhibits glycogen breakdown via glycogen phosphorylase inactivation.

Key biomarkers involved in glucose storage and uptake:

Glucose Transporter 4 (GLUT4): Mediates insulin-stimulated glucose uptake.

Glycogen Synthase (GS): Enzyme responsible for glycogen synthesis.

Glycogen Phosphorylase (GP): Catalyzes glycogen breakdown.

• Protein Synthesis

Insulin stimulates protein synthesis by activating the mTOR (mammalian target of rapamycin) signaling pathway. The mTOR pathway regulates translation initiation, ribosome biogenesis, and protein synthesis, leading to increased cellular growth and repair. Key intermediates in protein synthesis include the eukaryotic translation initiation factor 4E (eIF4E) and eukaryotic initiation factor 4E-binding proteins (4E-BPs).

Key biomarkers involved in protein synthesis:

mTOR: Serine/threonine kinase that serves as a central regulator of protein synthesis.

eIF4E: Mediates the binding of mRNA to the small ribosomal subunit.

4E-BPs: Regulate the activity of eIF4E by binding and preventing its interaction with eIF4G.

• Regulation of Lipid Synthesis

Insulin signaling exerts control over lipid metabolism by promoting fatty acid synthesis and inhibiting lipolysis in adipose tissue. It activates sterol regulatory element-binding proteins (SREBPs), which transcriptionally enhance the expression of lipogenic genes. Additionally, insulin suppresses hormone-sensitive lipase (HSL) activity, thereby reducing the breakdown of stored triglycerides.

Key biomarkers involved in regulation of lipid synthesis:

Sterol Regulatory Element-Binding Proteins (SREBPs): Transcription factors that regulate lipid metabolism.

Fatty Acid Synthase (FAS): Enzyme responsible for fatty acid synthesis.

Hormone-Sensitive Lipase (HSL): Catalyzes hydrolysis of stored triglycerides.

• Mitogenic Responses

Mitogenic responses induced by insulin involve cell growth, proliferation, and differentiation. Insulin activates various downstream signaling cascades, including the Ras/Raf/MEK/ERK pathway and the PI3K/Akt pathway. These pathways modulate transcription factors, growth factor receptors, and intracellular mediators, ultimately promoting cell cycle progression and mitogenic responses.

Key biomarkers involved in mitogenic responses:

Ras: GTPase that transmits signals from growth factor receptors to downstream effectors.

MEK: Dual-specificity kinase that phosphorylates and activates ERK.

ERK: Extracellular signal-regulated kinase involved in cell proliferation and differentiation.

PI3K: Phosphoinositide 3-kinase that phosphorylates and activates Akt.

Akt: Serine/threonine kinase involved in cell survival and proliferation.

Current treatment research for type 1 and type 2 diabetes encompasses diverse approaches, including artificial pancreas systems, islet cell transplantation, immunomodulation, glucose-lowering medications, personalized medicine and metabolic surgery. Looking ahead, precision medicine, advanced technologies, and regenerative medicine hold significant promise in revolutionizing diabetes management.

Some prominent areas of current treatment research include:

1.Type 1 Diabetes

• Artificial Pancreas Systems: While not directly involving mAbs or bsAbs, artificial pancreas systems utilize continuous glucose monitoring and automated insulin delivery to improve glycemic control. Examples include the Medtronic MiniMed 670G and Tandem Diabetes Control-IQ systems.
• Islet Cell Transplantation: Islet cell transplantation aims to replace destroyed beta cells with functional ones. The Edmonton protocol involves immunosuppression with mAbs such as anti-thymocyte globulin (ATG) and anti-CD25 antibodies (basiliximab, daclizumab) to prevent islet rejection.
• Immunomodulation and Immune Tolerance: Various mAbs are being studied for immune modulation in type 1 diabetes. Examples include teplizumab (anti-CD3), otelixizumab (anti-CD3), and alefacept (LFA-3/IgG1 fusion protein) to modulate T-cell response or promote regulatory T cells.
• Beta Cell Replacement: Genetic treatments utilizing gene therapy and genome editing techniques are being explored to generate functional beta cells. This includes approaches such as CRISPR-Cas9 gene editing to correct mutations or reprogram non-beta cells into functional beta cells.

2.Type 2 Diabetes

• Glucose-lowering Medications: Several mAbs and bsAbs targeting different pathways are approved or under investigation for type 2 diabetes treatment. Examples include:
• GLP-1 receptor agonists (mAb): Exenatide (Bydureon), dulaglutide (Trulicity), liraglutide (Victoza).
• SGLT-2 inhibitors (bsAb): Dulaglutide plus empagliflozin (SAR439954)
• DPP-4 inhibitors (mAb): Sitagliptin (Januvia), saxagliptin (Onglyza).
• Personalized Medicine: Genetic screening can help identify specific gene variants related to diabetes and tailor treatment. For example, certain genetic variants affect the response to metformin, guiding individualized medication selection.

Krishgen offers a range of ELISA for research of insulin and diabetes.

 Established Drug Classes for the Treatment of Diabetes:

1. Types of Insulin

Insulin is perhaps one of the most studied proteins and has been an integral part of Type 2 Diabetes treatment. Recombinant insulin analogues have been developed that act in several different ways. Rapid-acting insulin analogues supply a bolus insulin level needed at mealtimes (prandial insulin) and include insulin lispro, aspart, and glulisine. Longer-acting insulins released slowly over a more extended period supply the basal insulin level needed throughout the day and night (basal insulin) and include detemir, glargine, and the ultra-long-acting degludec. In addition to insulin plus insulin combination regimens, insulin plus glucagon-like peptide-1 (GLP1) receptor agonist combinations have also been approved.

General Insulin ELISA: