Diabetes and Insulin Signaling
Diabetes affects 25.8 million people in the US. The number of young people that are annually diagnosed with diabetes is on the rise, with 15,600 diagnosed with type-1 diabetes and 3,600 diagnosed with type-2 diabetes. In 2007, the estimated annual cost of diabetes was $174 billion dollars. Average medical expenditures of individuals with diabetes are 2.3 times higher than people without diabetes. The major complications with diabetes are heart disease, stroke, high blood pressure, blindness, kidney disease, nervous system damage, and amputation. Type-2 diabetes results from target cells that don't respond as well to insulin. If untreated, type-2 diabetes leads to excess glucose in the blood. If cells cannot use glucose metabolism for energy, they can start breaking down protein. Excess protein metabolism can lead to a buildup of byproducts known as ketoacids. These ketoacids in combination with excess blood glucose can lead to a host of physiological problems including:
- Blurred vision -> blindness
- Weak immune system
- Fatigue
- Impaired cognitive function
- Kidney problems (frequent urination, dehydration) -> dialysis
- Irregular heartbeat -> heart attack
- Loss of sensation in limbs (especially feet)
- Coma/death
- Poor wound healing - with foot lesions -> amputation
Insulin binds to the insulin receptor (1). The receptor is activated, causing a conformation change known as dimerization (the coming together of two insulin receptors). The receptor adds a phosphate to amino acids (tyrosines) on the tail of the other insulin receptor in the pair (2). Signal transduction proteins interact with the phosphate group (3). Interaction of the phosphate groups with all of the different signaling proteins occurs simultaneously, but each pathway will be discussed individually. Signaling proteins and pathways will cause the short-term and long-term changes in response to the increased glucose in the bloodstream. One major short-term change is the fusion of vesicles containing glucose transporter (GLUT4) to the cell membrane (4). Once these transporters are part of the cell surface, glucose is transported into the cell (5). Long-term cellular changes are caused by changes in gene transcription that result in specific proteins being made or not made. These pathways utilize many different signaling patterns, such as the direct activation of a transcription factor (T.F.) (6), the release of second messenger (7), and the activation of a kinase cascade (8). All of these signaling pathways can result in the activation of transcription factors and their movement to the nucleus to activate transcription (9).