Scientists decode the complicated functioning of insulin in order to formulate the most appropriate insulin therapy for diabetic patients.
Diabetes mellitus or just diabetes is an endocrine disorder of the pancreas. This metabolic disorder is mainly characterised by hyperglycemia (high blood sugar levels) over an extended period of time and is of two major types. Type 1 Diabetes is an autoimmune condition where the beta cells of the pancreatic islets are damaged followed by inadequate production of insulin. Type 2 Diabetes is when the cells in the body are unable to respond to insulin (insulin resistance) leading to lesser production of insulin and it is a lifestyle disorder. The third type of diabetes is the gestational type where women with no history of diabetes experience high blood sugar levels during pregnancy.
Treatment involves administering insulin and insulin sensitizers for type 2 patients along with dietary interventions. Insulin is taken in the form of timely injections and more recently through automated insulin pumps. The genetically engineered insulin should be similar to normal endogenous insulin so as to help maintain glucose homeostasis in diabetic patients. Administered insulin can work up to 24 hours which will help to maintain the basal blood glucose levels without severe fluctuations.
Insulin action is a very complicated process, thus contributing to the challenges for constructing the perfect insulin therapy. In a review published in the journal Diabetes Research and Clinical Practices, Bolli et al, go on to discuss the intricacies of insulin physiology. Insulin increases in a timely manner with increasing blood sugar levels and it works with other hormones like glucagon (secreted by the alpha cells of the pancreas), incretins and amylin to maintain homeostasis.
The liver can generate glucose through the breakdown of stored glycogen (glycogenolysis) or through producing new glucose molecules (gluconeogenesis). Insulin directly accesses the liver through the portal system and lowers hepatic glucose output by suppressing these processes. It simultaneously enables both glucose utilisation by various cells and suppresses endogenous glucose production in order to maintain homeostasis.
When asleep, glucose levels drop (hypoglycemia) as the body is in a state of fasting. Insulin production is at basal levels (60mg /ml) and glucagon takes over to increase the blood glucose levels to prevent hypoglycemia. The ratio of insulin to glucagon is very essential for glucose homeostasis. Insulin levels peak within 30-60 mins of food intake and increase by 5-10 fold. Incretin and amylin from the pancreas augment insulin production and suppresses glucagon secretion by delaying gastric emptying.
In diabetic patients, since insulin levels are low, glucagon overexerts its action which can lead to hyperglycemia. However, as diabetes progresses, the alpha cells become redundant, hence producing lesser amounts of glucagon leading to hypoglycemia. In a prolonged hypoglycemic state, there is less glucose supply to the brain (neuroglycopenia) accounting for the neuronal damage and altered brain function. Current day insulin therapies do not adapt to the altered glucagon function and thus, hypoglycemia occurs.
Insulin also impacts lipid and protein metabolism. Insulin helps to store ingested complex lipids by preventing their breakdown into fatty acids and glycerol. In turn, the lower quantity of circulating fatty acids reduces glucose production from the liver by suppressing gluconeogenesis. Insulin also promotes protein synthesis by preventing its breakdown. Increased plasma amino acid levels and increased urinary nitrogen levels are observed in diabetic patients. Hence diabetic patients lose fat, muscle and body weight. Insulin deficiency in children (type 1) can cause delayed growth and short stature.
Insulin therapies are administered through the subcutaneous route (under the skin) and not through the intravenous route. This can alter the dynamic of insulin due to its delayed absorption from the interstitial fluid into the bloodstream. The insulin is inadequate by the time it reaches the liver which needs high insulin exposure for maintaining homeostasis. This is achieved by increasing the amount of insulin administered, well above normal values. The resulting hyperinsulinemia in the peripheral blood can account for the increase in fat and body weight in long-term insulin-treated people.
“Despite intense research over decades, a fully automated beta-cell like system of insulin delivery is not available yet, and the dream of engineering body’s cells to function as beta-cells appears far away,” the researchers state. The most recommended insulin therapy is the bolus-basal insulin treatment which has proven to reduce glucose levels without the risk of hypoglycemia.
Ever since its discovery 100 years ago, insulin therapy has come a long way. As scientists continue to understand the complicated physiology of insulin, better therapeutic strategies can be formulated, making life easier for diabetic patients.
Author: Parvathi Nair