The tale of insulin and the episodes of hyperglycemia and hypoglycemia

I fondly remember the family meals which were not complete without any sweet stuff, the “minatamis” that my late mother was fond of cooking. Although the sweetness of my mother’s “minatamis” was extreme, we enjoyed her leche flan and sweetened preserved guavas, kundol, makapuno, mangoes and santol — fruits that were harvested in the backyard of my ancestral home. Despite the “sweet tooth” that obviously “runs in the family,” nobody then had been diagnosed with hyperglycemia or high blood glucose level that could be a risk factor affecting predisposition to diabetes mellitus, or simply referred to as diabetes. In fact, my parents lived their whole lives without diabetes. Until lately, my sister was diagnosed to have hyperglycemia typical of type 2 diabetes, and is now on medication.

Role of insulin in carbohydrate metabolism

The key substance that leads us to the understanding of diabetes is the peptide or protein hormone known as insulin. Insulin is produced by beta-cells of the pancreas, an organ that is located behind the stomach. After the digestion by enzymes of a meal that includes carbohydrates (such as those found in table sugar, rice, bread, pasta, pancit, cake, among others), glucose is absorbed in the small intestine and then carried into the bloodstream. Insulin is then secreted by the pancreas in response to the increase in blood glucose level. Insulin receptors in the cells bind the insulin molecules that are in circulation. Activation of insulin receptors found at the cell surface leads to internal cellular processes that influence glucose uptake by controlling the action of protein molecules which transport glucose into the interior of the cells. Glucose is the cells’ primary source of energy.

Normally, insulin is produced in a steady proportion to get rid of excess blood glucose which could be toxic. Without the action of insulin, one can consume a lot of carbohydrate-rich foods and still feel hungry because the cells cannot utilize the energy that can be derived from glucose. Insulin regulates the metabolism of glucose, and a deficiency of this hormone results in hyperglycemia and excretion of glucose in the urine.

When insulin fails in its regulatory function, diabetes can occur. Individuals with type 1 diabetes either do not produce insulin or produce very little of it, and can be severely ill without insulin injection or pump. Insulin cannot be taken orally because the enzymes in the stomach and intestinal juices can degrade it. More commonly, persons develop type 2 diabetes which is due to insulin resistance. In this case, the cells respond slowly to insulin so that they cannot effectively absorb glucose molecules. Metformin, an orally administered drug for type 2 diabetes, enhances insulin sensitivity causing increased glucose uptake by the cells, and also inhibits synthesis of glucose from non-carbohydrates by the liver cells. Often, treatment with oral medications is adequate for individuals with type 2 diabetes, but sometimes insulin may be needed. Prolonged starvation or complication of treatment of diabetes with insulin or oral medicine can cause depletion of glucose, causing hypoglycemia or low blood glucose level. Intake of carbohydrate-rich drinks or foods, or administration of dextrose (also known as glucose) is usually done to restore blood glucose level to normal.

Discovery and identification of insulin

The discovery of insulin was credited to Frederick Banting and John James Rickard Macleod who were awarded the Nobel Prize in Medicine or Physiology in 1923. Banting shared his prize with Charles Herbert Best while McLeod shared his prize with James Bertram Collip. Banting and Best, who worked in Macleod’s laboratory, tested the pancreases of dogs to pursue their search for the substance that could treat diabetes. They tied the dogs’ pancreatic ducts with ligature resulting in the death of the digestive cells, leaving the cells of the pancreatic islets called islets of Langerhans (named after the discoverer, Paul Langerhans). They prepared from the pancreatic islets an extract containing the substance called “isletin” (also named insulin) that was able to maintain diabetic dogs alive. Macleod also collaborated with Collip who isolated insulin that was sufficiently pure and suitable for use on diabetic humans in clinical trials.

Bovine insulin was the first protein whose sequence of amino acids (units of the “building blocks of protein”) was determined, for which Frederick Sanger was recognized with the Nobel Prize in Chemistry in 1958. Bovine insulin differs from human insulin in three amino acids, while porcine (pig) insulin differs from human insulin in only one amino acid, out of the total of 51 amino acids comprising the insulin molecule.

Sources of therapeutic insulin

Industrial preparations of insulin were earlier derived from the pancreatic islets of bovines and pigs. The insulin was isolated from those animals’ pancreases that were obtained from slaughterhouses. Because of the similarity to human insulin, bovine and porcine insulin were suitable for a majority of diabetic patients, but some individuals developed allergy or other side effects.

Later, technology was developed when human insulin could be produced with the use of recombinant DNA techniques. In this approach, the human insulin gene is inserted into a suitable cloning vector and introduced inside competent host bacterial cells which ultimately produce the human insulin. Later, production of human insulin is done with yeast cells. An advantage of the DNA recombinant technology is that the human insulin that is produced has less chance of causing side effects because it is not a foreign protein. In the early 80s, the first human insulin was introduced in the market.  

Missing the ‘minatamis’

Genetic predisposition, obesity and high intake of calories, appear to be major factors in type 2 diabetes. As one grows older, metabolic processes tend to slow down and the body tends to have less energy requirement. Proper diet, aside from regular physical exercise, work well for persons who wish to prevent or retard the onset of type 2 diabetes. Now I have to be watchful of my diet. But I am missing a lot the types of “minatamis” like those which my mother sweetly prepared for our family.

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Dr. Elsie C. Jimenez, a biochemist and molecular biologist, is a professor emeritus at the University of the Philippines Baguio. She can be reached at [email protected].