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Diabetes in Humans
type 1, 2 and 3

Leo Rogier Verberne


1. Regulation of the blood glucose concentration
The normal blood glucose concentration varies in the course of a 24-hour period from a minimum of 4 to a maximum of 8 mmol/l. The concentration is regulated by the β-cells in the pancreas, which produce insulin and regulate the release of glucagon by the α-cells. Physical exercise renders the glucose gates in the organ membranes more sensitive to insulin thus promoting the absorption of blood glucose in the organs, as a result of which the blood level drops. Certain intestinal hormones stimulate insulin secretion by the β-cells in the pancreas (the incretin-effect). In the event of manifest diabetes, the excretion capacity of the kidneys for glucose is not sufficient so that the blood glucose level rises over 11,0 mmol/l (the kidney threshold).

2. Various types of diabetes
Juvenile diabetes (type 1 diabetes) strikes about 100,000 people in the Netherlands. It develops as a result of an auto-immune reaction that shuts down the β cells in the pancreatic islets. Adult-onset (type 2) diabetes causes manifest diabetes in more than 1 million Dutch people. Moreover, about the same number of prediabetics is unaware of their (starting) disorder. Which brings the total number of type 2 (pre)diabetics to ± 10% of the Dutch population. In adult-onset diabetes, the functioning of the β cells in the pancreas quietly decreases due to a degeneration process. MODY (type 3 diabetes) strikes an estimated 20,000 Dutch people. It is caused by one single deviating gene-variant in the DNA. But that gene-variant differs in the various types of MODY. DNA research is required to distinguish between the various types (1-10).

3. Diabetes symptoms
The symptoms of manifest diabetes are excessive thirst with frequent urination of sugary urine and fatigue. Besides that, untreated juvenile diabetics (type 1 diabetics) are always hungry, but suffer severe weight loss despite the huge amounts of food that they consume. Untreated adult-onset diabetics (type 2 diabetics) also have an increased appetite; but they develop overweight or even obesity due to excessive eating. So overweight is not the cause of adult-onset diabetes, but rather type 2 diabetes causes overweight. Prediabetes is the foregoing ‘silent’ phase of adult-onset diabetes. Appetite is already increased and causes overweight even before the other diabetes symptoms become evident. In the case of MODY (type 3 diabetes), diabetes symptoms develop at a juvenile age, but they are milder than in type 1 diabetes. Acute hypoglycemia and severe hyperglycemia have largely the same symptoms, as a lack of glucose in the brain occurs in both cases.

4. How to diagnose Prediabetes and Manifest diabetes
Normal fasting blood glucose concentrations vary from 4.0 to 6.0 mmol/l.; values 6.1-7.0 indicate prediabetes; a glucose level >7.0 mmol/l means manifest diabetes. The glycated hemoglobin fraction (HbA1c) represents the average blood glucose concentration over the foregoing 2 months. Normal HbA1c values are between 20 and 42 mmol/mol; fractions 43-53 point to prediabetes; HbA1c >53 mmol/mol means manifest diabetes. Chronically increased levels are related to long-term complications. For example, diabetic retinopathy develops already during prediabetic HbA1c values. The incidence of this eye disease increases almost linearly with increasing HbA1c values starting from 48 mmol/mol. In nearly half of the diabetes type 2 patients, some retinopathy is already present when manifest diabetes is diagnosed. So it apparently starts already in the prediabetic phase.

5. How to differentiate between diabetes type 1, 2 and 3
The mere age of a diabetic does not offer enough to go on in distinguishing between diabetes type 1, 2 and 3. That occasionally leads to a faulty treatment. Juvenile diabetics have antibodies in their blood that target the enzyme GAD, resulting from the auto-immune reaction in the pancreas. Because they do not produce natural insulin, type 1 diabetics have no C-peptide in their blood. Adult-onset diabetics have no antibodies in their blood that target GAD because an auto-immune reaction against the β cells in their pancreas is lacking. Type 2 diabetics do produce (some) natural insulin and as a consequence they also have C-peptide in their blood. In humans with MODY (type 3 diabetes), the anti-GAD test is negative because there is no auto-immune reaction in the pancreas. They still produce some natural insulin and therefore the test for C-peptide is positive. The diagnosis of MODY(1-10) requires DNA research into the specific gene-variants. With that, a distinction can be made with certainty between MODY on the one hand and diabetes type 1 and 2 on the other. However, in the Netherlands the laboratory tests for C-peptide, anti-GAD and DNA-research are not routinely executed in diagnosing diabetes mellitus.

6. Treatment of diabetes type 1, 2 and 3
Physical exercise lowers the blood glucose concentration because it increases the sensitivity of the glucose gates in the organ membranes for insulin. Since 1797, a sugar-free and low-carbohydrate diet is used to reduce the blood glucose level in diabetics. It lowers the glucose level indeed, but the intake of glucose in the organs will remain insufficient or even impossible (for untreated juvenile diabetics) due to a lack of insulin. So fatigue and hunger will remain. A variety of herbs has been used as a therapy, but these have not been sufficiently researched. Alcohol consumption lowers the blood glucose level, but many alcoholic drinks also contain sugar. For the regulation of the blood glucose level, especially in type 1 diabetics and MODY3 patient, there is a range of synthetic insulins available with different speeds of insulin release. Blood glucose reducing tablets are effective in adult-onset diabetics or in MODY patients of various types:
1. by stimulating the glucose gates to absorb more blood glucose or
2. inciting the β-cells to step up the production of insulin or
3. boosting the incretin-effect.
MODY diabetics usually need less medication.

7. Long-term diabetes complications
More than half of the ± 1 million people with manifest diabetes in the Netherlands experience one or more severe long-term complications later on in life. Due to many years of elevated blood glucose levels. So diabetes regulation stands badly. To prevent complications HbA1c should be kept < 48 mmol/mol. Then diabetic deviations in small and large blood vessels and in certain nerves do not come about. After long-lasting increased HbA1c values, all the organs in the body and the limbs are at risk: the brains and eyes, the legs and feet,; the heart and kidneys, the sexual organs, tendons and joints. The life expectancy of people with diabetes is an average of 5 to 10 years lower due to the development of long-term complications.

8. Heredity and external factors
Juvenile diabetes is a hereditary disorder that is induced by external factors. But type 1 diabetes will not develop without the presence of any of 19 deviating gene-variants in the DNA. The risk of developing the disorder for children of a parent with type 1 diabetes varies between 1 to 10 %. The risk is 10 to 25% if both parents have type 1 diabetes. Adult-onset diabetes is a hereditary disorder that is also induced by external factors. But type 2 diabetes will not develop without the presence of any of 40 deviating gene-variants in the DNA. The risk of developing the disorder at a later age for children of parents with adult-onset diabetes is as yet unknown. MODY(1- 10) is an hereditary form of diabetes that is caused by only one dominant gene-variant. The chance of developing the same disorder for children of a parent with MODY is 50% for each type of MODY.

9. Epidemic
The number of people with manifest diabetes and prediabetes in the Netherlands is estimated at 1.8 million or over 10% of the population. The natural selection process for juvenile diabetes has ceased since insulin became available in 1922. Since then, the predisposition is expanding within the population with each generation. The hereditary predisposition for adult-onset diabetes is spreading more quickly in the population because deviating gene-variants are more and more present in the DNA of both parents. Therefore the risk of developing type 2 diabetes at a later age for their children is increasing considerably. Moreover, the predisposition manifests itself sooner as a result of our modern lifestyle. The hereditary predisposition for MODY(1-10) in one of the parents is passed on to half of the children. Some suggestions to restrain the ever-expanding costs for diabetes care:
1. A self-dosing insulin pump, driven by a glucose sensor can prevent both acute and long-term diabetes complications.
2. Screening people on the basis of overweight for prediabetes and its early treatment can reduce long-term diabetes complications.
3. Knowing the gen-variants present in the own DNA offers future parents the opportunity to prevent diabetes in their children by means of family planning, for example by embryo selection.
Because nobody wants a life with diabetes for her or his child.

10. The way juvenile diabetes develops
In juvenile diabetes, several gene-variants in the DNA code for deviations in the maturing processes of lymphocytes in the thymus. That leads to the production of islet autoreactive CD8 T lymphocytes. These derailed CD8 T cells mistakenly detect β cells in the pancreatic islets as cancer cells and shut them down. Which is called an auto-immune reaction leading to type 1 diabetes. So elimination of the autoreactive CD8 T lymphocytes will stop the auto-immune reaction in the pancreas, thus stopping the shut-down of β cells. Even after more than 50 years of manifest diabetes there remains, most of the time, a residual pool of functional β cells in the pancreas. They will restart insulin production as soon as the autoreactive CD8 T cells are effectively eliminated.

11. The way to cure juvenile diabetes
In the year 2016, there were between 20 and 40 million juvenile diabetics worldwide. So research into the cure for T1D is big business. Gene therapy is the preferable remedy when tackling a hereditary disease at its source. But that therapy is still in its infancy. Selective suppression of certain immune cells by monoclonal antibodies (so called biologicals) has only a temporary effect and it therefore calls for lifelong medication. Moreover, these biologicals evoke serious side effects. But if conjugated to a cytotoxic drug into an ADC, the side effects of both components considerably diminish because of far less dosages. Thus, a ‘fully human’ monoclonal antibody against islet autoreactive CD8 T lymphocytes (oktolimumab) can be conjugated to the cytotoxic vedotin into the ADC oktolimumab-vedotin. The biological oktolimumab will selectively target the derailed CD8 T cells and the cytotoxic vedotin will then destroy them. That will stop the shutdown of β cells and, as a result, residual β cells can restart insulin production. The older the type 1 diabetic at the moment of cure, the smaller the risk of a relapse. Because the thymus starts shrinking from puberty onwards. Spontaneous diabetes mellitus also affects dogs. In many of these animals the disease resembles type 1 diabetes in humans. That’s why they might serve to test the curing capacity of new drugs for juvenile diabetes.

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© Leo Rogier Verberne

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