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Diabetes in Humans
type 1, 2 and 3

Leo Rogier Verberne

3. Diabetes symptoms

A series of symptoms develops when the blood glucose level exceeds the kidney threshold (11.0 mmol/l). This condition is called ‘manifest’ diabetes. In the case of type 2 diabetes, the foregoing silent phase is ‘prediabetes’. Which proceeds unnoticed and it can last for 6 or more years until it becomes manifest (4).

Excessive thirst and frequent urination
The classic symptoms of manifest diabetes are excessive thirst and frequent urination of sugary urine (diabetes mellitus means ‘honey-sweet flow’). These symptoms develop as a result of glucose excretion by the kidneys if the blood level rises over 11.0 mmol/l. When this level is 20 mmol/l, approx. 100 grams glucose is excreted per day. In severe cases of diabetes, blood glucose concentrations may possibly exceed 60 mmol/l (4); loss of sugar in the urine is then major and large amounts of urine are produced. This causes thirst, which is why diabetics drink a lot: up to 10 litres per day (and night).

In manifest diabetes, the cause of hyperglycemia is a considerable lack of insulin. Untreated juvenile diabetics have no insulin whatsoever available, as a result of which the organs cannot absorb glucose from the blood. Untreated adult-onset diabetics and MODY patients have some, but not enough insulin available. As a result, an insufficient amount of glucose enters the organs while the blood glucose level rises. So all three types of diabetes cause a lack of glucose in the organs but to different degrees. And glucose is the fuel for bodily functions. Which is why untreated diabetics feel tired all the time. Their organs proceed to burn fat as an alternative supply of energy.

Disturbed brain functions
The human brain accounts for approx. 2% of the body weight and for 15% of the total glucose consumption in a state of rest (2). This can double to 30% during major brain activity. Unlike other organs, the brain cannot switch to fat combustion in the event of a shortage of glucose. So a lack of insulin has an immediate effect on brain functions. Shortage of glucose in the brain diminishes the ability to concentrate. In severe cases, the diabetic has slurred speech or even can’t respond to questions or comments. And his coordination becomes disrupted. In the utmost case, the failure of glucose in the brain will lead to loss of consciousness, called hyperglycemic coma, after the concurrent high blood glucose level.

Juvenile diabetes
A lack of glucose in the brain stimulates the hunger centre and brings about an increased appetite as a reaction. In the case of untreated juvenile diabetics, the lack of glucose in the brain is extreme and they feel incredibly hungry as a result. They therefore eat a lot and their blood sugar subsequently sky-rockets. But because of the lack of insulin, none of the organs can absorb glucose. The subsequent combustion of fat and protein in the organs leads to severe emaciation (left photo) despite excessive eating. As a consequence, juvenile diabetics will die of exhaustion if not injected with insulin.

first diabetes patient ever to be treated with insulin - Leonard Thompson

In 1922, Leonard Thompson was the first youngster to be treated with insulin;
he was 14 at the time. The photo on the right shows him 6 months later (6).

Adult-onset diabetes
Insulin is available in type 2 diabetics, but to an insufficient degree. The glucose gates in the organ membranes do not open completely and not enough glucose is absorbed. Which also concerns the brain. As a result, the hunger centre is stimulated and thus the appetite of untreated type 2 diabetics is constantly increased. As a result, they take in an excess of food. The surplus of it being stored in the fat depots. Thus, adult-onset diabetes causes overweight or even obesity. Not the other way round: overweight and obesity are not the cause of type 2 diabetes. Which is a widespread misunderstanding.

Overweight is more often observed in those with adult-onset diabetes compared to those who have no diabetes (3). This association (statistic correlation) is generally seen as a causal connection, that is to say, it is generally presumed that overweight causes adult-onset diabetes. That is statistically incorrect: an association demonstrates that a certain observation (overweight) more than coincidentally goes hand in hand with some other observation (adult-onset diabetes). But it does not prove that one causes the other. The same association equally applies the other way round: if adult-onset diabetes causes overweight. The latter interpretation also explains why the overweight of these diabetics often disappears once the blood glucose level is carefully regulated to a normal concentration.

Prediabetes is the foregoing, silent phase of manifest adult-onset diabetes. In the present year 2017, the estimated number of undiagnosed prediabetics in the Netherlands is about 1 million. Which is over 5% of the Dutch population. And their number is increasing. In the adult population of North-America, 10-15% has prediabetes (8). However, prediabetics are unaware of their disorder because most of the diabetes symptoms are lacking. Still their blood glucose level is beyond normal because insulin secretion is insufficient. Which results in a low intake of glucose into the brain. That causes a constant appetite resulting in overweight. In addition, arteriosclerosis (vascular damage) also originates from the chronically elevated blood glucose levels in prediabetics (3).

MODY (Maturity-Onset Diabetes of the Young) is the 3rd type of diabetes. It starts at a young age. So it is disguised as diabetes type 1, while it is in fact more like diabetes type 2 (1). There are at least 10 different kinds of MODY. In each case, something went wrong in the embryonic construction of the pancreas. As a result, the islets of Langerhans are exhausted early in life and produce less insulin (1). Thus, MODY is more like diabetes type 2, the adult-onset type of diabetes. But because symptoms usually start in children and young-adults, it is often wrongly diagnosed as diabetes type 1, resulting in improper treatment.

Acute hypoglycemia
As a result of a treatment error in the regulation of diabetes, an immediate drop in the blood glucose level to under 4 mmol/l can occur. That is referred to as hypoglycemia. Striking is that the symptoms of hypo-glycemia largely correspond with symptoms of severe hyper-glycemia. How is that possible?
Both, acute hypo- and severe hyperglycemia, involve a lack of glucose in the brain. In the case of a hypo, because the level of blood glucose is simply too low, as a result of too much injected insulin. In the case of a hyper, because of a lack of insulin so that no or not enough blood glucose can enter the brain. Thus in both situations, brain functions are disrupted due to a lack of glucose. In extreme cases, unconsciousness will occur, both at a very low blood glucose level (hypoglycemic coma) as well as at an extremely high level of blood glucose (hyperglycemic coma). So do take care with the treatment of an unconscious diabetic!

Alarm reaction
Acute hypoglycemia generates an alarm reaction in the body. Adrenaline and cortisol are then released from the adrenal glands. These hormones mobilize glucose from the reserves in the liver, subsequently increasing the blood sugar level (7). But they also cause paleness, trembling, sweating and heart palpitations. During a severe hypo, the diabetic is no longer able to take in glucose by eating (for example dextrose tablets) or drinking (for example apple juice). One of the parents, the partner or a housemate must then administer a glucagon injection while waiting for professional help. It is therefore of vital importance to adequately inform those people involved (5).

After having been at an evening party, a woman is awakened during the night because her partner is twitching in bed. He is sweating all over, talking nonsense and is unresponsive. Yet he was not drunk when they arrived home and they have meanwhile slept for a few hours. She knows that he is a diabetic, but they never discussed the matter in detail. And this has never happened before. She has no idea how to best respond and act on the situation. It is frightening and she calls the emergency number in a panic.
Shortly afterwards, the twitching subsides and when the ambulance and paramedics arrive fifteen minutes later, her partner can once again speak clearly. He drinks a glass of apple juice and chews on a few dextrose tablets. And with that, the threat of a coma is averted. A glucose drip or glucagon injection is no longer necessary and the ambulance leaves.

Before dinner, he had injected his usual dose of insulin. But because they were in a hurry, dinner had been limited to a cup of soup. And he had consumed a few glasses of beer at the party. By not eating as he normally did (no carbohydrates), the dose of insulin had actually been too high in this case. The alcohol then reduced his blood glucose level even further. Ultimately, in the course of the night, the usual evening injection of slow-acting insulin brought him to the verge of a hypoglycemic coma.

Diabetes type 1, 2 and 3
Acute hypoglycemia occurs more frequently in juvenile diabetics and is more severe compared to humans with adult-onset diabetes or MODY (4). The explanation for this: in type 1 diabetes, the β-cells are shut down and there is no more monitoring of the blood glucose level. When that level, after injecting too much insulin, drops too far, then this remains undetected and thus there is no response of the α-cells, meaning no production of glucagon. In adult-onset diabetes, β-cells are less sensitive as a result of degeneration. However, if the blood glucose level drops too far due to over-medication, then the α-cells are prompted to produce glucagon. Which prevents a hypo if the treatment error is not too severe; or at least it tempers the symptoms by the glucagon that will be released. In the case of MODY the reaction to over-medication is similar to that in type 2 diabetes.

1. The classic symptoms of manifest diabetes are excessive thirst with frequent urination of sugary urine and fatigue.
2. Untreated juvenile diabetics are always hungry, but suffer severe weight loss despite the huge amounts of food that they consume.
3. Untreated adult-onset diabetics have an increased appetite and develop overweight or even obesity.
4. Overweight is not the cause of adult-onset diabetes, but type 2 diabetes causes overweight.
5. Prediabetes is the foregoing silent phase of adult-onset diabetes, but an increased appetite initially leads to overweight.
6. The diabetic symptoms of MODY start in children and young-adults, but they resemble type 2 diabetes.
7. Symptoms of acute hypoglycemia and severe hyperglycemia are largely the same as a lack of glucose in the brain occurs in both cases.

1. Diabetes Fonds (2017). MODY
2. Guyton AC and Hall JE. Brain metabolism. p 749-750; Insulin, Glucagon and Diabetes Mellitus. p 939-954.
In: Textbook of Medical Physiology 12th ed. (2011); ISBN 978-1-4160-4574-8
3. Kooy A. Diabetes, een mondiale pandemie: de progressieve ijsberg.
In: Diabetes Mellitus (2010); ISBN 978-90-313-7434-2; p 17
4. Tack CJ en Stehouwer CDA. Diabetes mellitus In: Interne geneeskunde. eds. Stehouwer, Koopmans en van der Meer.14e druk (2010); ISBN 978-90-313-7360-4; p 835-865
5. Wientjes WHJM (2002). Diabeteszorg is onvoldoende, kwantitatief en kwalitatief.
In: Diabetes, de stille epidemie; Pfizer bv; p 8-19
6. Wientjens WHJM (2008). Diabetes … Nou en? zeventig jaar belevenissen.
Novo Nordisk BV; ISBN 978-90-804452-7-7; p 15
7. Wikipedia.en (2016) Hypoglycaemia
8. Wikipedia (2016). Impaired glucose tolerance

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© Leo Rogier Verberne