InsulinAbsorptive and post-absorptive statesRenal effectsMetabolic effects



Overview

Insulin is the most important hormone governing metabolism. When insulin is deficient (Type 1 diabetes mellitus) or cells become less sensitive to it (Type 2 diabetes mellitus) hyperglycaemia (excess blood glucose) is but one result. A large, prolonged rise in glucose produces the renal effect of osmotic diuresis, polyuria (going to pee a lot) and subsequent dehydration and hypovolaemia. This occurs because the kidneys can only reabsorb so much glucose and so the excess remains in urine; water then follows by osmosis. In T1DM, a further problem can be the increased production of ketones as an energy source – also as a consequence of low insulin - leading to metabolic acidosis (ketoacidosis). Again, the kidney is unable to reabsorb enough of the filtered ketones, leading to elevated urinary ketone levels and further water loss by osmosis. Finally, because ketones are generally excreted as negatively charged bases, some cations (notably Na+ and K+) follow leading to electrolyte imbalances.


Insulin and diabetes mellitus

There are two basic types of diabetes mellitus (DM): Type 1 and Type 2. In T1DM, autoimmune destruction of the insulin-secreting cells of the pancreas renders suffers unable to make this vital metabolic hormone. In T2DM, the cells of the body become insensitive to insulin (insulin resistance) which is present in blood at normal or even elevated levels. T2DM is by far the more prevalent form of diabetes and is associated with obesity, whereas the aetiology of T1DM is still unclear. Diabetes insipidus – which also causes polyuria – is an unrelated, rarer condition in which the body fails to produce (or becomes resistant to) vaspopressin (AKA antidiuretic hormone; ADH), a hormone which controls fluid balance, but has no significant role in metabolism.

Insulin doesn’t just control blood glucose levels, it is the main hormone regulating whole body metabolism. Insulin is sometimes called the “storage hormone” because its effects are to increase anabolism: the storage of energy by forming big molecules from small ones (e.g. glycogen from glucose). These can then be broken down later (catabolism) as an alternative fuel source when additional energy is required. Without insulin, the body becomes locked into a state of burning these alternative energy supplies, despite abundant glucose.


Absorptive and post-absorptive states

The body has two basic metabolic states, absorptive (during the approximately four hours it takes to digest a meal and store energy) and post-absorptive (when the body uses stored energy supplies). In most cultures, the human body is in the post-absorptive state for short periods between meals and during the night. What has this got to do with diabetes? In each state the body is using different fuel supplies to produce energy, and insulin - as the most important hormone governing the metabolic state of the body – is the master switch:

absorptive state post-absorptive state


In the absorptive state, glucose is abundant and is the main fuel for the body; the excess is stored. These processes are driven by insulin. In the post-absorptive state when glucose levels begin to taper off, insulin secretion ceases and stored glucose, and other fuels (fatty acids (FA) and ketones) are released into the blood to keep the body running until the next meal. Non-neuronal tissues do not utilise glucose as effectively in the absence of insulin (because expression of glucose transporters is controlled by insulin, leaving this vital fuel source for the nervous system. The problem in diabetes mellitus is that the body is inappropriately (and without treatment, permanently) stuck in the post-absorptive state due to the lack of (or lack of effect of) insulin. So, although the obvious symptoms of diabetes are renal, the key disturbance is metabolic.


Renal effects of diabetes

The high level of glucose in blood in diabetes mellitus (either Type 1 or Type 2) produces the interrelated symptoms of thirst, polyuria and dehydration. Under normal circumstances, the kidneys are able to produce concentrated urine, reducing water losses from the body via this route. In order to concentrate urine, solutes filtered out of the blood in the glomeruli must be reabsorbed to provide the osmotic gradient for water to follow. In diabetes, the kidneys are unable to completely reabsorb the high levels of glucose, resulting in sugary urine (an ancient observation and simple test for diabetes). This failure to reabsorb glucose has osmotic consequences: the increased osmolality of urine draws water into urine instead of into the body. This increase in water loss can lead to hypovolaemia, hypotension, inadequate perfusion of the brain and coma or death.


Metabolic consequences of diabetes

In T1DM, persistently low insulin levels promote lipolysis: the breakdown of triglycerides to fatty acids and glycerol. Ketones are the product of fatty acid catabolism by the liver. Two of these small (4 carbon) molecules are acidic at typical blood pH: hydroxybutyric acid and acetoactic acid. It is not unusual for the body to produce acids (e.g. lactic acid during exercise) and buffering mechanisms usually limit their effect on blood pH. However, prolonged production of organic acids can overcome endogenous buffers, leading to metabolic acidosis. When metabolic acidosis is due to a non-volatile acid (i.e. one that cannot be “blown off” by the lungs), a metabolic acidosis with an anion gap is the result.

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