How does the body regulate blood glucose?
At any given moment, there's ~4.5g of glucose in your blood (5mmol/L x 180g x 5L). As the brain alone uses about 6g of glucose per hour in the absence of ketones, blood glucose (BG) level could fall to zero within an hour if we ate no sugary/starchy carbs. If we ate a mere 5g of glucose, BG level could double. As very low BGs are fatal and very high BGs damage proteins by a process called glycation (a bit like caramelisation), the body keeps BG levels within fairly tight limits by the use of a negative feedback (NFB) control system.
How does a negative feedback control system work?
NFB systems consist of a non-inverting (more in → more out) part, which in this case are the islet cells of Langerhans (a.k.a. pancreatic beta cells), as increasing BG level results in increasing insulin secretion. It's actually more complicated than that. Beta cells can store insulin and dump it into the blood if there is a sudden increase in BG level. This is analogous to the accelerator pump in a carburettor, which dumps petrol into the engine if you slam your foot on the accelerator pedal, i.e. it produces a rapid response. The dumping of insulin from beta cell storage is known as the Phase 1 insulin response. If this (or the accelerator pump) fails, there is a lag in the response; this will become significant below.
Increasing BG level results in increasing insulin secretion from beta cells and is known as the Phase 2 insulin response.
The other part of a NFB system is the inverting (more in → less out) feedback part, which in this case is split into three parts, all working in parallel. They are:
- Liver - increasing insulin level results in decreasing Hepatic Glucose Production.
- Muscle cells - increasing insulin level shifts GLU-T4 transporters which shuttle glucose from the blood into cells, decreasing BG level.
- Fat cells - increasing insulin level shifts GLU-T4 transporters which shuttle glucose from the blood into cells, decreasing BG level.
What can go wrong?
There are three main types of diabetes:
1) Type 2 diabetes. This is by far the most common (about 95% of all cases) and is usually caused by abdominal obesity. Type 2 diabetes has two main mechanisms going on. The first is a progressive insulin resistance (IR) of target tissues, possibly caused by increased levels of saturated fatty acids being fed to the liver from abdominal fat stores, chronically-high BG and insulin levels caused by chronically over-consuming high glycaemic load carbohydrates, possibly accompanied by large amounts of saturated fat and/or large amounts of omega-6 fat. A sedentary lifestyle lowers the sensitivity of muscle cells to insulin. Insulin resistance also has a hereditary link. IR is reversible. See Insulin Resistance: Solutions to problems.
Insulin resistance weakens the feedback in the NFB system, resulting in increased BG level (hyperglycaemia) and increased insulin level (hyperinsulinaemia). See Hyperinsulinaemia and Insulin Resistance - An Engineer's Perspective. Increased BG level causes increased damage to beta cells by glycation. Increased insulin level gradually causes further insulin resistance as target tissues become increasingly insensitive (a bit like louder and louder music making you progressively deafer and deafer). Eventually, beta cells become too damaged to secrete sufficient insulin and insulin levels begin to fall. This results in a massive rise in BG level and this is now full-blown Type 2 diabetes. There are five main treatments for Type 2 diabetes:
- Lifestyle interventions - reduced intake of high glycaemic load carbohydrates and/or increased intake of omega-3 fats and/or increased intake of Vitamin D3 and/or increased intense exercise and/or loss of abdominal fat.
- Sulphonylureas - drugs which stimulate beta cells to secrete even more insulin. Unfortunately, that's a bit like flogging a dying horse as it doesn't address the problems caused by weakened feedback and eventual beta cell failure is inevitable, resulting in the need for insulin injections.
- Biguanide drugs such as Metformin - increase insulin sensitivity in target tissues. This strengthens the feedback in the NFB system, which results in reduced BG and insulin levels. This combined with lifestyle interventions can return the NFB system to normal operation.
- Thiazolidinediones - also increase insulin sensitivity in target tissues, e.g. muscle and fat, as well as possibly improving the secretory function of beta cells. Increases the number of new, empty fat cells.
- Insulin injections take the strain off beta cells, but may worsen insulin resistance.
2) Type 1 diabetes. This is much less common (about 5% of all diabetes cases) and is caused by an autoimmune disease. One possible mechanism is as follows: Due to an increase in Zonulin, the gut becomes more permeable than it should (a.k.a. Leaky Gut), which allows protein fragments to pass into the blood. These are locked-onto by antibodies, and destroyed by the immune system. However, if a protein fragment happens to have the same sequence of amino acids as a protein in your body, the immune system sets about destroying parts of your own body. Examples of this are gluten (proteins found in wheat, rye, barley and oats) producing antibodies in the blood that can destroy the gut causing Coeliac Disease, or skin cells causing Dermatitis Herpetiformis, or mucous membranes causing Sjogren's Syndrome, or brain cells causing Cerebellar Ataxia. As there's an association between the consumption of cows' milk and the incidence of type 1 diabetes (see here ), it's possible that, in susceptible individuals, casein protein fragments enter the blood, resulting in auto-immune destruction of pancreatic beta cells. Another possible mechanism is autoimmune attack after a viral infection. Once all beta cells have been destroyed, no insulin is secreted and insulin injections are required. If some beta cells survive, there's a possibility that normal BG levels can be maintained if sugary/starchy carbohydrate intake is reduced.
3) Latent Autoimmune Diabetes of Adulthood (LADA). This is a slow developing diabetes that is more like type 1 in origin (autoimmune with antibodies) but is often misdiagnosed as type 2 because of the age at diagnosis and the relatively slow progression of the disease (slow compared to type 1 but fast compared to type 2). It is believed that Sir Steven Redgrave has this. Whether or not his autoimmune disease was triggered by a huge intake of milk (to build those Olympic-winning muscles), we'll never know. To minimise your risk of developing autoimmune diseases, see Keep 'em tight.
What else can go wrong?
As stated earlier, loss of the Phase 1 insulin response can occur. This usually happens when beta cells are chronically over-secreting insulin due to a chronically-high intake of sugary/starchy carbs and are unable to store any. This results in a lag in insulin response. This isn't a problem if low glycaemic load carbs are eaten and BG levels change only a little or very slowly. However, if high glycaemic load carbs are eaten, this produces a rapid rise in BG level. If a NFB loop with a lag in it is presented with a step response change in input level, its output overshoots. This results in way too much insulin being secreted (a.k.a. massive postprandial hyperinsulinaemia), which causes feelings of postprandial sleepiness and also down-regulates insulin receptors in the brain, resulting in an eventual normal insulin level being interpreted by the brain as rebound hypoinsulinaemia, which causes feelings of ravenous hunger (as insulin acts as a satiety/satiation hormone in the brain).
Where does blood glucose come from if I haven't eaten?
When no sugary/starchy carbs are being digested, BG starts to fall. Adrenaline and noradrenaline (catecholamine hormones) are secreted by the adrenal medulla into the blood and also by sympathetic neurons. Like glucagon (see below), they stimulate the mobilisation of glycogen and triacylglycerols (stored fats) by triggering the production of cyclic AMP (adenosine mono-phosphate). Adrenaline and noradrenaline differ from glucagon in that their glucose-producing effect is greater in muscle glycogen than in liver. They also inhibit the uptake of glucose by muscle. Instead, fatty acids released from adipose tissue are used as fuel. Adrenaline also stimulates the secretion of glucagon and inhibits the secretion of insulin. Thus, catecholamines such as adrenaline and noradrenaline increase the amount of glucose released into the blood by the liver and decrease the utilization of glucose by muscle.
Pancreatic alpha cells secrete glucagon. This hormone mobilises the conversion of liver glycogen into glucose. The liver only stores about 70g of glycogen, but when combined with water, a larger mass of glucose is generated. Eventually, liver glycogen stores become depleted and BG level falls again. Glucagon also stimulates gluconeogenesis in the liver & kidneys, which is the production of glucose from non-carbohydrate precursors, like the conversion of glucogenic amino acids, such as glutamine, into glucose. This causes slow muscle wastage unless there is sufficient protein intake to provide the necessary amino acids. When BG falls to about 3.3mmol/L, the pituitary kicks-in and secretes ACTH (adrenocorticotropic hormone) which stimulates the release of cortisol from the adrenal cortex. Cortisol further stimulates gluconeogenesis in the liver & kidneys by catabolising (breaking down) muscle mass. When BG level falls to about 2mmol/L, the pituitary secretes GH (Growth Hormone) which has an anti-insulin effect.
What else does insulin do?
Insulin has many metabolic effects in the body apart from lowering BG level. It's a very anabolic hormone and an insulin spike is usually desired post workout to maximise the uptake of glucose and amino acids by muscle cells. There's nothing wrong with the occasional short-term insulin spike. It's chronically-high insulin levels that cause long-term health problems like high blood pressure and clogging of arteries.