1. INSULIN & GLUCOSE METABOLISM
Glucose, derivative of absorbed food, transforms into energy through a series of steps and helps maintain various cells in the body. Either persistently high or low Glucose levels in the blood can be fatal and there are several intricate processes in place to ensure a normal range. A key regulatory mechanism involves the hormone Insulin. The levels of Insulin and other counter-regulatory hormones see-saw on a minute to minute basis, in response to food intake and physical activity, to manage the levels of blood glucose.
High Insulin States
The β-cells in Pancreas release Insulin, in response to the elevated blood glucose post food intake, to push glucose from bloodstream into the cells in muscle and other organs. Insulin’s job, in simple words, is to clear Glucose from the body (& blood) and facilitate its use by the cells as fuel. To achieve these goals, Insulin is a key agent in promoting
- Glucose uptake in cells,
- Breakdown of Glucose (Glycolysis),
- Synthesis of Glycogen from Glucose and storage (Glycogenesis) in liver,
- Uptake and synthesis of amino acids, proteins, and fat.
High levels of Insulin, in normal non-disease conditions, indicates that body is tackling excess food. In fact, the mere sight and smell of food, triggers the preparation of β-cells for Insulin release, through Parasympathetic Nervous System.
Insulin level is also high in disease conditions where Glucose level is high, for instance in early Type 2 Diabetes. Whether there is excess food or not, the problem here is resistance to Insulin at Cellular receptor level.
Consumption of excess food with higher proportion of carbohydrates, leads to sustained high levels of Insulin. However, over time, even high Insulin levels won’t be able to push the already high Glucose levels into cells, beginning a state called Insulin resistance, a harbinger of Type 2 Diabetes. Lack of physical activity compounds this accumulation of surplus food (read obesity) and triggering of Insulin resistance.
Pancreas cannot continue to release high levels of Insulin forever, and β-cells begin to exhaust and gradually the Insulin levels would begin to wane, even in Type 2 Diabetics. So, say, 10-15 years down the line, the pathology milieu, in a Type 2 Diabetic, would begin to resemble that of Type 1 Diabetic, where Insulin supplements as Injections are order of the day.
|Insulin||Liver||Adipose or fat Tissue||Muscle|
|Triglyceride synthesis||Amino acid uptake|
Low Insulin States
On the other hand, if the blood glucose levels are low, as seen during fasting or exercise, Insulin levels are lowered. Low insulin setting, where several other counter-regulatory hormones including Glucagon are released en masse, will trigger breakdown of
- various substrates to release glucose (Gluconeogenesis),
- Glycogen to release glucose (Glycogenolysis),
- Lipids to release glucose (Lipolysis), and
- Proteins to release glucose (Proteolysis).
The low Insulin state milieu, though a slew of hormones will enable an ambiance where other hormones prepare the body for fasting and periods of scarcity. This is what was prevalent in our ancestors when food was scarce and hence Diabetes was a rarity.
Low Insulin is sine qua non for breaking the vicious cycle of Insulin resistance and forms the crux of prevention or reversal of Type 2 Diabetes either through low carbohydrate diet or/and intermittent fasting coupled with vigorous exercise.
2. THE COUNTER-REGULATORY HORMONES
Glucagon, epinephrine, cortisol and growth hormone are check-points to Insulin and lead to increased blood Glucose levels. Insulin, though, is the dominant hormone for managing Glucose metabolism in normal conditions, and keeps the secretion of these counter-regulatory hormones under check. However, both Insulin and Glucagon, secreted by pancreas, are key hormones in maintaining Regulation of blood sugar by the pancreatic “Glucostat”
Often, these hormones are released during periods of stress such as surgery, acute infection or pregnancy and raise blood sugar as part of the combative response, the so called “stress energy”. Managing diabetes becomes difficult during these conditions, requiring abundant vigilance and amplifying the dosage of diabetes medications –
Low blood Glucose (if less than less than 80mg/dl, Glucagon becomes the dominant hormone), as in prolonged fasting or vigorous exercise, trigger the α-cells in Pancreas to release Glucagon. Glucagon tries various methods to raise blood Glucose levels –
- Lipolysis: Breaking down stored fat (triglycerides) into fatty acids and glycerol, which in turn passes through liver to generate Glucose
- Conversion of various substrates (amino acids) to release glucose (Gluconeogenesis). Amino acids, released from muscles in periods of prolonged starvation, are expensive fuel as body virtually melts down.
- Force the liver to release its strategic reserves of glucose (Breakdown of glycogen – Glycogenolysis) into the bloodstream.
Epinephrine and Cortisol:
These are stress hormones released by Adrenal Medulla and Adrenal Cortex respectively and collectively cause lipolysis releasing free fatty acids and glycerol, which are in turn passed on to liver to release Glucose into the plasma.
Though the above three can individually raise blood Glucose, acting in cohesion, they can synergistically increase the Glucose levels in the blood to a much higher level, during the time of stress, led by Sympathetic nervous system.
The elevated Blood Glucose levels would then need Insulin to ensure the elevated blood glucose is pushed into the cells and alleviate the symptoms of low glucose blood levels. Hypoglycemia quickly can become catastrophic event.
Growth hormone secreted by the pituitary gland, increases glucose concentrations in the blood and decreases the body’s sensitivity to insulin, thus opposing the normal action of insulin. Growth hormone concentrations can be up to 2-3 times higher in diabetes patients compared to normal individuals. Increased Growth hormone secretion could be one of the driving factors of ‘dawn phenomenon’ – transient rise in blood glucose concentrations early morning before waking from sleep, to gear up the body for the day ahead.
3. NORMAL RESPONSES TO EATING AND FASTING
Understanding the normal metabolic changes during fasting and fed states helps us build appropriate strategies for tackling Diabetes. Comprehending these innards well will ensure compliance and stricter control of Diabetes disease.
Food intake triggers release of insulin. Elevated Insulin signals well fed state and leads to
- Glucose uptake by muscle and brain, to be used directly for energy
- Glycolysis – breakdown of glucose for energy
- Glycogenesis – Glycogen synthesis and storage in liver,
- Fatty acid (Triacylglycerol) synthesis/storage, and
- DNA, RNA and protein synthesis.
High insulin levels, during the fed state, also decreases
- Glycogen breakdown
- Fatty acid oxidation
- Protein degradation
In short, this is building or anabolic milieu in the body.
Human body is resilient and has several advanced ways to tackle periods of food scarcity. Series of contrary events, as opposed to fed states, take place in fasting states, proportional to the duration of fasting –
- Insulin levels start to fall and glucagon levels rise
- Breakdown of glycogen releases glucose for energy.
- Glycogen stores last for roughly 24 hours.
24 hours to 2 days:
- Gluconeogenesis ––liver manufactures new glucose from amino acids.
- Glucose levels remain within normal range in non-diabetic individuals.
2 to 3 days:
- Lipolysis – breakdown of Triglycerides (storage form of fat) into glycerol and fatty acids.
- Glycerol is used for gluconeogenesis.
- Fatty acids are used either directly for energy by many tissues in the body or are converted into Ketone bodies (fatty acids cannot cross blood-brain barrier) to be used by brain.
5 days and beyond (prolonged fast) –
- Extremely low insulin and glucagon levels, make lipolysis the mainstay for maintenance of basal metabolism.
- Gluconeogenesis is minimized, to prevent nitrogen wasting, ammonia build-up, and loss of muscle mass
- Growth hormone levels peak to maintain muscle mass and lean tissues.
- Any drop in metabolic rate is kept in check by elevated norepinephrine (adrenalin) levels.