Glucose is the primary energy source for the cells, muscles and brain. Glucose is transported around the body in the blood. The blood glucose concentration is ideally kept between 4.4 – 6.1 mmol/L. Insulin and glucagon are hormones that control the blood glucose concentration. This section covers:
- Carbohydrate absorption
- Insulin
- Glucagon
- Storage of excess glucose
- Ketosis
- Type 1 and type 2 diabetes
- Diabetic ketoacidosis
- Glucose testing
- Diabetes medications
Carbohydrate Absorption
Carbohydrates are consumed in food. Carbohydrate molecules range in complexity from polysaccharides, which are long chains of many monosaccharide units (sugar molecules), to individual monosaccharides (e.g., glucose, galactose and fructose), which are single carbohydrate molecules. Dextrose and glucose refer to the same molecule.
Carbohydrates are broken down into monosaccharides with the help of enzymes:
- Amylase from the saliva
- Amylase from the pancreas
- Lactase, maltase and sucrase from the surface of the small intestine wall
Monosaccharides are absorbed in the small intestine. The inner surface of the small intestine, the mucosa, is formed by many villi. The villi increase the surface area of the mucosa, improving absorption. The surface is formed by cells called enterocytes. On the inner surface of the enterocytes are proteins called sodium-glucose co-transporter 1 (SGLT1). SGLT1 transports glucose or galactose molecules and sodium ions out of the intestinal lumen and into the enterocytes. On the other side of the enterocyte, a glucose transporter (GLUT2) transports glucose or galactose out of the cell and into the blood.
CLINICAL RELEVANCE
Medications that inhibit SLGT-1 reduce the absorption of glucose in the small intestine. They have the potential to treat diabetes by helping to reduce glucose absorption and, therefore, lower blood glucose. However, they are not yet available in the UK as trials are ongoing to establish their benefits and safety.
Fructose is transported slightly differently, using GLUT5 (a fructose transporter on the cell membrane) on both sides of the enterocytes to move from the intestinal lumen to the blood.
After being absorbed in the small intestine, monosaccharides (e.g., glucose, galactose and fructose) travel in the portal vein to the liver for processing. From the liver, they enter the blood as glucose.
Insulin
Insulin is a hormone produced by the beta cells in the Islets of Langerhans in the pancreas. The beta cells create insulin and store it inside insulin secretory granules within the cell. Glucose enters the beta cells through GLUT2 on the cell membrane. The cells respond to glucose by triggering the insulin secretory granules to fuse with the cell membrane and release insulin in a process called exocytosis. The more glucose enters the cell, the more insulin is secreted.
Insulin is an anabolic hormone (a building hormone). Insulin binds to insulin receptors, primarily on liver, muscle and fat cells, leading to many effects within the cells:
- Glucose uptake by the cells
- Increasing glycogen synthesis (conversion of glucose to glycogen in liver and muscle cells)
- Increasing protein synthesis (creating new proteins, particularly in muscle cells)
- Increasing fat synthesis (creating new fats for storage in adipose tissue)
- Inhibiting gluconeogenesis (reduced glucose production by the liver)
- Inhibiting lipolysis (reduced fat breakdown in adipose tissue)
- Increasing Na+/K+-ATPase activity, driving potassium into and sodium out of the cells
Insulin is essential in enabling cells to take up glucose. When insulin binds to insulin receptors, it tells the cell to move the glucose transporter (GLUT4) from within storage vesicles inside the cell to the cell membrane on the cell surface. This is called GLUT4 translocation, meaning the GLUT4 glucose transporter moves location. GLUT4 is the doorway that allows glucose into the cell. Without insulin, there is no way for glucose to get into the cell.
Insulin lowers blood sugar levels in two main ways. First, it causes cells to absorb glucose from the blood and use it as fuel. Second, it causes muscle and liver cells to absorb glucose from the blood and convert it into glycogen for storage. This process is called glycogenesis. Glyco- refers to glycogen, and -genesis refers to its creation. Glycogen is a polysaccharide (complex carbohydrate) that stores excess glucose in the muscles and liver.
Insulin also increases the activity of the sodium-potassium pump (Na+/K+-ATPase pump) on the surface of cells. This pump uses energy (ATP) to pump two potassium ions into the cell while pumping three sodium ions out of the cell. Therefore, insulin drives potassium from the extracellular space to the intracellular space. The effect is that insulin lowers the potassium concentration in the blood.
CLINICAL RELEVANCE
Insulin is used to treat severe hyperkalaemia (high serum potassium). It stimulates the sodium-potassium pump, causing potassium ions to move from the extracellular space (including the blood) to the intracellular space. It is combined with glucose (in an insulin and dextrose infusion), as giving insulin without glucose would lead to hypoglycaemia (low blood glucose).
Glucagon
Glucagon is a hormone produced by the alpha cells in the Islets of Langerhans in the pancreas. Glucagon is a catabolic hormone (a breakdown hormone) released in response to low blood glucose levels or stress. It mainly targets the liver cells.
The main objective of glucagon is to increase blood glucose. It does this by binding to glucagon receptors, primarily on liver cells, causing:
- Increasing glycogenolysis (the conversion of glycogen into glucose)
- Increasing gluconeogenesis (the creation of new glucose from other molecules, such as amino acids and lactate)
- Inhibiting glycolysis (reduced breakdown of glucose)
Storage
Glucose is stored as glycogen in the muscles and liver. When glucose is being used up, and new glucose is not entering the digestive system (e.g., during exercise or fasting), stored glycogen is converted to glucose to maintain a steady blood glucose level and supply fuel for the cells.
Insulin tells the muscle and liver cells to store glucose as glycogen. Glucagon tells the muscle and liver cells to convert glycogen back to glucose.
The total amount of glycogen that can be stored varies depending on the person’s size and muscle mass. As a rough guide:
- The liver can store around 100 grams (or 400 calories) of glycogen
- The muscles can store around 400 grams (or 1600 calories) of glycogen
When the glycogen stores are full, excess glucose is converted to fat and stored in adipose tissue in a process called lipogenesis (the creation of fat). Fats are stored as triglycerides. The storage capacity of adipose tissue is almost indefinite. Fat tissue can continue expanding almost indefinitely to accommodate any excess glucose.
Ketosis
Ketones (or ketone bodies) are an alternative energy source when glucose is not readily available. Examples of ketone bodies are acetoacetate, 3-beta-hydroxybutyrate and acetone. They can cross the blood-brain barrier for use by the brain.
Ketogenesis (the production of ketones) occurs when there is insufficient glucose supply, and the glycogen stores are exhausted. Fatty acids are released from adipose tissue and make their way to the liver, where they are converted into ketones.
Key scenarios of when ketogenesis may occur include:
- Very low carbohydrate diets
- Prolonged fasting
- Reduced intake due to vomiting or illness (e.g., persistent vomiting in early pregnancy)
- Type 1 diabetes, where the absence of insulin makes it impossible for the cells to recognise and take up glucose
Producing ketones for fuel (ketosis) is a normal and non-harmful response to insufficient glucose. Ketones are weak acids, but do not cause acidosis under normal conditions due to:
- Utilisation by the tissues (they are used up so the levels do not get too high)
- The kidneys excrete excess ketones
- The kidneys produce bicarbonate to buffer the acid and maintain a normal pH
Ketone levels can be measured in the urine with a dipstick test and in the blood using a ketone meter. People in ketosis have a characteristic acetone smell to their breath.
CLINICAL RELEVANCE
A ketogenic diet, which involves high fat and low protein and carbohydrate intake, is sometimes used to treat certain types of severe and treatment-resistant epilepsy. The way it works is not fully understood. It can be very effective but difficult to maintain in the long term.
Type 1 Diabetes
Type 1 diabetes is a condition in which the pancreas stops producing adequate insulin. Without insulin, the cells cannot absorb glucose from the blood and use it as fuel. The cells think there is no glucose available, so the glucose level in the blood keeps rising, causing hyperglycaemia.
Type 1 diabetes may present with the classic triad of symptoms of hyperglycaemia:
- Polyuria (excessive urine)
- Polydipsia (excessive thirst)
- Weight loss (mainly through dehydration)
Treatment of type 1 diabetes involves replacing the missing insulin with regular subcutaneous insulin. Insulin is either given by regular subcutaneous injections or an insulin pump. Insulin pumps continuously push insulin through a small plastic tube (cannula) inserted under the skin. The insulin dose is adjusted to match the carbohydrate intake and the blood glucose level.
Diabetic Ketoacidosis
When type 1 diabetes is not diagnosed and treated, it progresses to diabetic ketoacidosis (DKA). DKA occurs as a consequence of inadequate insulin. Typical scenarios for DKA to occur in someone with type 1 diabetes are:
- The initial presentation
- During illness, often with an infection
- When there is poor adherence to their insulin regime
The three key features are:
- Ketoacidosis
- Dehydration
- Potassium imbalance
Without insulin, the body’s cells cannot recognise glucose, even when there is plenty in the blood, so the liver starts producing ketones for fuel. Over time, glucose and ketone levels increase. Initially, the kidneys produce bicarbonate to counteract the ketone acids in the blood and maintain a normal pH. Over time, the ketone acids use up the bicarbonate, and the blood becomes acidic. This is called ketoacidosis.
High blood glucose levels (hyperglycaemia) overwhelm the kidneys, and glucose leaks into the urine. The glucose in the urine draws more water out by osmotic diuresis. This causes increased urine production (polyuria) and severe dehydration, which results in excessive thirst (polydipsia).
Insulin drives potassium into cells. Without insulin, potassium is not added and stored in cells. The serum potassium can be high or normal as the kidneys balance blood potassium with the potassium excreted in the urine. However, total body potassium is low because very little is stored in the cells. When treatment with insulin starts, the potassium in the blood rushes into the cells, resulting in severe hypokalaemia (low serum potassium) very quickly, leading to fatal arrhythmias.
Diabetic ketoacidosis (DKA) is a medical emergency. The most dangerous aspects of DKA are dehydration, potassium imbalance, and acidosis. The priority is IV fluids with added potassium to correct the dehydration, electrolyte disturbance, and acidosis. This is followed by an insulin infusion to stop the cells from producing ketones.
Type 2 Diabetes
Type 2 diabetes is a condition where a combination of insulin resistance and reduced insulin production cause persistently high blood sugar levels (hyperglycaemia).
Repeated exposure to glucose and insulin makes the cells in the body resistant to its effects. More and more insulin is required to stimulate the cells to take up and use glucose. Over time, the pancreas becomes fatigued and damaged by producing so much insulin, and the insulin output is reduced.
A high carbohydrate diet combined with insulin resistance and reduced pancreatic function leads to chronic high blood glucose levels (hyperglycaemia). Chronic hyperglycaemia damages blood vessels and tissues and makes patients vulnerable to infections.
Testing
Glucose can be measured directly on a blood sample. The levels will vary depending on what the patient has eaten. Glucose levels will go up temporarily after a meal.
An HbA1c blood test measures glycated haemoglobin, which is how much glucose is attached to haemoglobin molecules inside red blood cells. This reflects the average glucose level over the previous 2-3 months (red blood cells have a lifespan of about 4 months). An HbA1c of 48 mmol/mol or above indicates type 2 diabetes.
Medications for Type 2 Diabetes
The main medication options for treating type 2 diabetes are:
- Metformin
- SGLT-2 inhibitors
- DPP-4 inhibitors
- GLP-1 mimetics
- Sulfonylureas (e.g., gliclazide)
- Pioglitazone
- Insulin
Metformin increases insulin sensitivity and decreases glucose production by the liver. It is the usual first-line treatment for type 2 diabetes.
The sodium-glucose co-transporter 2 (SGLT-2) protein is found in the proximal tubules of the kidneys. It acts to reabsorb glucose from the urine back into the blood. SGLT-2 inhibitors block the action of this protein, causing more glucose to be excreted in the urine.
DPP-4 inhibitors and GLP-1 mimetics work by increasing incretin activity. Incretins are hormones produced by the gastrointestinal tract in response to meals. They act to reduce the blood glucose level by:
- Increasing insulin secretion
- Inhibiting glucagon production
- Slowing absorption by the gastrointestinal tract
Incretins are broken down by an enzyme called dipeptidyl peptidase-4 (DPP-4). DPP-4 inhibitors (e.g., sitagliptin and linagliptin) block the action of DPP-4, allowing increased and prolonged activity of the incretins.
Glucagon-like peptide-1 (GLP-1) is the main incretin. GLP-1 mimetics (e.g., exenatide, liraglutide and semaglutide) mimic the action of GLP-1. They are given as a subcutaneous injection. Liraglutide and semaglutide may be used for weight loss in non-diabetic obese patients.
Gliclazide is the most common sulfonylurea. Sulfonylureas stimulate insulin release from the pancreas.
Pioglitazone is a thiazolidinedione that increases insulin sensitivity and decreases liver production of glucose.
Last updated July 2024
Now, head over to members.zerotofinals.com and test your knowledge of this content. Testing yourself helps identify what you missed and strengthens your understanding and retention.
