Insulin Resistance
PKGhatak, MD
Insulin is an essential hormone for glucose utilization. In the absence of Insulin, blood sugar is elevated and the body is unable to generate an adequate amount of energy and many other metabolic processes are derailed. Unless Insulin is administered, death is inevitable. This is called Type I Diabetes mellitus (DM1). Type I diabetes is not a part of today's insulin resistance discussion.
In Type II Diabetes mellitus (DM2) the Insulin is either structurally abnormal or due to the presence of circulating antibodies making Insulin less effective. In this condition the blood sugar is high and Insulin levels in high to high normal. A recent study from Japan showed DM2 might result from an increased renal insulin clearance and high sugar is due to relative insulin deficiency. WHO reported that Covid-19 can destroy beta cells of the pancreas as documented in long covid.
An outline of Insulin activities.
Chemically Insulin is a polypeptide. Polypeptide hormones are prone to structural abnormalities due to minor defects in the cleavage of the long chain amino acids which make the polypeptides. Some other non-insulin polypeptides have Insulin-like actions. Notable among them are Insulin-like growth factor I and II (IGF1 and IGF2).
Insulin Carrier Proteins:
Insulin molecules are transported by carrier proteins to cells. The cell surface contains receptors for Insulin. Insulin receptors are made up of two units - A unit and B unit. The distribution of A and B units is not uniform in the tissues. The binding of insulin with a specific receptor A or B determines the metabolic path the glucose molecule takes inside the cell. Moreover, when Insulin binds with one unit then the other unit becomes inactive. In the Liver, however, Insulin binds with both units A and B. As a result, Insulin in the liver makes multiple metabolic paths unlike in other tissues. Insulin on binding with the cell receptors facilitates Glucose entry inside the cell and also stimulates the hexokinase path for the utilization of glucose and ATP generation.
Transport of Glucose molecules in and out of cells:
The glucose transport proteins belong to two groups. One is energy-independent Glucose transport proteins (GTP 1 to 13) and the second one is Sodium-Glucose Linked Transporters (SGLTs) and this requires energy expenditure.
GTP 1. This transporter helps a low-level glucose entry into all cells for tissue respiration.
GTP 2. This transporter is bidirectional. In the intestine, renal tubules and beta cells of the pancreas GTP 2 ferries glucose in and out of cells in accordance with the concentration gradient.
GTP 3. This transporter is most active in the nerve cells of the brain and spinal cord.
GTP 4. It is most prevalent in cardiac and skeletal muscles.
Energy dependent SGLT.
Energy is used for Sodium, Potassium and H ion exchanges in order to maintain Intracellular pH and blood/cytosol Na and K concentration gradients.
During this process, Glucose enters the cell when a relative Na+ ion (sodium ion) deficiency develops. In high plasma glucose concentration, the process is reversed. In post digestion, glucose absorption in the small intestine and renal tubular conservation of filtered glucose are examples of SGLT1 transport.
Besides these sites, three other sites - Liver, Muscles and White Fat Cells (WFC) are the main focus of Insulin resistance and require attention.
Liver: The liver is the prime metabolic workshop. 1. Glucose is metabolized via tricarboxylic acid cycle, 2. Excess glucose is converted to glycogen, 3. Glucose is generated from fatty acids and amino acids and 4. Glycogen is broken down to glucose. All these metabolic processes are enzyme driven and take place in cellular mitochondria and endoplasmic reticulum (EPR).
Muscles: 1. Glucose is utilized in the muscles as fuel, 2. Excess glucose is stored as glycogen and 3. glucose is generated from glycogen.
White fat cells (adipocytes): 1. Fatty acids are stored as fat molecules. 2. And fat provides energy when needed by turning back into fatty acids and glycerol.
Just as these organs differ the way glucose is utilized, similarly when Insulin resistance develops, these organs are affected in different ways and the degree of effects are variable.
Clinical entities associated with Insulin resistance.
Metabolic syndrome. This entry consists of hypertension, fatty liver, hyperlipidemia, high blood sugar and abdominal obesity.
Polycystic ovary syndrome.
Pre-diabetic stage.
Lipodystrophy.
Non-alcoholic fatty liver disease.
Mechanism of intracellular Insulin resistance in Type II Diabetes mellitus.
1. Structural abnormality of Insulin.
2. Presence of circulating Insulin antibodies.
3. Inherited mutation of genes expressing Glucose transport proteins and glucose receptors of cells.
4. Acquired mutation of genes expressing glucose transport proteins and glucose receptors.
5. Stress and Inflammation.
Stress.
Stress. Excess accumulation of lipids inside the cells diverts the metabolic path from the tricarboxylic cycle to the utilization of fat. This puts an extra burden on mitochondria and the endoplasmic reticulum.
Inflammation
Inflammation. Inside the cell cytoplasm, various inflammatory cytokines like IL-6, IL-10 and TNF alpha1 accumulate. Obesity is now considered as a chronic inflammatory of fatty tissue.
6. Molecules of intermediate products of metabolism like bioactive lipids, diacetyl- ceramide, acyl carnitine produce mitochondrial stress and inflammatory cytokines.
7. Glucagon or ACTH, glucocorticoids secreting tumors
8. Endocrine abnormality. - Hyperthyroidism, Gigantism and Acromegaly. Cushing disease.
9. Growth hormone of the anterior pituitary is antagonistic to Insulin in the skeletal muscles and liver.
10. Medication. - A common cause of high blood sugar is chronic use of systemic steroids used in immunosuppression following organ transplants and asthma and certain hematological malignancies. Other drugs may elevate sugar are Hydrochlorothiazide, Statins, Beta blockers, Amiodarone, Niacin, Antipsychotic drugs and Prostaglandin E1.
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