Insulin Resistance.

 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.

1. Metabolic syndrome. This entry consists of hypertension, fatty liver, hyperlipidemia, high blood sugar and abdominal obesity.

2. Polycystic ovary syndrome.

3. Pre-diabetic stage.

4. Lipodystrophy.

5. 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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Immune Reaction

 Immune Reaction

PKGhatak, MD

While reading any medical journal one usually encounters various descriptions of tissue response to injuries, infections, and illnesses, described as reactions. Immune reactions are the body's attempts to stamp out or control infection, cancer and diseases in an orderly fashion by the use of specialized cells and biochemical molecules.

Our body is pre-programmed to repose by a set pattern of actions called Innate or inherited immune reaction. And by a separate set of actions, from experience gained from encounters with the offending agents, called Acquired Immune reaction.

Innate reaction.

The skin, surface layer of the nose, mouth, GI, Respiratory and Genitourinary tracts are the physical barriers to invaders. Once that defense is breached, then the responsibilities fall on the surveillance cells for finding the invaders or cancer cells. These immune cells are Dendritic cells They recognize the molecular patterns of the invaders' surface membrane, and they attach themselves cells attach to it, like a key fits a lock and release the chemicals, called Cytokines. In repose to cytokines, neutrophils, monocytes, eosinophils, phagocytes and complements gather at the site. And a series of actions and reactions take place in the local area resulting in increased blood flow, redness, swelling, temperature elevation and temporary loss of function.

The complement pathway of action is described as the Classical Pathway. Other pathways are also present, these are Alternate Pathway, and Mannose-Lectin Pathway. These pathways are activated by yeasts, viruses and certain bacteria.

The end result of this action is that the invasion is checked, the invaders are paralyzed and eaten alive by the macrophages and the dead bodies are removed from the area in order for healing to take place.

Adaptive Immune Reaction:

Acquisition of adaptive immunity is a learned process. During the first encounter with a pathogen a signature part of the pathogen - usually, a protein molecule called antigen is recognized by the dendritic cells and the information is passed in succession to lymphocytes of various designations like B-cells, T-cells and ultimately to antibody producing B-lymphocytes. B-cells produce immunoglobulin, specific for that antigen, which combines with that antigen and neutralizes the pathogen. This antigen remains in memory in a subset of B -cells in the regional lymph nodes, but the memory is short-lived. Some memory B-cells move to the bone marrow and there retain memory permanently. 

Like innate immunity, adaptive immunity also consists of a cellular component and a Humoral component.

Adaptive immunity has a wide range of actions on pathogens and can be obtained in various ways.

Classification of adaptive immunity.

A. Natural

1. Passive immunity. A developing child in the mother's womb gets antibodies from the mother's blood via the placenta, and in some cases also from breast milk.

2. Active immunity is acquired from prior infection by that pathogen.

B. Artificial.

1. Active. Use of vaccine to generate antibodies, which protects an individual for a period of time depending on the nature of the pathogen.

2. Passive. By given IV antibodies, obtained from recovered patients or generated in animals by inoculating the animal, or obtained in the laboratory by the cell culture methods.

Abnormal Immune reaction.

Not every attempt to generate an adequate number of immune cells and antibodies against a pathogen will go smoothly. In some cases, the defect may lie in abnormal genes in a family or gene mutation of the individual. The response may be either excessive called Hypersensitivity reactions or cross reacts with normal body cells called Autoimmune diseases.

A. Hypersensitivity.

1. Immediate. The reaction happens within 24 hours after exposure to an allergen (pathogen).

Immediate hypersensitivity is of 3 different types.

Type I hypersensitivity reaction.

Also known as Immediate immune reaction, Allergy, Anaphylaxis and Atopy. The body produces Immunoglobulin E (IgE) instead of Immunoglobulin M or G (IgM, IgG). The circulation IgE binds with Mast cell receptors. When sensitized mast cells encounter the same pathogen again (like pollen, bee stings, peanuts, etc.), the encounter causes the mast cell to release the preformed granules containing Histamine, and other enzymes at the site and the consequence of that is the dilated blood vessels, fluid escaping locally. Nasal discharge, cough, parochialism, and itching is produced depending on whether it occurs in the nose, lungs, or skin respectively.

Anaphylaxis.

Anaphylaxis is an excessive amount of cytokines released in a minute after exposure resulting in a drop in blood pressure, severe tightness in the chest, low blood oxygen and cardiovascular collapse.

Type II hypersensitivity reaction.

In type II reaction, the IgM and IgG antibodies are involved. Examples of clinical conditions are Acquired hemolytic anemia, Rheumatic heart disease, Good Posture syndrome, Myasthenia gravis, Pemphigus Vulgaris, etc. 

Type III hypersensitive reaction.

Type III reaction is known as Immune complex mediated reactions. Here IgG, complement and neutrophils are involved. Clinical examples are Serum sickness, Rheumatoid arthritis, Lupus erythematosus, Glomerulonephritis, Hypersensitive pneumonitis, etc.

B. Delayed reaction.

The delayed hypersensitive reaction is also known as Type IV reaction, Cytotoxic or Cell mediated hypersensitive reaction. The reaction starts at 48 to 72 hours after exposure.

In type IV reaction, Thymic Th1 and Th17 cells are participants. Clinical examples are Contact dermatitis, poison ivy, Chronic transplant rejection, Multiple sclerosis, Celiac disease, Hashimoto thyroiditis, Granuloma annuaries, etc.

Autoimmune disease.

The acquisition of knowledge by the immune cells that are foreign is gained in the developing T cells in the thymus in the developing embryo, and the learning process continues at a slow pace during the rest of life.

                                         [https://humihealth.blogspot.com/2021/08/thymus.html]

The mutated genes, either inherited or acquired gene mutation, result in misdirected immune attacks against its own normal tissue or organ.

Clinical examples are Crohn's disease, Acquired hemophiliac anemia, Aplastic anemia, Thrombotic thrombocytopenic purpura (TTP), SLE, Multiple sclerosis, Rheumatoid arthritis, Type1 Diabetes mellitus. Pernicious anemia, etc.

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