# RKS: INSULIN - THE KEY FOR DIABETES LOCK - Enjoy Pill Life & Not Prick Life

 

# RKS: INSULIN – THE KEY FOR DIABETES LOCK

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RKS / 2026-2027 / Ser 9 / Blog 6

1st September 2026

MOST DIABETICS ARE NOT INSULIN DEFICIENT

FUNCTIONAL INSULIN KEEPS DIABETES AT BAY

Dear Reader,

Although diabetes was first recorded in the ancient Egyptian Ebers Papyrus around 1552 BCE it was only in 1889 that German scientists Joseph von Mering and Oskar Minkowski were credited relating the disease with pancreatic secretion. However, it was Belgian investigator de Meyer (1909), and also a British researcher Schaefer (1916), who proposed the name “insuline” for the hormone manufactured by pancreas.

Diabetes is usually equated with diminished insulin secretion by most but the fact is it is because of it’s defective functioning in most cases. 90% of patients have Type 2 Diabetes Mellitus (T2DM) and the goal of treatment lies therefore in not giving insulin but in increasing its functionality (or sensitivity). On the other hand, T1DM, whose incidence is a mere 10%, is hereditary and occurs because of failure of pancreas to manufacture insulin.

The focus of this blog is to fathom the fact that ~90% diabetics are of T2DM category and they, at least for many decades, have more than plentiful circulating insulin in blood. The problem  lies in insulin’s defective functioning and information regarding the same is very crucial to understand how T2DM can be best addressed.

INSULIN BASICS

The role of insulin is primarily to keep the blood glucose within the normal range of 70-100 mg/dL (normoglycemia). If it fails to do so, either one has pre-diabetes or is a diabetic patient. 

The God-given blessing is pancreas ability to up-scale insulin production whenever blood glucose is higher as in a diabetic or a prediabetic. This higher than normal insulin fasting levels is hyperinsulinemia which is defined as:

• Early hyperinsulinemia: Plasma concentrations 10-15 mIU/mL

• Definite hyperinsulinemia: Plasma concentrations >25 mIU/mL

Thus, the body makes its full attempt to get rid of excess glucose and, if unsuccessful in its attempt, pre-diabetes of T2DM is the consequence.

INSULIN MECHANISM

• Excess glucose, over and above the normal blood concentrations, enters the beta-cells in pancreas and is metabolized to adenosine triphosphate (ATP).
• ATP opens calcium (Ca++) channels in beta-cells.  
• Ca++ influx through the opened channels activate the vesicles in beta-cells and release the stored insulin in response to higher glucose blood concentrations-stimulated trigger mechanism [Glucose-Stimulated Insulin Secretion (GSIS)]. 
• Receptors of insulin (IR) are predominantly present primarily on muscle cells (myocytes) and fat tissue cells (adipocytes).
• The excess insulin released as a result of GSIS binds with insulin receptors (IR).
• The lock and key interaction between insulin and IR triggers a chain reaction within the myocytes and adipocytes.
• Signals are generated within the cell (intracellular) and specialized proteins transporters called GLUT4 (glucose transporters) move the cell's outer membrane and create gaps. 
• The glucose lthat leaves the bloodstream and enters the various target cells through the gaps is used for ATP manufacturing.

INSULIN TARGET TISSUES 

The intent of insulin is to ensure all the meal-derived glucose that has entered in blood should be pushed into cells and tissues such that normoglycemia is restored. However, there are 2 types of tissues:

• Insulin-Dependent Tissues: Muscles (70-80% of glucose) and fat cells (0-10% of glucose) require insulin for glucose to enter.
• Insulin-Independent Tissues: 20-30% of blood glucose enters organs like the brain, nerves and liver but do not require insulin for its uptake.

If the insulin is not able to efficiently remove all the glucose that has entered blood within 2-3 hours following consuming meals it is referred to as insulin resistance – meaning insulin has lost its sensitivity (ability) to deal with blood glucose efficiently.

INSULIN RESISTANCE

The only defect that can hinder insulin functioning is when it is unable to interact with IR and bind with it tightly enough akin to key exactly fitting in keyhole of a lock. Since insulin does not work the pancreas is forced to manufacture more of the hormone in an effort to neutralize hyperglycemia. The resultant higher fasting levels of insulin are indicative of insulin resistance.

• Fasting Insulin: Higher if blood glucose exceeds 100 mg/dL.
• Optimal levels are usually <8.5 mIU/mL, with metabolic experts often aiming for <5 IU/mL.
• Borderline / Early resistance: 8.5-10 mIU/mL
• Moderate / Significant resistance: >10-25 mIU/mL

Insulin resistance is typically graded using the HOMA-IR (Homeostatic Model Assessment for Insulin Resistance) score.

GRADING INSULIN RESISTANCE

HOMA-IR score vs insulin sensitivity / resistance:

• Grade 0 – Optimal sensitivity: HOMA-IR <1.0
• Grade 1 – Normal sensitivity: HOMA-IR 1.0-1.9
• Grade 2 – Early / Mild resistance: HOMA-IR 2.0-2.9
• Grade 3 – Significant / Moderate resistance: HOMA-IR 3.0-4.9
• Grade 4 – Substantial / Severe resistance: HOMA-IR >5.0

Hence, in a normal individual (nondiabetic / non-prediabetic), sans insulin resistance, the fasting plasma insulin concentrations always are below 8.5 mIU/mL. 

2 hours post-meals the amount of insulin in blood can measure between 18-166 mU/mL in a normal non-pre-/diabetic individual vs >166 mU/mL in T2DM. However, the level eventually returns back to within normal range in those whose insulin sensitivity is maintained but in the prediabetic and diabetic individuals, the baseline concentrations remain high and this constitutes insulin resistance.

DIAGNOSING INSULIN RESISTANCE

C-Peptide is a by-product of conversion of pro-insulin to insulin by pancreas and released into the bloodstream in equal amounts to insulin. Because it persists in the blood for much longer duration than insulin, a C-Peptide Test is used to accurately measure how much insulin the body is making naturally.

• Normal C-Peptide (0.5-2.0 ng/mL): Pancreas produce the required amounts of insulin which are effective in facilitating glucose uptake by target tissues.
• Low C-Peptide (<0.5 ng/mL): In late-stage T2DM pancreas struggle to produce insulin and also in T1DM wherein insulin production is virtually non-existent. In T2DM the low C-Peptide is because the blood glucose has not been kept under tight check and the pancreatic beta-cells become exhausted in keeping up with higher insulin demands to try negate hyperglycemia over the decades.
• High C-Peptide (>2.0 ng/mL): To overcome insulin resistance, the body manufactures excess insulin which is reflected in the higher C-Peptide levels. This is the most common scenario seen in prediabetes as well as in those T2DM who have not reached the stage of beta-cell exhaustion.

There are 250 million to 1 billion beta-cells and only when >75% of these are destroyed hyperglycemia results since the pancreas can the no longer cope with the higher glucose levels in blood. In most Asians, beta-cell reserves are depleted by ~50% at the time of diagnosis of diabetes, but absolute depletion of insulin production typically takes 2 to 8 years occur and it is at this juncture there becomes a medical necessity for insulin jabs for T2DM individuals. 

MANAGING INSULIN RESISTANCE

For optimizing insulin functioning there are two mechanisms:

1. Ensure the IRs are accessible.
2. Facilitate the tight binding of insulin with IR so as to trigger the required intracellular signaling mechanism for facilitating glucose entry into the target cells and thereby its utilization for ATP production.

INCREASING CELL MEMBRANE FLUIDITY

If the insulin has to interact with IR, naturally the latter must be easily accessible and hence be superficially present right on surface of the cell wall.

Fig: A floating vs sunken object depiction for understanding positions of IRs.

It is but logical that, if the IR is sunk and lie at bottom of cell wall the insulin cannot interact with the its drowned receptor when it reaches the target cell. Omega-3 fatty acids are best bet to keep the IR floating primarily because of eicosapentaenoic acid (EPA). The fluidity of a membrane is dictated by the ratio of cholesterol vs the phospholipid (PL) molecules present – PL, because of its EPA content, is fluidizing whilst cholesterol is rigidizing for cell wall.

Fig: Cell membrane structure.

The ideal normal Cholesterol-to-Phospholipid (Chol/PL or C/PL) molar ratio for a healthy human plasma membrane ranges between 0.5 and 1.0.

High concentrations of cholesterol can even cause the formation of immiscible cholesterol domains or crystals. Hence, when the C:PL ratio spikes (e.g., beyond 1.0), the membrane becomes excessively rigid and viscous. EPA enhances by fluidity by reducing the size and formation of rigid cholesterol-crystalline domains by up to 65.5%. This makes the IR more likely to float, rather than sink to bottom of cell wall, and thereby allows insulin to interact with its receptor and trigger chain of events leading to glucose uptake.

INSULIN & IR TIGHT BINDING

Glucose Tolerance Factor (GTF) is an organic chromium complex that acts as a physiological enhancer of insulin activity. By binding to IRs, GTF increases the receptor's affinity for insulin, which improves cellular responsiveness and helps the body efficiently clear glucose from the blood. Chromium supplementation can increase the number of active IRs on cell surfaces and improve the binding affinity of insulin to these receptors. 

• Chromodulin (an oligopeptide) is present in all insulin-sensitive cells and occurs in two forms.
• Chromium binds with free apochromodulin within the myocytes and adipocytes.
• When the four trivalent chromium ions bind tightly with apochromodulin it is transformed to active holochromodulin.
• The holochromodulin binds to IR and wakes up the enzyme tyrosinase present in the receptor part that is submerged within the target cell.
• Tyrosinase kinase activates PI3K (phosphoinositide 3-kinase) which is present in cytoplasm and close to inner surface of cell membrane.
• PIP2 (phosphatidylinositol 4,5-bisphosphate) is a lipid present in cell membrane. When PI3K is activated it converts PIP2 to PIP3 (phosphatidylinositol 3,4,5-triphosphate). 
• PIP3 creates a docking site for Akt (protein kinase B) enzyme present in cell membrane.
• Activated Akt signals the release of GLUT4 storage vesicles (GSVs) present in cytoplasm.
• GSVs are the container whose cargo is GLUT4. When GSVs are stimulated they move and merge with cell membrane and GLUT4 within these create holes or gaps in adipocyte / myocyte wall for facilitating blood glucose in blood to enter the target cell. 

Fig: Insulin and IR interaction and glucose uptake sequential triggers.

Summarizing, chromium complex moves into the cell to amplify the signal, driving the translocation of GLUT4 transporters to the cell membrane. This allows the cell to pull glucose out of the blood more efficiently, ultimately lowering HOMA-IR score.

CONCLUSION 

Insulin resistance is a harbinger of T2DM and its primary reasons include:

• Excess body weight (especially belly fat)
• Physical inactivity
• Family history of T2DM
• Age 35 years and older
• PCOS (polycystic ovary syndrome)
• Sleep apnea

T2DM is undeniably one of the greatest healthcare challenges worldwide, fuelled by an escalating global prevalence that exceeds 800 million cases. It operates as a silent epidemic driving severe complications like heart disease, kidney failure, blindness, paralysis and amputations, and thereby placing unsustainable burdens on both patients and family members. India is widely considered the "Diabetes Capital of the World" due to its staggering burden of the disease, with an estimated 212 million adults living with either diabetes or pre-diabetes. South Asians naturally have higher insulin resistance and are more prone to storing visceral fat (fat around the belly and organs), which severely drives up the diabetes risk. 

Regular consumption of nutraceuticals like omega-3 fatty acids and chromium can facilitate insulin binding to IR and maintain insulin sensitivity. Besides, exercising also fights insulin resistance which is only inevitable as one piles on years. Exercise lowers insulin resistance primarily by stimulating muscle contraction. Following exercising the myocytes are forced to absorb and use glucose independently of insulin. Consistent physical activity also improves insulin sensitivity by increasing muscle mass, enhancing cellular energy pathways, namely, adenosine monophosphate (AMP) – activated protein kinase (AMPK). AMPK is present in sarcoplasm as well as nucleus of myocytes. Whilst exercising the ATP stores deplete and AMP or adenosine diphosphate (ADP) spikes to activate the AMPK present. The latter then tiggers GSVs relocation to cell membrane resulting in GLUT4-mediated pores formation and thereby glucose uptake by the muscles.

Since 1 in 3 Indians is already at risk, or is having diabetes, it is best to endeavor fight insulin resistance by exercising and regular consumption of beneficial nutraceuticals. 

Opt for EPA + Chromium (especially) to ...

Save your nerves.

Save your heart.

Save your brain.

Save your eyes.

Save your limbs.

Save your kidneys.

Save your Quality of Life (QoL).

Timely.

DR R K SANGHAVI

Prophesied Enabler

Experience & Expertise: Clinician & Healthcare Industry Adviser

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