Nitric Oxide - A key proponent to prevent onset & progression of type 2 diabetes

Abstract

As of today, 537 million people deal with type 2 diabetes globally(1) & 1.5 million deaths are attributed to diabetes every year. In India alone,100 million people are diabetic while 136 million are just on the border line( pre-diabetes), waiting to enter the end stage of this metabolic syndrome.? However, these numbers are just the tip of the iceberg.?

Type 2 diabetes, an inflammatory disease, manifests 2 decades before the symptom shows up. There are molecular signals before & disease onset but none of the conventional diagnostics tests could identify & measure them.These signals are asymptomatic & we wait for these signals to convert into post disease symptoms ( consider high blood sugar, high HBa1c, frequent urination & more) which we end up tracking & managing via CGM & modern medicine methods.

In brief, we may be carrying this disease as we speak but we are not aware of its manifestation.

It is a cause of concern that? almost 99% of the diabetes solutions are around healthcare delivery & tracking & managing symptoms via CGM & fad diets rather than understanding the changes in biology & chemistry before the onset & progression of type 2 diabetes. To add to this disaster, most of these CGM are not regulated & not authorized by drug control organization in India(2)(3)

The number of people suffering from diabetes is expected to rise to 643 million by 2030 and 783 million by 2045(4)

Diabetes- a financial model for many?

The global diabetes drug market was pegged at US $ 66 billion in the year 2023 & is expected to reach US $ 118 billion by year 2032(5). This becomes a compelling Pharma business case which could enable businessmen to make handsome profits with no interest in curing or preventing diabetes. Infact, these companies only make money when people are sick & spend endlessly on treatments.?

In addition to this, new age diabetes management companies do not apply any science including studying gut & oral microbiome functions & lacks primary evidence to carve out solutions that could prevent, treat or reverse chronic diseases. These new age startups, propelled by VC money, make obnoxious claims & equate temporarily suppression of Hba1c levels & /or getting rid of medicines temporarily with reversal of diabetes while tracking blood sugar level via unregulated CGM. In reality they are just suppressing symptoms. Clearly, their primary objective is to show revenue growth to raise the next round of funding irrespective of impact on metabolic health of patients.?

Last but not the least, new age FMCG companies selling cocktail snacks, drinks, supplements & OTC probiotics are laden with external chemicals, artificial sweeteners & more but lacks application of science?

Understanding human biochemical functions key to prevent type 2 diabetes

Human body is a sack of tens of thousands chemicals & chemical reactions.These biochemical reactions stimulate production of thousands of molecules & gases which program our biology for either health or disease.Any dysregulation in these biochemical activities &/or changes in chemistry(genes expression) results in production of pro-inflammatory molecules & lack of production of anti-inflammatory molecules that upregulates cytokines/ causes cytokine storm & triggers disease onset. Secretion of these molecules, also referred to as molecular signals, unfortunately cannot be identified or measured by conventional diagnostic tests as mentioned above. This mechanics applies to every single disease including diabetes

One the most essential & beneficial gas produced inside our body that regulates our insulin response & prevents type 2 diabetes is NITRIC OXIDE. However, none of healthcare practitioners or diabetes management companies care about biochemical pathways or application of science involved in production of this beneficial gas.?

Nitric oxide perform various beneficial functions which includes:?

• Facilitate how our cells inside the body communicate
• Dilate blood vessels & control oxygen & nutrient uptake & delivery in every cell?
• Controls cellular respiration
• Regulates mitochondrial biogenesis & ATP production
• Regulates insulin signaling
• Promotes blood flow
• Controls length of telomeres which predicts longevity?
• Improves exercise performance

There are two pathways that produce nitric oxide.

1. Endothelial Cell function: Endothelial cells line every single blood vessel inside our body. There is a specific enzyme -Endothelial Nitric oxide synthase(ENOS) underlying the blood vessel that in presence of oxygen converts L-arginine, a semi essential amino acid our body produces via urea cycle( we do not to take from the diet/supplementation, high amount of L-arginine could be counterproductive & cause oxidative stress via activation of arginase that competes with ENOS for Arginine ), into L-citrulline & Nitric Oxide. This Nitric oxide synthase is functional when it is coupled with an endothelial cell. However, chronic inflammation caused by gut dysbiosis(consider LPS Production, P-cresol, Indoxyl sulfate, Oxalate metabolism & more), oxidative stress & oxidation of tetrahydrobiopterin(8)-the cofactor of ENOS(BH4 to BH2) can uncouple this ENOS which leads to disruption in nitric oxide. However, as we age, ENOS’s ability to produce nitric oxide falls by 10% every year, thereby reducing our ability to produce nitric oxide by 50% by the time we reach the age of 50. Therefore the second pathway, as discussed below, becomes all the more important
2. Nitrate-Nitrite conversion via Oral Microbiome: Microbes living in our mouth convert nitrate in green vegetables such as Spinach, beetroot, arugula & more into nitrite. This nitrite when mixed with stomach acid produces nitric oxide. Use of mouthwash & fluoride in toothpaste could lead to oral microbial dysbiosis & disrupt nitric oxide production. Oral administration of PPI & antacids wipes of the stomach acid, thereby interfering with nitric oxide production

Role of Nitric oxide in insulin signaling & preventing type 2 diabetes(6)(7)

Let us dive into the role of nitric oxide in insulin signaling & how constant flow of nitric oxide could help us regulate our insulin response & keep us away from type 2 diabetes. The following chronological process explains this nitric oxide driven insulin signaling

1. We ingest a meal which is predigested by microbes in our mouth. These microbes send a biochemical signal via metabolite to pancreas to be ready to release insulin.
2. Pancreas releases insulin which binds to insulin receptors on most cells but specifically fat cells, liver cells & muscle cells which starts intracellular cascades & activates AMP Kinase & PI3 ATP Kinase
3. As a terminal step, AMP Kinase/ PI3 ATP Kinase will communicate with ENOS to activate protein GLUT4 which will go to the cell membrane, bind to glucose & remove it from circulation by transporting it to cells for storage or energy.
4. Activating GLUT4 needs a signal. This signal is nothing but nitric oxide.
5. If eNOS is uncoupled due to oxidative stress or gut microbiome driven inflammation or there is low nitric oxide production due to oral microbial dysbiosis, the process of glucose transport is impaired. This raises glucose level, leading to hyperglycemia
6. Pancreas senses it & releases more insulin. What happens next is a vicious cycle, triggering wave of hyperinsulinemia & hyperglycemia, causing insulin resistance & type 2 diabetes

To summarize, if our body cannot produce nitric oxide, we will develop insulin resistance & type 2 diabetes. Understanding our unique biochemistry, human- microbiome interactions & downstream functions of gut & oral microbiome is the key to stimulate production of nitric oxide & modulate our metabolic health.

We at Genefitletics work at the interaction of human microbiome, cloud computing & machine learning to collect, process & analyze 5 mn plus molecular datasets from oral & gut microbial genes expressed per sample & translate them into 36 plus biochemical pathways to not only determine your microbiome ability to produce nitric oxide but also construct precision nutrition interventions to stimulate nitric oxide production & regulate your overall systemic biology. More details here:www.genefitletics.com??

References below

1.https://idf.org/about-diabetes/diabetes-facts-figures/

2.https://www.fda.gov/medical-devices/safety-communications/do-not-use-smartwatches-or-smart-rings-measure-blood-glucose-levels-fda-safety-communication

3.https://theprint.in/health/using-smartwatch-to-monitor-blood-glucose-level-us-fda-strongly-advises-against-it/1980140/?amp

4. https://worlddiabetesday.org/about/facts-figures/

5. https://www.precedenceresearch.com/diabetes-drug-market

6.https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2927936/?

7.https://www.frontiersin.org/journals/endocrinology/articles/10.3389/fendo.2023.1119201/full?

8. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3749361/