NMN supplementation increases NAD+ levels, activates Sirtuins proteins, inhibits oxidative stress/inflammation and maintains mitochondrial function, and has therapeutic effects on insulin resistance and type 2 diabetes.

Sirtuins are an evolutionarily highly conserved class of NAD+-dependent histone deacylases that regulate numerous key signalling pathways in prokaryotes and eukaryotes and are involved in many biological processes, including DNA damage repair, cellular metabolism, mitochondrial function and inflammation.

It has been shown that the sirtuins proteins associated with insulin resistance and type 2 diabetes are mainly SIRT1, SIRT2, SIRT3, and SIRT6, which are implicated in their resistance to oxidative stress, inflammation, and the maintenance of mitochondrial function, and would serve as pharmacological targets for the prevention of insulin resistance and type 2 diabetes.


1. SIRT1 and insulin resistance and diabetes.

In a 2011 report, it was noted that NMN increased NAD+ levels, insulin levels, improved glucose tolerance, and lowered blood glucose in mice with type 2 diabetes, thereby alleviating the symptoms of type 2 diabetes.

In a 2019 article, it was noted that NAD+ is also activating SIRT1 and allowing it to play a role in resisting oxidative stress, inflammation, and maintaining mitochondrial function to enhance glycolipid metabolism.

SIRT1 deacetylates NF-κB (p65), leading to reduced expression of inflammatory mediators such as tumour necrosis factor-α (TNF-α) and chemotactic protein-1 (MCP-1).

SIRT1 deacetylates PGC-1α, increases fatty acid oxidation and oxidative phosphorylation, ameliorates oxidative stress, maintains mitochondrial function, improves glucose-lipid metabolism and exercise tolerance, and thus improves insulin resistance and type 2 diabetes.


2. SIRT2 and insulin resistance and diabetes.

SIRT2 is the homologue with the highest homology to SIRT1 and shares the same effect of deacetylating NF-κB (p65) and inhibiting inflammation.

Secondly, glucose-6-phosphate dehydrogenase (G6PD), a key enzyme in the pentose phosphate pathway (PPP), plays a crucial role in the oxidative stress response by producing nicotinamide adenine dinucleotide phosphate (NADPH) and reduced glutathione (GSH).

In addition, in vitro SIRT2 deacetylates NLRP3, inhibits NLRP3 inflammatory vesicle activation, and reverses aging-associated inflammation as well as insulin resistance. In vivo SIRT2 deacetylation of NLRP3 improves senescence-associated glucose homeostasis, thereby ameliorating diabetes-related symptoms.


3. SIRT3 and insulin resistance and diabetes.

Maintaining mitochondrial health during the aging process is critical for the prevention of insulin resistance and type 2 diabetes.SIRT3, which is primarily localised to mitochondria, is a major mitochondrial deacetylase that plays a major role in deacetylating and modifying the enzymatic activity of several mitochondrial proteins.

Polymorphisms in the SIRT3 gene have been associated with reduced enzyme efficiency and the development of metabolic syndrome.SIRT3 is also considered an anti-aging molecule, and high levels of SIRT3 expression have been associated with human longevity.

Previous studies have shown that SIRT3 protects organisms from metabolic stress, cancer, cardiac hypertrophy and oxidative stress, and has a key role in insulin resistance and diabetes treatment.


4. SIRT6 and insulin resistance and diabetes.

SIRT6 is located in the nucleus and is associated with longevity regulation as an adenosine diphosphate (ADP)-ribosyltransferase and NAD +-dependent deacetylase.

The article reports that SIRT6 expression extends lifespan in male mice, and that SIRT6 is associated with reduced serum levels of insulin-like growth factor (IGF)-1 and increased levels of IGF-binding protein 1. SIRT6 also attenuates NF-κB signalling at the chromatin level through histone H3K9 deacetylation.

SIRT6 is involved in DNA repair, telomere maintenance, genome stability and cellular senescence, and has a key role in the treatment of insulin resistance and diabetes.


5. Summary.

The main Sirtuins proteins associated with insulin resistance and type 2 diabetes are SIRT1, SIRT2, SIRT3, and SIRT6, which are implicated in their resistance to oxidative stress, inflammation, and maintenance of mitochondrial function.

In addition to this, other Sirtuins proteins, such as SIRT4, SIRT5, and SIRT7, play crucial roles in intracellular homeostasis and functions including redox homeostasis, anti-inflammation, cell survival, and mitochondrial quality control, and may be involved in the pathogenesis of insulin resistance and type 2 diabetes.

In conclusion, NMN supplementation has an important role in the treatment of insulin resistance and diabetes mellitus, and it plays a role in the treatment of insulin resistance and diabetes mellitus by increasing the level of NAD+ through NMN supplementation and activating the function of Sirtuins proteins.