FOR IMMEDIATE RELEASE
Orthomolecular Medicine News Service, December 27, 2025

Niacin, NAD⁺, and Insulin Resistance

An Integrative Orthomolecular Medicine (IOM) Analysis of Benefits, Risks, and Proper Use

Richard Z. Cheng, M.D., Ph.D.
Editor-in-Chief, Orthomolecular Medicine News Service

In recent months, I have received repeated questions regarding the relationship between niacin use and insulin resistance.

Executive summary

• Niacin is one of the most powerful metabolic vitamins in medicine, but also one of the most misunderstood.
• Claims that "niacin causes insulin resistance" are context-dependent, not universally true.
• Niacin, niacinamide, NMN, NR, and lifestyle NAD⁺ strategies are not interchangeable-they act through different pathways and carry different tradeoffs.
• In an IOM framework, niacin's risks can often be neutralized and its benefits amplified by correcting the metabolic terrain.
• Dose, form, diet, redox status, and the ICV axis determine whether niacin heals-or harms.

1. Why niacin matters (and why it keeps coming back)

Niacin (vitamin B3) occupies a unique position in medicine:

• Precursor to NAD⁺ / NADH
• Essential for:
  • Mitochondrial ATP production
  • DNA repair (PARPs)
  • Sirtuin signaling
  • Redox balance
• One of the few nutrients ever shown to reduce cardiovascular events (pre-statin era)

Yet niacin has been progressively abandoned-not because it stopped working, but because it was used in the wrong metabolic context.

2. The mainstream objection: "Niacin causes insulin resistance"

This concern comes primarily from studies showing that high-dose niacin can:

• Increase fasting glucose
• Increase HOMA-IR
• Worsen glycemic control in diabetics

Mechanistically, this is not mysterious

Niacin (nicotinic acid):

• Activates GPR109A in adipocytes
• Suppresses lipolysis acutely
• Triggers rebound free-fatty-acid (FFA) release
• Interferes with insulin signaling via PDE3B

📌 These effects are real, reproducible, and dose-dependent.

But they are also terrain-dependent.

Importantly, HPS2-THRIVE evaluated extended-release niacin in statin-treated, high-risk populations without orthomolecular cofactor optimization, limiting the applicability of its conclusions to integrative practice. [9]

3. The IOM reframing: niacin is a metabolic amplifier, not a toxin

From an Integrative Orthomolecular Medicine (IOM) perspective:

Niacin does not "cause" insulin resistance. It amplifies pre-existing metabolic fragility.

Most negative niacin studies involved patients who were:

• On high-carbohydrate diets
• Chronically hyperinsulinemic
• Magnesium-deficient
• Vitamin C-deficient
• Often on statins
• With mitochondrial dysfunction unaddressed

In other words, niacin was layered onto a broken terrain.

4. Niacin Used Within an IOM Protocol: Why Insulin-Resistance Risk Is Largely Mitigated

A major source of confusion in the "niacin causes insulin resistance" debate is the implicit assumption that niacin is being used as a standalone intervention. In Integrative Orthomolecular Medicine (IOM), this assumption is categorically false.

In IOM practice, niacin is never prescribed as monotherapy.

When niacin is used as part of a structured IOM protocol, its purported insulin-resistance (IR) risks are substantially attenuated-and often clinically irrelevant.

4.1 Niacin is always embedded in a low-insulin metabolic context

In IOM practice, niacin is introduced only within a metabolic terrain characterized by:

• A low-carbohydrate or ketogenic dietary baseline
• Suppressed chronic hyperinsulinemia
• Reduced post-prandial glucose excursions

Under these conditions, the biochemical drivers of niacin-associated IR signaling-namely high insulin + high glucose + impaired fatty-acid handling-are absent.

👉 Niacin amplifies the existing metabolic state.
👉 In a low-insulin terrain, NAD⁺ repletion and lipid-signaling benefits dominate.

4.2 Niacin is paired with orthomolecular cofactors that counter IR mechanisms

Within IOM protocols, niacin is always combined with nutrients that directly oppose the mechanisms implicated in insulin resistance:

Magnesium

• Enhances insulin receptor signaling
• Stabilizes ATP-dependent kinases
• Reduces catecholamine-driven glucose output

Vitamin C (central to IOM)

• Improves insulin sensitivity
• Buffers oxidative stress from transient FFA flux
• Stabilizes adrenal and redox physiology

Vitamin D (terrain stabilizer in IOM)

• Improves insulin receptor expression and signaling
• Reduces inflammatory cytokine signaling (e.g., TNF-α, IL-6)
• Enhances intracellular magnesium utilization
• Supports immune-endocrine-metabolic balance

Mitochondrial support

• CoQ10
• α-lipoic acid
• Carnitine
• Adequate protein intake

These are not optional "adjuncts" but core elements of the protocol. Clinically, niacin behaves very differently in this context than when used alone.

4.3 Niacin's IR signal is a terrain marker, not an intrinsic toxicity

From an IOM perspective, transient changes in glucose or insulin metrics during niacin use do not indicate that niacin is inherently diabetogenic. Instead, they signal:

• Pre-existing hyperinsulinemia
• Mineral insufficiency (especially magnesium)
• Redox fragility
• Mitochondrial underperformance

In this sense, niacin functions as a metabolic amplifier and diagnostic signal, exposing weaknesses in terrain that require correction-not avoidance of niacin itself.

4.4 Clinical implication

This explains a consistent clinical observation:

👉 Niacin + high-carbohydrate diet = IR concern
👉 Niacin + IOM protocol = NAD⁺ benefit with minimal IR signal

Most negative niacin trials reflect context failure, not vitamin failure. Their metabolic setting does not resemble IOM practice.

Summary statement

Niacin does not "cause" insulin resistance.

Used alone, in a high-insulin terrain, it may amplify metabolic dysfunction.

Used within an Integrative Orthomolecular Medicine protocol, its insulin-resistance risk is largely mitigated-and its therapeutic value preserved.

With this clinical context established, the differences among NAD⁺-related compounds can be interpreted correctly.

5. Niacin vs niacinamide vs NMN vs NR

These are NOT the same intervention

5.1 Niacin (nicotinic acid)

Strengths

• Raises NAD⁺
• Lowers triglycerides
• Lowers Lp(a) (unique)
• Raises HDL
• Improves endothelial function

Limitations

• Flush (dose-dependent)
• GPR109A activation
• Potential IR signal in the wrong terrain

IOM interpretation

Niacin is a systemic metabolic signaling molecule, not just a vitamin.

5.2 Niacinamide (nicotinamide)

Strengths

• Raises NAD⁺ via salvage pathway (NAM → NAMPT → NAD⁺)
• No flush
• No GPR109A activation
• Minimal effect on insulin or FFAs

Limitations

• No lipid benefits
• No Lp(a) reduction
• High doses may:
  • Inhibit sirtuins
  • Increase methylation burden

IOM interpretation

Niacinamide is a metabolically quiet NAD⁺ support tool.

5.3 NMN (nicotinamide mononucleotide)

Strengths

• Direct NAD⁺ precursor
• Bypasses rate-limiting NAMPT step
• Improves mitochondrial and vascular function in models

Limitations

• Cost
• Long-term human data limited
• Effects may plateau without redox support

IOM interpretation

NMN increases NAD⁺ availability, not necessarily NAD⁺ utilization.

5.4 NR (nicotinamide riboside)

Strengths

• Oral bioavailability
• Increases NAD⁺ in humans
• Less flush, fewer lipid effects

Limitations

• Still metabolized to NAM
• Similar methylation considerations
• No lipid signaling benefits

6. The missing piece in most discussions: terrain

In Integrative Orthomolecular Medicine, "terrain" is not a metaphorical construct but a biochemical state defined by insulin signaling pressure, redox buffering capacity, mitochondrial oxidative throughput, mineral sufficiency (notably magnesium), and neuroendocrine tone. Niacin's effects on lipolysis, free-fatty-acid flux, and glucose handling are therefore not intrinsically pathological but context-dependent: in a hyperinsulinemic, magnesium-deficient, oxidatively stressed state, niacin amplifies dysregulation; in a low-insulin, redox-replete, mitochondrially supported state, the same signaling shifts favor NAD⁺ repletion and metabolic repair.

In IOM, niacin's IR risk is countered upstream, not "managed downstream."

6.1 Low-insulin dietary context (non-negotiable)

• Low-carbohydrate or ketogenic baseline
• Stable insulin levels
• Avoidance of chronic post-prandial hyperglycemia

👉 Niacin + high insulin = IR signal
👉 Niacin + low insulin = NAD⁺ benefit dominates

6.2 Magnesium sufficiency

Magnesium:

• Improves insulin receptor signaling
• Reduces catecholamine-driven glucose output
• Stabilizes ATP-dependent kinases

Magnesium deficiency is common in insulin-resistant states and is independently associated with impaired insulin signaling and glucose metabolism.

Niacin without magnesium is incomplete orthomolecular therapy.

6.3 High-dose vitamin C (central in IOM)

Vitamin C:

• Improves insulin sensitivity
• Buffers oxidative stress from FFA flux
• Supports adrenal function
• Stabilizes the redox terrain

Experimental and clinical data suggest vitamin C improves insulin sensitivity and mitigates oxidative stress associated with dysregulated lipid and glucose metabolism.

This is why, clinically, niacin + vitamin C behaves very differently from niacin alone.

6.4 Mitochondrial throughput

If NAD⁺ is increased but mitochondria are weak:

• Substrate backs up
• FFAs accumulate
• IR worsens

Support includes:

• CoQ10
• α-lipoic acid
• Carnitine
• Adequate protein
• Avoiding chronic calorie starvation

6.5 The ICV axis (Insulin-Cortisol-Vitamin C)

Niacin can transiently increase sympathetic tone.

If cortisol rhythm is already abnormal, glucose dysregulation follows.

Niacin must be used with, not against, circadian biology.

In this sense, niacin acts less as a drug with fixed effects and more as a metabolic signal whose consequences depend on the underlying biochemical terrain.

7. Practical dosage guidance (IOM-aligned)

Niacin (nicotinic acid)

• 250-500 mg/day
  → Generally safe in optimized terrain
• 500-1,000 mg/day
  → Requires low-carb diet + magnesium + vitamin C
• >1,000 mg/day
  → Selected patients only, time-limited, monitored

Avoid "set-and-forget" sustained-release niacin.

Niacinamide

• 250-500 mg/day
  → Excellent for NAD⁺ support with IR concern
• 500-1,000 mg/day
  → Short-term or targeted use
• Avoid chronic megadoses (>1.5 g/day)

NMN / NR

• NMN: 250-500 mg/day
• NR: 300-600 mg/day
• Best combined with:
  • Magnesium
  • Vitamin C
  • Mitochondrial cofactors
  • Lifestyle NAD⁺ strategies

8. Lifestyle NAD⁺ boosters (often underestimated)

• Intermittent fasting
• Ketogenic phases
• Exercise (especially zone 2 + resistance)
• Circadian alignment
• Toxin reduction

Supplements raise NAD⁺.

Lifestyle teaches the cell how to use it.

9. Final synthesis

Niacin is not anti-insulin. It is anti-fragility when used in the right terrain.

Niacinamide and NMN are safer for NAD⁺ repletion in insulin-resistant patients, but they cannot replace niacin's unique lipid and vascular effects.

In IOM, the question is never:

"Is niacin good or bad?"

The real question is:

"What terrain am I giving niacin to work in?"

References

1. Carlson LA. Nicotinic acid: the broad-spectrum lipid drug. A 50th anniversary review. J Intern Med. 2005 Aug;258(2):94-114. doi: 10.1111/j.1365-2796.2005.01528.x. PMID: 16018787.

2. Kamanna VS, Kashyap ML. Mechanism of action of niacin. Am J Cardiol. 2008 Apr 17;101(8A):20B-26B. doi: 10.1016/j.amjcard.2008.02.029. PMID: 18375237.

3. Ganji SH, Kashyap ML, Kamanna VS. Niacin inhibits fat accumulation, oxidative stress, and inflammatory cytokine IL-8 in cultured hepatocytes: Impact on non-alcoholic fatty liver disease. Metabolism. 2015 Sep;64(9):982-90. doi: 10.1016/j.metabol.2015.05.002. Epub 2015 May 7. PMID: 26024755.

4. Cantó C, Menzies KJ, Auwerx J. NAD(+) Metabolism and the Control of Energy Homeostasis: A Balancing Act between Mitochondria and the Nucleus. Cell Metab. 2015 Jul 7;22(1):31-53. doi: 10.1016/j.cmet.2015.05.023. Epub 2015 Jun 25. PMID: 26118927; PMCID: PMC4487780.

5. Kirkland JB. Niacin status, NAD distribution and ADP-ribose metabolism. Curr Pharm Des. 2009;15(1):3-11. doi: 10.2174/138161209787185823. PMID: 19149597.

6. Trammell SA, Schmidt MS, Weidemann BJ, Redpath P, Jaksch F, Dellinger RW, Li Z, Abel ED, Migaud ME, Brenner C. Nicotinamide riboside is uniquely and orally bioavailable in mice and humans. Nat Commun. 2016 Oct 10;7:12948. doi: 10.1038/ncomms12948. PMID: 27721479; PMCID: PMC5062546.

7. Pelczyńska M, Moszak M, Bogdański P. The Role of Magnesium in the Pathogenesis of Metabolic Disorders. Nutrients. 2022 Apr 20;14(9):1714. doi: 10.3390/nu14091714. PMID: 35565682; PMCID: PMC9103223.

8. Carr AC, Maggini S. Vitamin C and Immune Function. Nutrients. 2017 Nov 3;9(11):1211. doi: 10.3390/nu9111211. PMID: 29099763; PMCID: PMC5707683.

9. HPS2-THRIVE Collaborative Group; Landray MJ, Haynes R, Hopewell JC, Parish S, Aung T, Tomson J, Wallendszus K, Craig M, Jiang L, Collins R, Armitage J. Effects of extended-release niacin with laropiprant in high-risk patients. N Engl J Med. 2014 Jul 17;371(3):203-12. doi: 10.1056/NEJMoa1300955. PMID: 25014686.

10. Rajman L, Chwalek K, Sinclair DA. Therapeutic Potential of NAD-Boosting Molecules: The In Vivo Evidence. Cell Metab. 2018 Mar 6;27(3):529-547. doi: 10.1016/j.cmet.2018.02.011. PMID: 29514064; PMCID: PMC6342515.

11. Ames BN. Prolonging healthy aging: Longevity vitamins and proteins. Proc Natl Acad Sci U S A. 2018 Oct 23;115(43):10836-10844. doi: 10.1073/pnas.1809045115. Epub 2018 Oct 15. PMID: 30322941; PMCID: PMC6205492.

12. Cheng, R. Z.; Levy, T. E.; Hunninghake, R. The Insulin-Cortisol-Vitamin C Axis: A Missing Regulatory Framework in Metabolic and Hormonal Homeostasis A Narrative Review. Preprints 2025, 2025120217. doi: 10.20944/preprints202512.0217.v2

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