: Are there beneficial compounds in cigarette smoke? The UKPDS 50 study suggested that smokers experience lower rates of diabetic retinopathy Somewhat counter-intuitively, smoking status was inversely related to the development

In short: In some studies, smoking was associated with reduced risk of retinopathy only in individuals with diabetes type 2, but with an increased risk in those with type 1. In diabetes type 2, nicotine may further increase insulin levels, which may be protective against retinopathy.

In this study UKPDS 50: Risk factors for incidence and progression of retinopathy in Type II diabetes over 6 years from diagnosis", Diabetologia, 2001) they have found an association between diabetic retinopathy and:

High blood glucose levels
High blood pressure
Not smoking

The authors of the study concluded:

Somewhat counter-intuitively, smoking status was inversely related to
the development of new lesions and to the progression of established
retinopathy. This finding is not likely to be chance alone because of
the strength of the association. It, however, is at variance with
much of the published epidemiology of diabetic retinopathy.

Studies with no or mild positive association between smoking and diabetic retinopathy:

Diabetes, 1977: "The numbers of patients with proliferative retinopathy rose with increasing tobacco consumption."

American Journal of Epidemiology, 1983: "These data suggest that there is no excess risk of retinopathy in smokers or ex-smokers when contrasted with those who never smoked."

Diabetes Research, 1985: "Cigarette smoking was related to retinopathy in men but not in women."

Diabetologia, 1986: "Proliferative retinopathy was present in 12.5% of the smoking and in 6.8% of the non-smoking patients [with diabetes type 1]."

Diabetes Care, 1991: "Smoking is not likely to be an important risk factor for diabetic retinopathy."

Ophtalmology, 1996 "Cigarette smoking is not a risk factor for the long-term incidence of retinopathy."

Karger, 2013: "We found neither a beneficial nor a harmful effect of smoking on long-term incidence" [in diabetes type 1].

Diabetes Care, 2012, Diabetes Care, 2017, BMJ, 2017: They don't even mention smoking as a risk factor.

Studies with negative association between smoking and diabetic retinopathy:

American Journal of Epidemiology, 1983: "In participants diagnosed before age 30, the relative risk for the presence of retinopathy in smokers compared with those who had never smoked was 1.06 (95% confidence limits (CL) 0.97-1.18); in participants diagnosed at 30 years or older it was 0.89."

A meta analysis in Endocrine, 2018: "Compare with non-smokers, the risk of diabetic retinopathy significantly increased in smokers with type 1 diabetes while significantly decreased in smokers with type 2 diabetes."

Possible explanation: In the study mentioned in the question UKPDS 50 and in the 2018 meta analysis, smoking was negatively associated with retinopaty only in individuals with diabetes type 2. In diabetes type 2 with elevated insulin levels, nicotine could further increases insulin levels (Circulation, 1996), which could be protective against retinopathy (Cell Metabolism, 2014, Fig. 1):

PYRAZINES

A part of diabetic retinopathy pathophysiology is that excessive glucose is converted to sorbitol, which is trapped in the retinal cells and damages them (Hindawi). Pyrazines, which appear as additives in tobacco, can stimulate the clearance of sorbitol by converting it to fructose; they can also lower blood glucose and increase insulin levels (Metabolism, British Journal of Pharmacology), all of which may help prevent retinopathy. Fenugreek is high in pyrazine (PubChem).

In one systematic review of Chinese herbal medicines, including the ones with pyrazine, the authors were not able to make any conclusions about their effectiveness in diabetic retinopathy (Cochrane, 2018).

Tetramethylpyrazine (Ligustrazine)

Studies about potential beneits of tetramethylpyrazine on retina.

Single herbal medicine for diabetic retinopathy (Cochrane, 2018)
Tetramethylpyrazine Protects Retinal Capillary Endothelial Cells (TR-iBRB2) against IL-1?-Induced Nitrative/Oxidative Stress (International Journal of Molecular Science, 2015)
Neural protection by naturopathic compounds—an example of tetramethylpyrazine from retina to brain (Journal of Ocular Biology, Diseases, and Informatics, 2009)
Protective effects of tetramethylpyrazine on rat retinal cell cultures (Neurochemistry International, 2008)
Tetramethylpyrazine nitrone protects retinal ganglion cells against N?methyl?d?aspartate?induced excitotoxicity (Journal of Neurochemistry, 2017)

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I've previously researched the answer to this question. I've inserted my research on this answer below. I'm very interested to hear what you think.

Nicotine is a component of cigarette smoke. Nicotine promotes angiogenesis in the laboratory (1), including in human retinal endothelial cells.(2) However, surprisingly “cigarette smoke” inhibits angiogenesis in the laboratory(3) and epidemiological studies suggest smoking is actually protective against developing proliferative diabetic retinopathy.(4)

Pyrazine compounds have been shown to be highly potent inhibitors of angiogenesis and the growth of chorioallantoic membranes (CAM). CAM are vascular membrane found in eggs of birds and reptiles which is analogous to the mammalian placenta.(5, 6)

Tobacco leaf contains very low levels of pyrazines and contains the precursors for pyrazine formation. After the tobacco leaf is roasted, the levels of pyrazines increases dramatically whilst the levels of amino acids in the leaf simultaneously decrease.(7) Pyrazines comprise a very small fraction of cigarette smoke condensate by weight (5-50µg/cig).(7)

Internal documents obtained through litigation reveals cigarette manufacturers have added a range of non-nicotine compounds initially referred to as known as “Super-juice” to cigarettes since approximately 1976.(8) Manufacturers have disclosed that Pyrazine compounds are currently 10 of out of the 599 ingredients in cigarettes. These compounds provided users who smoke “light” cigarettes with the flavor profile of high-tar cigarettes. Pyrazines were may enhance the perceived smoothness of the cigarettes, increasing the tolerability of irritation to the respiratory tract during consumption. Furthermore, pyrazine compounds were may have complex chemosensory effects which appeared to influence the ‘learned behavior’ of consumers, promoting and enhancing consumer acceptance and ongoing usage.(8)

To date, 106 pyrazines are found in either tobacco or tobacco smoke, with 40% of these pyrazine being found in both.(7)

The effect of nicotine and pyrazine on endothelial growth and survival has been compared, confirming that nicotine acts as a growth factor for endothelial cells and pyrazine acts as a death factor for endothelial cells. The following compounds were found to inhibit the growth of endothelial cells: 2-ethylpyridine, 3-ethylpyridine, and pyrazine.(9)

One component of cigarette smoke 2,3,5,6-tetramethylpyrazine (also known as ligustrazine, used in Chinese herbal medicine), has undergone a pharmacokinetic evaluation.(10) It found that tetramethylpyrazine is rapidly absorbed from the nasal mucosa into the systemic circulation, and then crosses the blood–brain barrier (BBB) to reach the cerebral cortex.

In 2005, a group accidentally discovered that various compounds with a pyrazine-pyridine backbone are potent inhibitors of vascular endothelial growth factor receptor-2 (VEGFR2).(11)

Thus, in isolation nicotine promotes angiogenesis of retinal endothelial cells partially via the VEGF pathway. However, cigarette smoke contains not only nicotine but also pyrazine compounds which antagonize VEGF receptors, potently inhibiting the angiogenic drive of nicotine.

References

Ma X, Jia Y, Zu S, et al. alpha5 Nicotinic acetylcholine receptor mediates nicotine-induced HIF-1alpha and VEGF expression in non-small cell lung cancer. Toxicology and applied pharmacology 2014;278:172-179.
Dom AM, Buckley AW, Brown KC, et al. The ?7-nicotinic Acetylcholine Receptor and MMP-2/-9 Pathway Mediate the Proangiogenic Effect of Nicotine in Human Retinal Endothelial Cells. Investigative Ophthalmology & Visual Science 2011;52:4428-4438.
Michaud SE, Menard C, Guy LG, Gennaro G, Rivard A. Inhibition of hypoxia-induced angiogenesis by cigarette smoke exposure: impairment of the HIF-1alpha/VEGF pathway. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 2003;17:1150-1152.
Stratton IM, Kohner EM, Aldington SJ, et al. UKPDS 50: Risk factors for incidence and progression of retinopathy in Type II diabetes over 6 years from diagnosis. Diabetologia 2001;44:156-163.
Ivnitski-Steele I, Walker MK. Inhibition of neovascularization by environmental agents. Cardiovascular toxicology 2005;5:215-226.
Melkonian G, Eckelhoefer H, Wu M, et al. Growth and Angiogenesis Are Inhibited in Vivo in Developing Tissues by Pyrazine and Its Derivatives. Toxicological Sciences 2003;75:393-401.
Rodgman A, Perfetti TA. The Chemical Components of Tobacco and Tobacco Smoke, Second Edition: CRC Press; 2016.
Alpert HR, Agaku IT, Connolly GN. A study of pyrazines in cigarettes and how additives might be used to enhance tobacco addiction. Tobacco Control 2016;25:444.
Yu R, Wu M, Lin S, Talbot P. Cigarette Smoke Toxicants Alter Growth and Survival of Cultured Mammalian Cells. Toxicological Sciences 2006;93:82-95.
Meng D, Lu H, Huang S, et al. Comparative pharmacokinetics of tetramethylpyrazine phosphate in rat plasma and extracellular fluid of brain after intranasal, intragastric and intravenous administration. Acta Pharmaceutica Sinica B 2014;4:74-78.
Kuo G-H, Prouty C, Wang A, et al. Synthesis and Structure?Activity Relationships of Pyrazine-Pyridine Biheteroaryls as Novel, Potent, and Selective Vascular Endothelial Growth Factor Receptor-2 Inhibitors. Journal of Medicinal Chemistry 2005;48:4892-4909.

Very interested to get your thoughts on this. Thank you

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