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May 18

Beyond the Lipid Hypothesis (Part 3): What’s Insulin Got to Do With It?

It Began With a Question…

In the two previous parts of this series I covered what I had learned about how foam cell and plaque formation occur, and the process and circumstances of LDL modification. Throughout learning and writing about those topics I kept thinking about Ivor Cummins’ presentation, in which he discussed insulin’s role in heart disease. Although I found the presentation compelling, it also left me with a few questions. For one, I wondered if insulin was somehow involved in the actual process of disease, or whether insulin resistance was merely just a very early red flag for an overall unhealthy system. Was insulin resistance and hyperinsulinemia a contributory factor or was it merely a proxy marker for something else going on that was causal? 

If it was a proxy marker, what exactly caused the hyperinsulinemia and insulin resistance that also resulted in increased risk for cardiovascular disease? From my understanding “overstuffed fat cells” could result in insulin resistance of fat tissue, but what of other factors like smoking or stress? Do they also cause the same problem? Perhaps these answers should have been obvious, but I wanted to really understand, which led me to digging in-depth into the research on the topic.

How does insulin relate to heart disease?

As I continued my research on heart disease risk factors, I saw that peripheral symptoms like high blood pressure 1, 2, hypertriglyceridemia 3, 4, low HDL 5, 6, high hs-CRP 7, large waist circumference 8, and others 9 that went “hand in hand” with hyperinsulinemia (and “insulin resistance”) almost every single time.  

an insulin molecule

Insulin Molecules

Indeed, when looking at people who have already had heart attacks, if  one was looking for symptoms of diabetes (de facto hyperinsulinemia) who were not already diagnosed as diabetic, a whopping 3/4 of the people were hidden diabetic (again, hyperinsulinemic by definition).10 Likewise, the reverse is true: people with diabetes 11, and perhaps also hyperinsulinemics in general12, 13, are at a higher risk of cardiovascular disease. I have seen this correlation explained away by saying it is due to the high rates of diabetes in those who are obese. But, the question nagged at me: could the hyperinsulinemia that comes with diabetes, and often with obesity, be a contributing factor to the progression of the disease on some mechanistic level?

No Smoke, No Fire

To get a clearer idea of the situation, I began by looking at the initial indications of heart disease.  I hoped to find studies that showed whether those indicators are present when insulin is not elevated, or whether an increase in insulin exposure could be associated with a progression in the disease. The information that I found, with the help of Richard Morris of the 2KetoDudes podcast, happened to address this exact issue. In short, the original studies, and additional follow up study (involving rabbits and dogs) he mentioned, demonstrate that – at least in the animals used – when the animal is prevented from making insulin the ability to develop atherosclerosis appears to cease, or is significantly lessened 14. On the flip side, once exogenous insulin is introduced into the pseudo-diabetic animals, they appear to develop atherosclerosis “normally” 15, and in the case of the dog study, it appears to only develop atherosclerosis in the arteries in which they were injected with insulin.16

As always, animal models should be taken with a grain of salt. But the proposed model does provide a framework with which to work off of when comparing it to human cases of the disease. Although the evidence so far isn’t conclusive it does appear as though, even in humans, that insulin could also be an exacerbating factor. This is supported by worsened cardiovascular outcomes for diabetics who use primarily insulin for controlling hyperglycemia compared to other therapies.17 Additionally, one study demonstrated that in those with Familial Hypercholesterolemia the difference between those who had had a Myocardial Infarction (heart attack) and those who didn’t was that those who did have a heart attack were less insulin sensitive, and had higher insulin levels.18

Looking Beyond the Plate

If hyperinsulinemia is mechanistically involved in the progression of atherosclerosis then how could the other lifestyle risk factors for atherosclerosis be explained? For example, how could atherosclerosis be a disease of hyperinsulinemia if – for example – smoking increases the risk but does not also increase insulin resistance and hyperinsulinemia? Often I heard hyperinsulinemia referred to as something influenced by diet, namely carbohydrate levels in the diet, but I wondered if this were truly the only influence. 

Non-dietary environmental factors have been said to demonstrate an effect over heart disease risk. Could it be possible that these too are influencing insulin sensitivity and levels? The first step to finding out the answer to this question was to see if non-dietary risk factors can induce hyperinsulinemia, or worsened insulin sensitivity. The four risk factors I saw referenced most frequently were stress 19, sleep 20, infection 21, and smoking 22. All of these appear to be linked to increased risk of heart disease, and thus if insulin is truly such a crucial factor they must induce hyperinsulinemia or worsen insulin resistance in some capacity. The first clue I received that this may in fact be true was Ivor Cummins mentioning on his podcast appearance on Ketogeek that smoking and infection do in fact result in insulin resistance and hyperinsulinemia. In fact, digging into these claims, I found evidence that this was true, not only for infection 23 and smoking 24, 25 but for poor sleep 26, and some evidence pointing towards acute 27 and chronic stress,28 as well. Non-dietary risk factors do appear to influence insulin sensitivity, and hyperinsulinemia.

Merely a Red Flag?

Insulin certainly appears to relate to heart disease, but is this purely association – as is likely the case with high triglycerides or high remnant cholesterol – in other words, merely a sign of trouble elsewhere? Or, could hyperinsulinemia mechanistically contribute to the worsening of heart disease? In the research I’ve done so far, I found some interesting, although nowhere close to conclusive, hints. By no means are they proven mechanisms, nor are they all encompassing ones. These are merely minuscule puzzle pieces in an overwhelmingly large puzzle, but they may provide insight into certain facets of this chronic disease.

So what are these possible factors then? I found a few choice in vitro studies which show that insulin may have some interesting effects on certain immune cells – namely macrophages, dendritic cells, and T-cells. Perhaps not-so-coincidentally some of the influence that insulin has on the immune system ties in to some aspects of atherosclerosis.

In one study, for example, insulin inhibited T-cell’s anti-inflammatory functions thereby promoting further inflammation.29 In other words, insulin kept the immune cells on “high alert” possibly providing one reason for the higher inflammation in people with developing atherosclerosis. But, insulin’s influence on immune cells stretches far further than promoting inflammation alone.

What Goes In…

As mentioned in part 1 of the series, the special immune cells macrophages, central to the formation of foam cells via the intake of damaged LDL, may actually become better able to take in more damaged particles when exposed to insulin. In vitro, macrophages exposed to insulin doubled their expression of scavenger receptors, which resulted in an 80% increase of oxidized LDL uptake.30 

A dendritic cell.

Scavenger receptors ‘recognize’ and take up damaged or apoptotic cells and other debris in the bloodstream, including damaged LDL, and an increase in their expression turns macrophages into lean-mean cleanup machines.   If modified LDL were readily available for the macrophages to take up, this would result in increased amounts of cholesterol trapped (or perhaps more accurately, “collected”) in the arteries. The effect of insulin on immune cells doesn’t appear to be limited to macrophages, as similar results were found with regards to dendritic cells (DCs), which typically act as messengers to T-cells to provide information about pathogens but can also contribute to foam cell formation. In vitro, exposure to insulin upregulated their uptake of damaged LDL, increasing their formation into foam cells, just like what occurred with macrophages.31

… Must Come Out

But, insulin’s potential influence doesn’t stop there. The study on macrophages also showed that insulin may also inhibit cholesterol efflux from cholesterol engorged macrophages.30 Cholesterol efflux, in this case mediated through a transporter called ABCA1, work to remove cholesterol from the foam cells to HDL, so it can be thrown out (if damaged), or recycled. Although foam cell formation and cholesterol efflux are two very small parts of a very complex disease, if this works similarly in vivo (in the human body) this may shed some light on one reason how hyperinsulinemia might relate to atherosclerosis, especially longer term. It would also demonstrate just how complex the life of a foam cell truly is, and how certain environments may result in pathological outcomes.

The Life and Death of a Macrophage

But beyond even the function of a macrophage, insulin appears to affect their lifespan as well. Mouse derived macrophages exposed to insulin in vitro were less likely to “retire” themselves (a process called apoptosis; essentially, cell suicide) than those that were not exposed to insulin.32 So, not only would macrophages be more active, but also active for longer than usual, in hyperinsulinemic states, assuming the mechanisms apply in the body the same (or similar to) how they do in lab studies. But just like fat cells, or liver cells, or many other cell types, macrophages can become insulin resistant. According to in vivo mouse studies, macrophages taken from obese mice were less receptive to insulin than normal (in other words insulin resistant to a degree).33 Just as anywhere else, if a macrophage becomes sufficiently insulin resistant it no longer “sees” the insulin and acts as though it isn’t there. The result, is that the ‘longevity’ effect on macrophages no longer works and they are more likely to become apoptotic when faced with certain stressors.34 A large amount of apoptotic macrophages can result in plaques with a “necrotic” core 35, which is one of the hallmarks of unstable plaques more likely to rupture. If macrophages also become more insulin resistant in humans as they do in mice, this may be one (likely of many) contributing factors to unstable plaques and disease progression.

What Does It All Mean?

Assuming that the insulin signalling effects are similar in the human body as to what occurs in test tubes, and mouse derived cells in some cases, the effects may explain some of the later stages of atherosclerosis. If the framework is correct, we are seeing a situation in which particles in the body are being damaged en masse, being pulled over, and the cholesterol stored – either until they can be disposed of and recycled or for some further purpose that is currently unknown. When inflammation – and insulin – is high, such as from environmental factors like poor diet or smoking, this process is accelerated, made more efficient, by the macrophages ability to bring in this material – damaged LDL in this case – being increased through increased expression of scavenger receptors (garbage collectors).

 

A ceaseless onslaught of damage decade after decade…

This is the job of the macrophage with scavenger receptors at hand – to pull out potentially harmful debris and dispose of it or send it back for recycling if it would be beneficial to do so. In the case of cholesterol accumulated as a result of damaged LDL being “pulled over”, it is stored within the macrophages until it can be given to HDL. But, if insulin and inflammation remain chronically high, perhaps this efflux to HDL is delayed, and perhaps even the work and longevity of macrophages is impaired as well.

The general pathways may actually be entirely appropriate in the case of acute danger and damage – just as inflammation is helpful in the shorter term to fight off infection or help heal a wound. The issue appears to be when these reactions are no longer acute. The inflammation doesn’t cease, the insulin resistance doesn’t resolve, the hyperinsulinemia worsens, the damage that initiates it all never goes away. An immune response driven to the breaking point over the course of decades.

The Story Continues

The above only touches on a miniscule amount of the influence of insulin, as the cells with insulin receptors are numerous, the effects have likely only just begun to be documented, and I’ve only just begun to look into this area. There are many other areas to explore, including how insulin resistance could influence the energy distribution system and other peripheral markers like remnant cholesterol. As such, this is not meant to be a full explanation for why and how hyperinsulinemia may exacerbate atherosclerosis, but rather to share what I have learned so far, in order to document the exploration into the topic, ready to be corrected, or updated, as time goes on.

Even of the mechanisms described here aren’t accurate, as may be the case with any in vitro or animal study, at the very least it can be said that chronically high insulin goes hand in hand with very, very bad things. If something is chronically causing insulin resistance and hyperinsulinemia (like sleep deprivation, smoking, or poor diet) it may just be better to avoid it as best as possible to preserve your health. Likewise, if one has hyperinsulinemia and signs of insulin resistance, it may be time to take a close look at the environment you’re living in, before it is too late.
Sources

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2 Zhou, Ming-Sheng, et al. “Link between Insulin Resistance and Hypertension: What Is the Evidence from Evolutionary Biology?” Diabetology & Metabolic Syndrome, BioMed Central, 31 Jan. 2014, doi:10.1186/1758-5996-6-12.

3 Lewis, Gary F, and George Steiner. “Acute Effects of Insulin in the Control of VLDL Production in Humans: Implications for the Insulin-Resistant State.” Diabetes Care, American Diabetes Association, 1 Apr. 1996, doi:10.2337/diacare.19.4.390.

4 Al-Mahmood, AK, and N Hoque. “Dyslipidemia in Insulin Resistance: Cause or Effect.”Bangladesh Journal of Medical Biochemistry, Bangladesh Journals Online, 2014, doi:10.3329/bjmb.v7i1.18576.

5 Reaven, Gerald M. “Insulin Resistance, Compensatory Hyperinsulinemia, and Coronary Heart Disease: Syndrome X Revisited.” Wiley Online Library, American Cancer Society, 2 June 2017, 10.1136/bmjsem-2017-000236.

6 Saku, Keijiro, et al. “Hyperinsulinemic Hypoalphalipoproteinemia as a New Indicator for Coronary Heart Disease.” Journal of the American College of Cardiology, vol. 34, no. 5, Nov. 1999, pp. 1443–51. CrossRef, doi:10.1016/S0735-1097(99)00372-1.

7 Yang, June S., et al. “Association between Fasting Insulin and High-Sensitivity C Reactive Protein in Korean Adults.” BMJ Open Sport & Exercise Medicine, vol. 3, no. 1, June 2017, p. e000236. CrossRef, doi:10.1136/bmjsem-2017-000236.

8 Tabata, Shinji, et al. “Waist Circumference and Insulin Resistance: a Cross-Sectional Study of Japanese Men.” BMC Endocrine Disorders, BioMed Central, 12 Jan. 2009, doi:10.1186/1472-6823-9-1.

9 Duvillard, L., et al. “Chronic Hyperinsulinemia Does Not Increase the Production Rate of High-Density Lipoprotein Apolipoprotein AI: Evidence From a Kinetic Study in Patients With Insulinoma.” Arteriosclerosis, Thrombosis, and Vascular Biology, vol. 33, no. 10, Oct. 2013, pp. 2460–65. CrossRef, doi:10.1161/ATVBAHA.113.301597.

10 Gyberg, Viveca, et al. “Screening for Dysglycaemia in Patients with Coronary Artery Disease as Reflected by Fasting Glucose, Oral Glucose Tolerance Test, and HbA1c: A Report from EUROASPIRE IV–a Survey from the European Society of Cardiology.” European Heart Journal, vol. 36, no. 19, May 2015, pp. 1171–77. PubMed, doi:10.1093/eurheartj/ehv008.

11 Stamler, J., et al. “Diabetes, Other Risk Factors, and 12-Yr Cardiovascular Mortality for Men Screened in the Multiple Risk Factor Intervention Trial.” Diabetes Care, vol. 16, no. 2, Feb. 1993, pp. 434–44. CrossRef, doi:10.2337/diacare.16.2.434.

12 Lakka, Hanna-Maaria, et al. “Hyperinsulinemia and the Risk of Cardiovascular Death and Acute Coronary and Cerebrovascular Events in Men: The Kuopio Ischaemic Heart Disease Risk Factor Study.” Archives of Internal Medicine, vol. 160, no. 8, Apr. 2000, p. 1160. CrossRef, doi:10.1001/archinte.160.8.1160.

13 Després, Jean-Pierre, et al. “Hyperinsulinemia as an Independent Risk Factor for Ischemic Heart Disease.” New England Journal of Medicine, vol. 334, no. 15, Apr. 1996, pp. 952–58. CrossRef, doi:10.1056/NEJM199604113341504.

14 Duff, G. L., and G. C. McMILLAN. “The Effect of Alloxan Diabetes on Experimental Cholesterol Atherosclerosis in the Rabbit.” The Journal of Experimental Medicine, vol. 89, no. 6, June 1949, pp. 611–30.

15 Duff, G. L., et al. “The Effect of Alloxan Diabetes on Experimental Cholesterol Atherosclerosis in the Rabbit. IV. The Effect of Insulin Therapy on the Inhibition of Atherosclerosis in the Alloxan-Diabetic Rabbit.” The Journal of Experimental Medicine, vol. 100, no. 4, Oct. 1954, pp. 371–80.

16 Cruz, A. B., et al. “Effect of Intra-Arterial Insulin on Tissue Cholesterol and Fatty Acids in Alloxan-Diabetic Dogs.” Circulation Research, vol. 9, no. 1, Jan. 1961, pp. 39–43. CrossRef, doi:10.1161/01.RES.9.1.39.

17 Currie, Craig J., et al. “Mortality and Other Important Diabetes-Related Outcomes With Insulin vs Other Antihyperglycemic Therapies in Type 2 Diabetes.” The Journal of Clinical Endocrinology & Metabolism, vol. 98, no. 2, Feb. 2013, pp. 668–77. CrossRef, doi:10.1210/jc.2012-3042.

18Sebestjen, M., et al. “Fibrinolytic Parameters and Insulin Resistance in Young Survivors of Myocardial Infarction with Heterozygous Familial Hypercholesterolemia.” Wiener Klinische Wochenschrift, vol. 113, no. 3–4, Feb. 2001, pp. 113–18.

19 Stress and Heart Health. American Heart Association, 2014, www.heart.org/HEARTORG/HealthyLiving/StressManagement/HowDoesStressAffectYou/Stress-and-Heart-Health_UCM_437370_Article.jsp.

20 American Heart Association. “Quality of Sleep Could Increase Heart Risk — Go Red For Women.” Go Red For Women, 13 Mar. 2018, www.goredforwomen.org/about-heart-disease/heart_disease_research-subcategory/quality-of-sleep-could-increase-heart-risk/.

21 Roivainen, M., et al. “Infections, Inflammation, and the Risk of Coronary Heart Disease.” Circulation, vol. 101, no. 3, Jan. 2000, pp. 252–57. Crossref, doi:10.1161/01.CIR.101.3.252.

22 Smoking & Cardiovascular Disease (Heart Disease). American Heart Association, www.heart.org/HEARTORG/HealthyLiving/QuitSmoking/QuittingResources/Smoking-Cardiovascular-Disease_UCM_305187_Article.jsp.

23 Sammalkorpi, K. “Glucose Intolerance in Acute Infections.” Journal of Internal Medicine, vol. 225, no. 1, Jan. 1989, pp. 15–19.

24 Facchini, F. S., et al. “Insulin Resistance and Cigarette Smoking.” The Lancet, vol. 339, no. 8802, May 1992, pp. 1128–30. Crossref, doi:10.1016/0140-6736(92)90730-Q.

25 Reaven, Gerald, and Philip S. Tsao. “Insulin Resistance and Compensatory Hyperinsulinemia: The Key Player between Cigarette Smoking and Cardiovascular Disease?” Journal of the American College of Cardiology, vol. 41, no. 6, Mar. 2003, pp. 1044–47. Crossref, doi:10.1016/S0735-1097(02)02982-0.

26 Broussard, Josiane L., et al. “Impaired Insulin Signaling in Human Adipocytes After Experimental Sleep Restriction: A Randomized, Crossover Study.” Annals of Internal Medicine, vol. 157, no. 8, Oct. 2012, p. 549. Crossref, doi:10.7326/0003-4819-157-8-201210160-00005.

27 Shiloah, E., et al. “Effect of Acute Psychotic Stress in Nondiabetic Subjects on -Cell Function and Insulin Sensitivity.” Diabetes Care, vol. 26, no. 5, May 2003, pp. 1462–67. Crossref, doi:10.2337/diacare.26.5.1462.

28 Aschbacher, Kirstin, et al. “Chronic Stress Increases Vulnerability to Diet-Related Abdominal Fat, Oxidative Stress, and Metabolic Risk.” Psychoneuroendocrinology, vol. 46, Aug. 2014, pp. 14–22. Crossref, doi:10.1016/j.psyneuen.2014.04.003.

29 Han, J. M., et al. “Insulin Inhibits IL-10-Mediated Regulatory T Cell Function: Implications for Obesity.” The Journal of Immunology, vol. 192, no. 2, Jan. 2014, pp. 623–29. Crossref, doi:10.4049/jimmunol.1302181.

30 Park, Young M., et al. “Insulin Promotes Macrophage Foam Cell Formation: Potential Implications in Diabetes-Related Atherosclerosis.” Laboratory Investigation, vol. 92, no. 8, Aug. 2012, pp. 1171–80. Crossref, doi:10.1038/labinvest.2012.74.

31 Lu, Hao, et al. “Insulin Enhances Dendritic Cell Maturation and Scavenger Receptor-Mediated Uptake of Oxidised Low-Density Lipoprotein.” Journal of Diabetes and Its Complications, vol. 29, no. 4, May 2015, pp. 465–71. Crossref, doi:10.1016/j.jdiacomp.2015.03.005.

32 Iida, K. T. “Insulin Inhibits Apoptosis of Macrophage Cell Line, THP-1 Cells, via Phosphatidylinositol-3-Kinase-Dependent Pathway.” Arteriosclerosis, Thrombosis, and Vascular Biology, vol. 22, no. 3, Mar. 2002, pp. 380–86. Crossref, doi:10.1161/hq0302.105272.

33 Liang, Chien-Ping, et al. “Increased CD36 Protein as a Response to Defective Insulin Signaling in Macrophages.” Journal of Clinical Investigation, vol. 113, no. 5, Mar. 2004, pp. 764–73. Crossref, doi:10.1172/JCI19528.

34 Han, Seongah, et al. “Macrophage Insulin Receptor Deficiency Increases ER Stress-Induced Apoptosis and Necrotic Core Formation in Advanced Atherosclerotic Lesions.” Cell Metabolism, vol. 3, no. 4, Apr. 2006, pp. 257–66. Crossref, doi:10.1016/j.cmet.2006.02.008.

35 Seimon, Tracie, and Ira Tabas. “Mechanisms and Consequences of Macrophage Apoptosis in Atherosclerosis.” Journal of Lipid Research, vol. 50, no. Supplement, Apr. 2009, pp. S382–87. Crossref, doi:10.1194/jlr.R800032-JLR200.

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Kelly Roberts
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Kelly Roberts

Thank you so much for this article, Siobhan! This makes the ultimate goal
Of lowering insulin levels (as per Dr Fung) the key In a multifaceted approach to regaining our health and reversing atherosclerosis, as well as weight loss (if needed).

Nick Andre
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Nick Andre

Thanks for this! I’m continually surprised at the dirth of information on the IR-CVD link and mechanisms.

A note: inflammation typically is synonymous with healing, so chronic inflammation would imply sustained damage or impaired healing (or both). Malcom Kendrick suggests damage is a fact of life in the high pressure and turbulent areas of the arteries and further that the processes (clotting and repair and clot removal) are rather complex and subject to disruption. Your description sounds to me like it fits well with a disrupted healing mechanism. So for instance it would be possible that the damage itself is both frequent and doesn’t change but rather the clotting/EPG covering/healing process is what’s thrown out of whack. It’s also possible that there are other particular vectors whereby insulin precipitates stress or damage of some sort on the endothelium.

Gus Karageorgos
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Gus Karageorgos

You might find this interesting, if you haven’t already come across it:

“Although insulin resistance is associated with increased incidence of cardiovascular disease, whether it leads to atherosclerosis independently of its accompanying dyslipidemia remains unclear, largely because of the lack of a suitable animal model to address this question. The CarcinoEmbryonic Antigen-related Cell Adhesion Molecule-1 (CEACAM1) regulates insulin sensitivity by promoting insulin clearance in liver. Accordingly, global null deletion of Ceacam1 gene impairs hepatic insulin clearance and causes hyperinsulinemia, which in turn, results in systemic insulin resistance. Preliminary data show: (i) that global Cc1–/– null mice develop early atherosclerotic lesions and vascular dysfunction even under normal feeding conditions, and (ii) that this occurs in the absence of hyperlipidemia, despite VLDL/LDL cholesterol levels that are usually associated with atherosclerosis regression, not development. This unique animal model of atherogenesis with isolated insulin resistance in the absence of hyperlipidemia demonstrates that systemic insulin resistance resulting from hyperinsulinemia leads to vascular dysfunction and atherosclerosis in the absence of hyperlipidemia.”

https://www.utoledo.edu/research/pdfs/Najjar-R01-atherosclerosis.pdf

Stacy Huggins
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Stacy Huggins

It emphasizes, again, the importance of a consistently healthy diet.

Leyland
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Leyland

Hey, great article!

Wanted to say though the inconsistent line spacing due to the references makes it a little hard to read. This can be fixed by having in a style sheet (CSS) something like this:

sup {
vertical-align: top;
position: relative;
top: -4px;
}

Eric
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Eric
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[…] transient insulin resistance (and hyperinsulinemia) as a result of viral infection. As I’ve discussed previously, insulin resistance may be more than just a response to overstuffed fat cells, but rather may also […]

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[…] the ratio of triglycerides to HDL were predictive of carotid plaque11, insulin resistance12, 13 (which is related to increased cardiovascular disease risk), cardiovascular mortality14 and all-cause mortality in women.15 Atherogenic Index of Plasma […]

Les
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Les

I am looking for info on HbA1c and what levels are to be expected in low carb, any help would be appreciated.