What Might Fasting Insulin Predict About Health?

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In the comment section of my recent Definitive Guide to Blood Sugar, someone asked about fasting insulin. What does it predict? Is it the preeminent health marker? Does it actually cause harm, or is it just an indicator? Great questions and a great idea, I thought. Let’s do it. Let’s dig in.

It looks like it’s all true. Elevated insulin is both a direct cause of certain unwanted health conditions and an indicator of several other unwanted health conditions.

There are difficulties inherent to insulin. It varies wildly. There is no universally-agreed-upon reference range for healthy and unhealthy insulin levels. In the studies that find connections between elevated insulin and disease, they use quantiles—breaking up the subjects into groups of low, medium, and high insulin levels. It’s all relative.

We need to figure out what normal looks like. We can’t measure the insulin levels of paleolithic hunter-gatherers (insulin degrades pretty quickly and cannot be recovered from fossils). We can look at extant hunter-gatherers, but those are slipping away with every passing year (and to my knowledge, no one has actually tested the Hadza or Tsimane). The best way do it would be to measure the fasting insulin in a healthy, non-industrialized population largely free of disease, like the Kitava of the South Pacific. Staffan Lindeberg did test their fasting insulin levels, finding them to be very low—an average range of 3-6 uIU/mL in both men and women of all ages. He then compared them to modern Swedes, whose insulin ranged from 4-11 uIU/mL and went up with age. The average American fasting insulin runs about 8.4 uIU/mL, which likely isn’t physiologically normal.

That the Kitavans’ fasting insulin was relatively low and consistent throughout their entire lives, and they were largely free of the degenerative diseases that plague industrialized societies, suggests that a fasting insulin somewhere between 3-6 uIU/mL is the physiological norm for humans. It’s what we should be walking around with.

What’s the problem, exactly, with hyperinsulinemia?

Insulin and Overweight

One primary function of insulin is to suppress lipolysis—the release of fatty acids from body fat to be burned. This makes sense. You eat carbohydrates, glucose goes up, and the glucose has to go somewhere. Insulin rises to help you dispose of the glucose and suppress the release of free fatty acids. It’s harder to burn fat when glucose is in the picture, and insulin keeps fat locked away so you can dispose of the glucose.

Studies as far back as the 80s are pretty clear that the higher your insulin level, the higher your hunger and the more you eat. These aren’t just observational, either. Researchers actually pushed subjects’ insulin higher or lower, both with and without increasing their glucose, and found that raising their insulin was the most reliable way to increase hunger, food intake, and junk food cravings.

So hyperinsulinemia hits you from two sides:

• It prevents you from burning your own body fat.
• It makes you hungrier than your energy stores would actually suggest you should be.

That’s probably why a recent study found that reducing insulin could reduce diet-induced weight gain.

Insulin and Cancer

Another major function of insulin is to make things grow. This is an important function that makes total sense in certain situations, like when you’re trying to gain muscle, heal a wound, or if you’re a toddler who needs to grow your skeleton and get taller. But there are times where cellular growth is unwanted. Consider cancer, a disease of unchecked cellular growth. It’s no surprise that hyperinsulinemia is a risk factor for most, if not all cancers. 

While insulin isn’t everything when it comes to cancer, the links are undeniable and myriad—and worrying.

The link between colon cancer and hyperinsulinemia likely involves the tendency of insulin to increase the availability and potency of insulin-like growth factor. Post-menopausal women with genetic variants related to insulin resistance and hyperinsulinemia have a greater risk of colorectal cancer, and colon cancer patients who eat the most insulinogenic foods have poorer outcomes.

In breast cancer, hyperglycemia increases the tumors’ resistance to chemotherapy. Fixing the hyperglycemia makes chemotherapy more effective.

People with a genetic predisposition toward hyperinsulinemia have a higher chance of developing pancreatic cancer.

Independent of bodyweight, hyperinsulinemia predicts endometrial cancer; so does a high postprandial insulin response.

Diabetics who use insulin therapy have an increased risk of liver cancer. One study of Taiwanese diabetics found that those on insulin therapy have an elevated risk of dying from cancer and from non-cancer.

Most cancer cells overexpress insulin receptors, suggesting a unique affinity of cancer for circulating insulin.

Across the board, in both obese and people of normal bodyweight, hyperinsulinemia, whether it’s genetic, simulated, or diet-driven, increases cancer incidence and mortality. 

Okay, okay. That’s all rather convincing, but there’s a chance that these are merely associations and some common factor is causing both the hyperinsulinemia/insulin resistance and the cancer. Right?

What seems to counter that hypothesis is the effect of metformin, an anti-diabetic drug, on cancer. Compared to other diabetic drugs, metformin reduces the risk of cancer in type 2 diabetics. Metformin’s mechanism of action? A reduction in insulin levels and improvement of insulin resistance.

Insulin and Heart Disease

As far as heart disease risk factors go, hyperinsulinemia might be the strongest one yet. Hyperinsulinemia predicts the risk of heart attack. And it’s an independent risk factor. That’s key. You can control for LDL cholesterol, LDL particle number, triglycerides, HDL cholesterol, and it doesn’t matter. You can control for blood pressure and family history of heart disease, and it doesn’t matter. Among middle-aged men who do not have heart disease, hyperinsulinemia remains a significant and independent predictor of their risk of having a heart attack.

What about ApoB, the lipoprotein biomarker that most of the top cardiovascular health experts are pointing to as “causative” of heart disease? It’s actually one of the better predictors of insulin resistance and hyperinsulinemia. Whichever way you approach heart disease, insulin keeps popping up. Can’t escape it.

These are association studies, but the mechanisms for causality exist. As far back as 1990, researchers had established the pro-atherogenic effects of elevated insulin levels. As a review from that year explains:

Long-term treatment with insulin results in lipid-containing lesions and thickening of the arterial wall in experimental animals. Insulin also inhibits regression of diet-induced experimental atherosclerosis, and insulin deficiency inhibits the development of arterial lesions.

Could what they call an “insulin deficiency” be physiologically-normal levels of insulin? Could we all use a little “insulin deficiency”?

Insulin and Hypertension

Elevated insulin levels lead to sodium retention and water retention, which increases blood pressure. Dropping insulin—like, say, by eating a low-carb or keto diet—will counteract this effect and reduce blood pressure.

That’s why hyperinsulinemia is a consistent and independent predictor of hypertension, especially in women. Controlling for BMI doesn’t affect this relationship.

Insulin and Arthritis

There is growing evidence that insulin has an inflammatory effect on joints, reducing collagen deposition and increasing collagen degeneration. That’s in vitro research, but it jibes with many hundreds of anecdotes from people who went keto or low-carb or carnivore, dropped their insulin, and improved their arthritis—and with the common experience of reintroducing carbs and seeing the pain return.

Insulin and Fatty Liver

Among patients with non-alcoholic fatty liver, insulin resistance is almost a law. It’s very rare to see fatty liver without elevated insulin levels. Cause or effect?

Well, one job of insulin is to shove glucose into cells. It does this quite well, so long as there are vacancies. If the cell is already loaded with glucose, the liver converts the glucose into fat in a process called de novo lipogenesis. Some of this fat is exported to other cells, but a large portion is stored in the liver, especially in hyperinsulinemia.

Insulin and Mortality

Mortality is the endpoint of all endpoints. When it comes down to it, we’re trying to avoid dying. We don’t hope to live forever, but we do hope to live long and well as late into the game as possible. One way to do it is to reduce our insulin levels.

In cancer patients, for example, those who eat the most insulin-producing foods have worse cancer and overall mortality.

In middle aged adults, hyperinsulinemia predicts cancer mortality, even when you control for diabetes, obesity, and metabolic syndrome.

In older adults with type 2 diabetes, insulin use predicts mortality.

You won’t find a dietary philosophy that promotes the “benefits of hyperinsulinemia.” At the very worst, you might find folks who think elevated insulin is merely an indicator, and not a cause of disease. But this is one of those areas where almost everyone agrees “less is better.”

Where people disagree is on how to reduce hyperinsulinemia and maintain a healthy insulin level. That’s a post for another time.

Thanks for reading, everyone. Take care and be well, and may your insulin levels approach that of a Kitavan!

References

Chakrabarti P, Kim JY, Singh M, et al. Insulin inhibits lipolysis in adipocytes via the evolutionarily conserved mTORC1-Egr1-ATGL-mediated pathway. Mol Cell Biol. 2013;33(18):3659-66.

Rodin J, Wack J, Ferrannini E, Defronzo RA. Effect of insulin and glucose on feeding behavior. Metab Clin Exp. 1985;34(9):826-31.

Kaur P, Choudhury D. Insulin Promotes Wound Healing by Inactivating NFk?P50/P65 and Activating Protein and Lipid Biosynthesis and alternating Pro/Anti-inflammatory Cytokines Dynamics. Biomol Concepts. 2019;10(1):11-24.

Jung SY, Rohan T, Strickler H, et al. Genetic variants and traits related to insulin-like growth factor-I and insulin resistance and their interaction with lifestyles on postmenopausal colorectal cancer risk. PLoS ONE. 2017;12(10):e0186296.

Yuan C, Bao Y, Sato K, et al. Influence of dietary insulin scores on survival in colorectal cancer patients. Br J Cancer. 2017;117(7):1079-1087.

Al qahtani A, Holly J, Perks C. Hypoxia negates hyperglycaemia-induced chemo-resistance in breast cancer cells: the role of insulin-like growth factor binding protein 2. Oncotarget. 2017;8(43):74635-74648.

Carreras-torres R, Johansson M, Gaborieau V, et al. The Role of Obesity, Type 2 Diabetes, and Metabolic Factors in Pancreatic Cancer: A Mendelian Randomization Study. J Natl Cancer Inst. 2017;109(9)

Nead KT, Sharp SJ, Thompson DJ, et al. Evidence of a Causal Association Between Insulinemia and Endometrial Cancer: A Mendelian Randomization Analysis. J Natl Cancer Inst. 2015;107(9)

Liu XL, Wu H, Zhao LG, Xu HL, Zhang W, Xiang YB. Association between insulin therapy and risk of liver cancer among diabetics: a meta-analysis of epidemiological studies. Eur J Gastroenterol Hepatol. 2018;30(1):1-8.

Bowker SL, Majumdar SR, Veugelers P, Johnson JA. Increased cancer-related mortality for patients with type 2 diabetes who use sulfonylureas or insulin. Diabetes Care. 2006;29(2):254-8.

Baghbani-oskouei A, Tohidi M, Hasheminia M, Azizi F, Hadaegh F. Impact of 3-year changes in fasting insulin and insulin resistance indices on incident hypertension: Tehran lipid and glucose study. Nutr Metab (Lond). 2019;16:76.

Qiao L, Li Y, Sun S. Insulin Exacerbates Inflammation in Fibroblast-Like Synoviocytes. Inflammation. 2020;

Yuan C, Bao Y, Sato K, et al. Influence of dietary insulin scores on survival in colorectal cancer patients. Br J Cancer. 2017;117(7):1079-1087.

Perseghin G, Calori G, Lattuada G, et al. Insulin resistance/hyperinsulinemia and cancer mortality: the Cremona study at the 15th year of follow-up. Acta Diabetol. 2012;49(6):421-8.

Damluji AA, Cohen ER, Moscucci M, et al. Insulin provision therapy and mortality in older adults with diabetes mellitus and stable ischemic heart disease: Insights from BARI-2D trial. Int J Cardiol. 2017;241:35-40.

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