March 1988 to January 2001


This subject is near and dear to my heart because of that good-looking pooch in the picture. My pet Gorky was an exceptionally beautiful Siberian Husky with piercing blue eyes and the personality of a loveable oaf.

Unfortunately, at the age of ten he was diagnosed with diabetes. He let us know by peeing in front of the TV one night right before dinner. Having never done anything like that before, we knew something was terribly wrong. The vet broke the bad news to us shortly afterwards.

Twice-daily insulin shots followed for nearly three years until his quality of life had deteriorated to such an extent, we felt it best to say goodbye. A piece of my heart went with him.

As terrible as that experience was, I credit Gorky’s illness with igniting my interest in health and nutrition. Up to that point I had never given the subject much thought. Eat, drink and poop were the extent of my concern with the topic. He changed that and I’m forever grateful.

Until his diagnosis, Gorky had been eating a grain-based kibble which contained wheat. He had also received multiple courses of antibiotics to treat various infections. In addition, he had terrible hot spots. These were itchy skin outbreaks that would drive him crazy to the point of pulling out his hair with his teeth. Allergy testing and shots finally brought that under control, but not before numerous prednisone shots were administered.

He had also steadily gained weight, but we put that down to normal aging and less exercise even though he was a consummate escape artist who enjoyed self-walking much to our dismay.

At one point he was taken to the vet because he had not defecated in days. He was found to have an impacted colon and treated. This struck us as odd as he was walked twice a day without fail and had the run of the yard.

We didn’t know what caused his diabetes and none of the various vets he saw had any clue other than to blame genetics. I find that in medicine, blaming genetics has taken the place of saying it’s “God’s Will”; meaning they have no idea what causes the condition or illness but feel it’s better to say something “sciency” lest the patient or customer doubt their abilities or question the bill.

Because of this experience, I’ve always been fascinated with insulin resistance and diabetes. As you recall, human insulin resistance is a major player in nonalcoholic fatty liver disease. It’s also a major player in cardiovascular disease, obesity, Alzheimer’s and a whole host of other disorders grouped under the heading of metabolic syndrome.

Today I want to blog about an interesting human experiment that may someday be looked upon as groundbreaking because for the first time researchers were able to induce transient insulin resistance in a group of healthy humans.

This study was conducted at the University of Pennsylvania and published in the journal Diabetes in 2010. It sought to answer the following question: Would low-level endotoxemia induce the same symptoms and markers of insulin resistance in humans that had been observed in numerous rodent studies up to that time?

To answer that question, twenty healthy Caucasian subjects all in their 20’s–10 men and 10 women–were enrolled in the trial.

Their first visit consisted of a medical screening where all the volunteers were found to have healthy blood pressure and cholesterol, an age-appropriate BMI and body-fat distribution, proper pancreatic beta cell function (beta cells produce insulin) and normal glucose control.

On their second visit two weeks later, their glucose regulation was measured using a frequently sampled intravenous glucose tolerance test or FSIGT. This would serve as a baseline against which any future glucose deviations would be measured.

The third visit consisted of an overnight stay at the testing facility. The first 24 hours consisting of an intravenous saline drip followed by a one-time intravenous infusion of lipopolysaccharide (LPS) followed by another 24-hour study phase that measured a variety of inflammatory markers and blood glucose metrics.


Not surprisingly, the endotoxin caused an immune response that the subjects experienced as an increase in temperature, heart rate and white blood cell count, which resolved 8 to 12 hours after LPS exposure.

But as can be seen from the following charts, these were not the only effects observed:


Click for larger image
Reprinted from: Experimental Endotoxemia Induces Adipose Inflammation and Insulin Resistance in Humans.


Plasma levels of the cytokines tumor necrosis factor (TNF) and interleukin 6 (IL-6) increased rapidly shortly after endotoxin exposure.

Other inflammatory markers like MCP-1 and C-reactive protein, free fatty acids and the hormones cortisol and growth hormone spiked as well.

Sustained increases in free fatty acids or lipid toxicity is recognized as a cause for the loss of pancreatic beta cell function leading to insulin-dependent diabetes.

The increases in both cortisol and growth hormones also grabbed by attention.

Cortisol is a stress hormone. Stress has always been a risk factor for cardiovascular disease hence the recommendation by every health authority under the sun to control these levels through relaxation and moderate exercise.

I’m all for stress reduction but as demonstrated in this study, it isn’t entirely under your control. Infections, both acute and chronic, raise cortisol levels which in turn raise blood glucose levels through gluconeogenesis. Chronically raised cortisol levels can also lead to muscle wasting through amino acid breakdown.

And the increase in growth hormone brings to mind a review article published in 2004 that found that shorter people, even after adjusting for income, age, social status and place of origin, have substantially lower rates of cardiovascular disease mortality and moderately lower levels of stroke fatalities.

Healthy primitive populations like the Kitavans are typically shorter than their modern-day counterparts. Could increases in growth hormone induced by endotoxemia early in life be the cause of the tall stature so prized by Western societies and also serve as a marker for increased cardiovascular risk later in life? This study would seem to suggest that the answer is yes.

Resistin levels also increased. Resistin is a hormone produced in adipose or fat tissue that inhibits insulin action hence the name.

Also noted were delayed but significant increases in leptin. Leptin is also an adipose tissue hormone that communicates with the hypothalamus to regulate long-term body-weight. Elevated leptin levels are a hallmark of obesity.

But the most important finding of the study was that sensitivity to insulin in liver, muscle and fat cells decreased by 30% from baseline in these healthy subjects.


Click to enlarge.


In the top left corner, you can see how insulin sensitivity decreased and on the bottom-left how a measure of insulin resistance increased. No change in pancreatic function as displayed in the graphs on the right was noted.

So for the first time in humans, researchers were able to show how LPS could initiate an inflammatory cascade that caused transient insulin resistance after 24 hours without any effect on pancreatic function.

To further support this hypothesis the authors noted:

  • The common observation of inflammation and development of type 2 diabetes that may emerge in patients during acute human infections and sepsis.
  • Experimental animal models of endotoxemia that elicit both fat-tissue inflammation and changes in blood lipids resembling those seen in metabolic syndrome.
  • Animal experiments in which genetic and drug blocking of cytokine receptors suppresses the inflammatory response to endotoxins and blocks the onset of insulin resistance.
  • Endotoxemia in animal studies induces gene changes in fat tissue that are remarkably similar to changes observed in the visceral fat of those afflicted with type 2 diabetes.

So now imagine a scenario of low-grade LPS translocation from the gut to systemic circulation day after day, year after year. How long would it take to develop insulin resistance that manifests itself as type 2 diabetes or cardiovascular disease?

That would depend on the genetic predisposition of the person or animal, the amount of pathogens that have taken up residence in the gut and the rate these endotoxins cross the gut wall.

Assuming this hypothesis is verified, does this mean LPS is the only cause of insulin resistance. Perhaps but I doubt it. Once you have impaired gut barrier function anything that appears in the gut lumen can potentially enter the blood stream and play a complimentary role: yeast, gram-positive bacteria, viruses, food molecules or xenobiotics like heavy metals or pollutants.

The analogy I like to use is of an open sore anywhere on your skin. Once there, your blood stream is vulnerable to whatever else happens to come into contact with that opening.

Remember that while your digestive tract is inside of you, as far as your body is concerned, its contents are as much outside of you as anything your skin comes in contact with. And there is no possible way to keep that internal “skin” healthy without the friendly gut microbes that make it and the lumen their home. Disturb them and you can rest assured that sooner or later inflammation and endotoxemia will follow.

I truly believe Gorky paid the price for his disordered gut flora. I don’t intend to make the same mistake with my family, myself or my other pets.



Mehta N. N., McGillicuddy F. C., Anderson P. D., Hinkle C. C., Shah R., Pruscino L., Tabita-Martinez J., Sellers K. F., Rickles M. R., Reilly M. P. (2010) Experimental Endotoxemia Induces Adipose Inflammation and Insulin Resistance in Humans, Diabetes, 59: 172-181.

Samaras T.T., Elrick H., Storms L. H. (2004) Is short height really a risk factor for coronary heart disease and stroke mortality? A review. Medical Science Monitor, 10(4): RA63-76.

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