Giving Monkeys Diabetes

I listened to an interesting Break Nutrition podcast (Episode 13 – What happens to fructose-fed monkeys?) on a study of Rhesus Monkeys who were fed fructose meals (Bremer AA, Stanhope KL, Graham JL, Cummings BP, Wang W, Saville BR, Havel PJ. Fructose-fed rhesus monkeys: a nonhuman primate model of insulin resistance, metabolic syndrome, and type 2 diabetes. Clin Transl Sci. 2011 Aug;4(4):243-52). (Full PDF).

…a high-fructose diet in rhesus monkeys produces insulin resistance and many features of the metabolic syndrome, including central obesity, dyslipidemia, and infl ammation within a short period of time; moreover, a subset of monkeys developed type 2 diabetes

A Rhesus monkey used in the study is closer genetically to a human than the typical mouse study.

Numerous animal studies, mostly conducted in rodents, have shown that diets high in fructose produce metabolic perturbations associated with the metabolic syndrome and T2DM. 

However, important metabolic differences exist between rodents and primates, particularly with respect to lipoprotein metabolism,the major site of lipogenesis (liver vs. adipose), and the physiology of thermogenesis.

Therefore, the results of metabolic studies performed in primates are substantively more applicable to human physiology and medicine than those from rodent studies, underscoring the importance of developing standardized nonhuman primate models of insulin resistance for the study of metabolic syndrome and T2DM.

Kimber Stanhope was one of the authors of this study. See her other study on Fructose (Not All [Sugar] Is Bad).

The charts in the study are very interesting. Gabor discusses them on the podcast.

Am I Still a Diabetic?

That’s a challenging question since by most tests I am not a diabetic. I no longer take diabetic meds and have good control of my blood sugars. The Type 2 Diabetes ADA Diagnosis Criteria are any of the following:

  1. A hemoglobin A1c (HbA1c) level of 6.5% or higher; the test should be performed in a laboratory using a method that is certified by the National Glycohemoglobin Standardization Program (NGSP) and standardized or traceable to the Diabetes Control and Complications Trial (DCCT) reference assay, or
  2. A fasting plasma glucose (FPG) level of 126 mg/dL (7 mmol/L) or higher; fasting is defined as no caloric intake for at least 8 hours, or
  3. A 2-hour plasma glucose level of 200 mg/dL (11.1 mmol/L) or higher during a 75-g oral glucose tolerance test (OGTT), or
  4. A random plasma glucose of 200 mg/dL (11.1 mmol/L) or higher in a patient with classic symptoms of hyperglycemia (ie, polyuria, polydipsia, polyphagia, weight loss) or hyperglycemic crisis

I have changed the bullet-ted list to a numbered list for convenience. I am on no diabetes medications to mask the results here:

  1. My last HbA1C was 5.2 so I pass this test.
  2. My fasting plasma glucose is less than 100 typically so I pass this test.
  3. I have not had an OGTT (more on this to follow).
  4. I have none of the symptoms of hyperglycemia at all and I have had no blood sugar measurements of 200 or higher (or anywhere near that level) since I started Low Carb.

Oral Glucose Tolerance Test (OGTT)

I don’t know if I would pass an OGTT or not. I assume I would fail such at test in spite of losing 120 lbs, etc. The reason I assume I would fail is that I think part of being on a Low Carb ketogenic diet is that my body has developed peripheral insulin resistance.

Peripheral Insulin Resistance

PIR is a normal response to the ketogenic diet and happens as a response to lowered glucose availability. Here’s a mouse study which shows that Peripheral Insulin Resistance got worse under a ketogenic diet (Kinzig KP, Honors MA, Hargrave SL. Insulin sensitivity and glucose tolerance are altered by maintenance on a ketogenic diet. Endocrinology. 2010;151(7): 3105-14.). The study measured:

After 8 wk of consuming chow or KD, caloric intake after peripheral or central insulin and insulin and glucose levels after a glucose challenge were assessed. In a separate group of rats, glucose and insulin responses to either a low- or high-carbohydrate test meal were measured. Finally, rats maintained on KD were switched back to a chow diet, and insulin sensitivity and glucose tolerance were evaluated to determine whether the effects of KD were reversible.

That answers the test that I would want to do to determine if I would pass an OGTT. What happened to the mice?

Maintenance on KD resulted in decreased sensitivity to peripheral insulin and impaired glucose tolerance.

So after 8 weeks of not eating carbohydrates the mice had trouble eating carbohydrates. Not much of a surprise there. It would take a deeper dive to see how much worse their PIR and IGT became.

Furthermore, consumption of a high-carbohydrate meal in rats that habitually consumed KD induced significantly greater insulin and glucose levels for an extended period of time, as compared with chow-fed controls.

So the mice over-reacted to carbohydrate meals by producing more glucose and insulin.

Responsivity to central insulin was heightened in KD rats and associated with increased expression levels of insulin receptor mRNA.

Not sure how to understand that if the mice were more insulin resistant. But was this effect a permanent change or was it temporary and a side effect of the diet itself?

Finally, returning to a chow diet rapidly reversed the effects of KD on insulin sensitivity and glucose tolerance. These data suggest that maintenance on KD negatively affects glucose homeostasis, an effect that is rapidly reversed upon cessation of the diet.

Although 8 weeks isn’t that long to a human it’s a long time to a mouse. I don’t know the scaling factor but it’s reasonable to assume it is years rather than the two months of the study.

So, if someone is concerned about whether or not they would pass an OGTT it seems like they probably could stop the ketogenic diet for some time (weeks maybe?) and then take the test. Most of us who do LC / Keto won’t be trying it anytime soon.

The fact is your doctor is not going to order an OGTT for you if you don’t fail one or more of the other numbers. In fact, if you fail the fasting blood sugar test the doctor might order you an HbA1C test for confirmation. And then, depending on other factors, may just decide to keep an eye on it.