Ketogenic diets insulin resistance

Ketogenic or very-low carbohydrate diets have gained widespread popularity in recent years. These diets have shown promise as a first line treatment of type 2 diabetes(T2D), and have recently been added to the American Diabetes Association(ADA) as an appropriate form of medical nutrition therapy(MNT)^[1]. VitraHealth, among others has had resounding success in the treatment of T2D through ketogenic and low carbohydrate diets^[2]. Despite this success, there has been some contention over the poor results when these patients are confronted with an oral glucose tolerance test(OGTT).

Dr. Feinman^[3] offers the following as appropriate definitions of carbohydrate restricted diets:

Very low-carbohydrate ketogenic diet (VLCKD): Carbohydrate, 20–50 g/d or <10% of the 2000 kcal/d diet, whether or not ketosis occurs.
- Derived from levels of carbohydrate required to induce ketosis in most people.
Low-carbohydrate diet: <130 g/d or <26% total energy
- The ADA definition of 130 g/d as its recommended minimum.

Diabetes is defined by the ADA as a progressive loss of b-cell insulin secretion frequently on the background of insulin resistance^[4]. This coincides with in elevations in blood glucose levels and elevated insulin levels^[5].

Diabetes is typically diagnosed using HbA1c, fasting plasma glucose(FPG), and/or an oral glucose tolerance test(OGTT)^[6]. HbA1c is a long term measure of blood sugar control. A reading of >6.5% is indicative of poor blood sugar control over the previous 3 months. FPG is measured following a minimum of an 8 hour fast. A FPG reading >126mg/dl indicative of diabetes. OGTT are preformed following a minimum 8 hour fast, after which the patient will consume a 75g glucose solution. Plasma glucose readings are taken at pre-determined intervals. After the 2 hour mark a plasma glucose reading of >200mg/dl is indicative of diabetes.

So diabetes is defined by increased insulin resistance, elevated blood glucose levels(hyperglycemia), and elevated insulin levels(hyperinsulinemia). Diabetes is not defined by OGTT results. OGTT is an approximation of insulin resistance, but does not measure insulin resistance itself^[7]. Changes in beta-cell sensitivity or glucose absorption can effect test results. OGTT is a useful test, but we should not have a myopic view of diabetes screening tools.

Ketogenic diets do result in increased peripheral insulin resistance, but enhanced central insulin sensitivity. The peripheral insulin resistance in ketogenic diets does result in a poor OGTT test result like in diabetes. However these effects are rapidly reversed if the subjects are returned to a moderate carbohydrate diet.

“Responsivity to central insulin was heightened in KD rats and associated with increased expression levels of insulin receptor mRNA. Finally, returning to a chow diet rapidly reversed the effects of KD on insulin sensitivity and glucose tolerance”.^[8]

Ketogenic diets result in normal fasting insulin levels, and lower fasting glucose levels. This is not the case in diabetes.

“… after 3 days of KD feeding, plasma glucose was slightly reduced compared to chow or HFD (Fig. [1](https://physoc.onlinelibrary.wiley.com/doi/full/10.1113/JP275173#tjp13127-fig-0001)A), whereas plasma insulin levels (Fig. [1](https://physoc.onlinelibrary.wiley.com/doi/full/10.1113/JP275173#tjp13127-fig-0001)B) were not significantly different after a 6h fast, although they were elevated in HFD fed mice compared to KD.”^[9]

So where does this discordance between FPG, OGTT and HbA1c come from? There are several glucose dependent cells in the human body, namely red blood cells(RBC) and brain cells. RBC lack mitochondria, and require glucose to great ATP via anaerobic glycolysis. Fatty acids, bound to albumin cannot cross the blood brain barrier. This limits the brain cells to glucose and ketone metabolism for generation of ATP. The liver is capable to generating glucose via gluconeogenesis from glycerol, the glucogenic amino acids, odd-chain fatty acids, lactate, and pyruvate, but is limited in the quantity its able to produce. The peripheral insulin resistance in ketogenic diets can be thought of as physiological glucose sparing for the glucose dependent cells. A similar change occurs during gestation to ensure adequate nutrients are delivered to the fetus^[10].

During fasting there is an increase in peripheral insulin resistance just as in ketogenic diets. This has been termed “starvation diabetes” or pseudo-diabetes^[11]. Following an extended fast when subjected to an OGTT there will be an artificially high reading. If the subjects are returned to a moderate carbohydrate diet, this insulin resistance will rapidly revert to normal levels.

The discordance between FPG, OGTT, and HbA1c tests in subjects on a ketogenic diet clearly sets it apart from T2D. Physiological glucose sparing requires peripheral insulin resistance due to the limited amount of glucose available for the glucose dependent RBC and brain cells. This is further evidenced by similar effects during gestation, and fasting. We have to ask ourselves how appropriate is an OGTT in individuals on a ketogenic diet? How concerning is insulin resistance when low serum insulin, and low plasma glucose levels occur simultaneously?

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Ketogenic diets insulin resistance

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