High Blood Sugar Without Side Effects?

There’s a small set of people who have a genetic defect (GCK-MODY) which gives them high blood sugar levels but they have no diabetic side effects. This paper looks at this group (Ali J. Chakera, Anna M. Steele, Anna L. Gloyn, Maggie H. Shepherd, Beverley Shields, Sian Ellard, Andrew T. Hattersley. Recognition and Management of Individuals With Hyperglycemia Because of a Heterozygous Glucokinase Mutation. Diabetes Care Jul 2015, 38 (7) 1383-1392).

Even after 50 years of mild hyperglycemia, people with GCK-MODY do not develop significant microvascular complications, and the prevalence of macrovascular complications is probably similar to that in the general population.

They don’t treat these people since they don’t respond to medications.

Treatment is not recommended outside pregnancy because glucose-lowering therapy is ineffective in people with GCK-MODY and there is a lack of long-term complications.

These people don’t get extra high levels of blood sugar but they are in the range diagnosed for pre-diabetic up to diabetic.

People with GCK-MODY have an HbA1c between 5.8 and 7.6%.

It seems to me that this might be evidence of something other than the blood sugar being the cause of damage in diabetics. Could it be the higher Insulin levels (hyperinsulinemia)? The paper presents some possibilities.

This is likely to be due to a number of factors: the hyperglycemia is mild, stable, and under homeostatic regulation; the hyperglycemia is often lower than the threshold above which the risk of diabetes complications increases; and people with GCK-MODY do not have the additional burden of the metabolic syndrome, with weight, lipid profile, and blood pressure being comparable with the general population 

Protein Leverage Hypothesis Counterpoint

In 2005, Simpson and Raubenheimer postulated the ‘protein leverage hypothesis’ (PLH) to address the question of which nutrient (fat or carbohydrates) is responsible for obesity. The PLH idea is that like numerous other animal species, human macronutrient regulation minimizes variation in absolute protein intake. There is a lot of evidence to this effect (Martínez Steele E. Ultra-processed foods, protein leverage and energy intake in the USA. Public Health Nutr. 2018 Jan;21(1):114-124.).

A New Study

There’s a new study which shows that fat intake, not protein or carbohydrate intake, regulates weight gain in mice (Hu S1, et.al. Dietary Fat, but Not Protein or Carbohydrate, Regulates Energy Intake and Causes Adiposity in Mice. Cell Metab. 2018 Jul 4. pii: S1550-4131(18)30392-9).

The study exposed C57BL/6 mice to 29 different diets varying from 8.3% to 80% fat, 10% to 80% carbohydrate, 5% to 30% protein, and 5% to 30% sucrose. The study concluded that:

Mice regulate their food consumption primarily to meet an energy rather than a protein target, but this system can be over-ridden by hedonic factors linked to fat, but not sucrose, consumption.

The study has a cute graphic.

Examining the Graphic

An ad libitum fed lean mouse didn’t get leaner on higher protein. A lean mouse didn’t get fatter on high carbohydrates.

It took higher fat to make a mouse fatter. Interestingly the steps for fat were much larger than the steps for carbohydrates or protein. I can understand why protein would be limited but why did they limit carbohydrates to 30% maximum? Also, what were the other macros when protein was provided?

Fat Source

The fat source was “a mix of cocoa butter, coconut oil, menhaden oil, palm oil and sunflower oil” (‘Proof’ it’s fats, not carbs, that cause weight gain – but only in mice. Tuesday July 17 2018.) All of these are refined plant based fats with different types of fats.

Sugar and Carbohydrates

The base carbohydrate source was corn starch and maltodextrose. The sugar content (sucrose) was varied.

Protein Source

The protein source was casein (found in animal milk).

Men are not Mice

The ‘Proof’ cited above details some of the issues with the mice/men difference (‘Proof’ it’s fats, not carbs, that cause weight gain – but only in mice. Tuesday July 17 2018.).

The Peak Point

Turned out that there was a peak point in fat when more than 70% of calories from fat resulted in a drop of calories eaten. Lower levels of fat would have had higher levels of carbohydrates.

Low Carb is Killing Me

A new study in the Lancet tells me that my low carb diet is going to make me die sooner (Sara B Seidelmann, et.al. Dietary carbohydrate intake and mortality: a prospective cohort study and meta-analysis The Lancet, August 16, 2018). Turned out that people who were eating relatively lower carbs back 25 years ago were more likely to have died than those who ate a “moderate” amount of carbohydrates.

The study is one of the weakest forms of study which used one of the weakest forms of evidence and reaches marginal conclusions. 

Questionable Assumptions

  • The definition of low carbs is less than 40%. That’s not ketogenic levels at all.
  • Association studies do not show causation (Studying Research – Part 5 – Types of Studies). The rooster crowing does not cause the sun to rise.
  • People who did Low Carb diets back in the Atkins diet days were more likely to have done so for health reasons at the time (Wikipedia – Atkins Diet).
  •  The study showed that these people were also more likely to be obese, diabetic and smokers. Teasing out these differences can be tough.
  • What someone ate as their regular diet 25 years ago is not a very good indication of what they ate in the following 25 years (Studying Research – Part 4 – Methodological Problems).
  • A Food Frequency Questionaire used to determine diet. There are many issues with this methodology (Food Frequency Questionnaire at a Glance). 
  • All-cause mortality rates don’t filter out irrelevant causes (What does all-cause mortality mean?).
  • The hazard ratio for low carb eaters was 1.20 which means that the low carb eaters were 20% more likely to die (Wikipedia – Hazard ratio).
  • The hazard ratio for high carb eaters was even higher. High carb is defined as 70% or higher.
  • The study was slanted towards plant based sources rather than animal based sources.
  • The study mashed together studies which controlled for different elements. 
  • The society as a whole has shifted in what we have eaten over this 25 year period. How is that factored into this?
  • The study lead, Sara B Seidelmann, is a well published cardiologist but this seems to be her only paper on this particular subject (list of her papers). The same with most of the rest of the authors.

Let’s compare the Hazard Ratio in the paper (HR=1.2) with Type 2 Diabetes (Tancredi M, et.al. Excess Mortality among Persons with Type 2 Diabetes. 
N Engl J Med. 2015 Oct 29;373(18):1720-32.):

As compared with controls, the hazard ratio for death from any cause among patients younger than 55 years of age who had a glycated hemoglobin level of 6.9% or less (≤52 mmol per mole of nonglycated hemoglobin) was 1.92 (95% CI, 1.75 to 2.11)

No, low carb is not killing me. Diabetes was killing me. 

How Much Protein on Low Carb Diets?

The DRI (Dietary Reference Intake) is 0.8 grams of protein per kilogram of body weight, or 0.36 grams per pound.  This amounts to:

* 56 grams per day for the average sedentary man.
* 46 grams per day for the average sedentary woman.

As I noted in a prior post (Overfeeding Studies) minimum protein requirements are determined by nitrogen studies which typically give standard diets with adjusted protein contents until excess nitrogen is produced in the urine. This indicates that the person is in a positive protein intake since the excess protein is being expelled as urea (nitrogen).

The problem is the standard diet is used for the baseline which includes carbohydrates. In the standard diet glucose needs are completely met from carbohydrates. In a Low Carb diet glucose needs come from fat and protein in the diet (via GNG).

It is important to determine if the Dietary Recommended Intake (DRI) for protein is adequate for people on a Low Carb Diet (Protein Intake – How Much Protein Should You Eat Per Day?).

So how should we determine if those are adequate levels for a person on a low carb diet? Protein Sparing Modified Fasts (PSMF) are low carb diets which also are low fat. They are typically higher levels of protein with the intent of preserving Lean Body Mass (LBM) in the face of a high caloric deficit. There is a study which determined the Protein needs via nitrogen balance on the PSMF diet (Bruce R Bistrian, George L Blackburn, Jean-Pierre Flatt, Jack Sizer, Nevin S Scrimshaw, Mindy Sherman. Nitrogen Metabolism and Insulin Requirements in Obese Diabetic Adults on a Protein-Sparing Modified Fast. Diabetes Jun 1976, 25 (6) 494-504).

 In the three patients who had extensive nitrogen-balance studies, balance could be maintained chronically by 1.3 gm. protein per kilogram IBW, despite the gross caloric inadequacy of the diet. 

This seems like a reasonable approximation for the minimal protein needs on a Low Carbohydrate Diet. The number 1.3g/kg of body weight is significantly more than 0.8g/kg of body weight. A 200 lb (100kg) person would need to eat a minimum of 130g of protein a day.

Here is a similar view from Dr Donald Layman (Donald K. Layman; The Role of Leucine in Weight Loss Diets and Glucose Homeostasis, The Journal of Nutrition, Volume 133, Issue 1, 1 January 2003, Pages 261S–267S).

More recently, the overall contribution of dietary amino acids to glucose homeostasis received further support on the basis of quantitative evaluations of hepatic glucose production. Jungas et al. provided an elegant argument that amino acids serve as a primary fuel for the liver and the primary carbon source for hepatic GNG. Other investigators extended this thinking with the findings that endogenous glucose production in the liver is a critical factor in maintenance of blood glucose. After an overnight fast, GNG provides 70% of hepatic glucose release, with amino acids serving as the principal carbon source. These studies provide further evidence for a linkage between dietary protein and glucose homeostasis.


…a diet with low carbohydrates and increased protein would reduce the role of insulin in managing acute changes in blood glucose and maximize the liver’s role in regulating blood glucose through hepatic GNG.

We need additional protein in a low carb diet to provide the substrate for GNG.

A Tale of Two Breakfasts

Some people have Bulletproof coffee for breakfast. For myself, I eat four eggs and four pieces of bacon for breakfast. What’s the nutritional difference between the two meals?

Here is the nutritional facts for Bulletproof coffee compared to 4 Eggs and 4 slices of bacon.

The calories are nearly identical. The energy cost of eating protein (about 35%) more than offsets the small number of calories more in the bacon and eggs. There’s almost no energy cost to eating fat (around 95% gets stored).

The Bulletproof Coffee recipe is almost all fat. The bacon and eggs breakfast provides a nearly matched number of fat and protein grams.

Protein Components in the Bacon/Eggs

The protein components of the bacon and eggs are:

I specifically selected the ingredients to meet the Leucine Threshold for Muscle Protein Synthesis. It is valuable to hit this threshold after the overnight fast.

What About Vitamins?

Once again, bacon and eggs for the win. The complaint could then be made that vitamins are fat soluble. The beauty of the bacon and eggs breakfast is that there’s still plenty of fat.

Glucose Needs on Low Carb Diet

We have a dietary requirement for some glucose. When we eat a Low Carbohydrate Diet we don’t get enough glucose directly from our diet. In that case our bodies will make glucose from either protein or fat either from our diet or from our body via Gluconeogenesis (GNG). This is shown in this study (A Paoli, A Rubini, J S Volek & K A Grimaldi. Beyond weight loss: a review of the therapeutic uses of very-low-carbohydrate (ketogenic) diets. European Journal of Clinical Nutrition volume 67, pages 789–796 (2013):

…glucose is formed from two sources: from glucogenic amino acids and from glycerol liberated via lysis from triglycerides.

There’s a study which looked at the increase in Gluconeogenesis from a Low Carbohydrate diet (Veldhorst MA1, Westerterp-Plantenga MS, Westerterp KR. Gluconeogenesis and energy expenditure after a high-protein, carbohydrate-free diet. Am J Clin Nutr. 2009 Sep;90(3):519-26.


Ten healthy men with a mean (+/-SEM) body mass index (in kg/m(2)) of 23.0 +/- 0.8 and age of 23 +/- 1 y received an isoenergetic H diet (H condition; 30%, 0%, and 70% of energy from protein, carbohydrate, and fat, respectively) or a normal-protein diet (N condition; 12%, 55%, and 33% of energy from protein, carbohydrate, and fat, respectively) for 1.5 d according to a randomized crossover design, and EE was measured in a respiration chamber.

Endogenous glucose production (EGP) and fractional gluconeogenesis were measured via infusion of [6,6-(2)H(2)]glucose and ingestion of (2)H(2)O; absolute gluconeogenesis was calculated by multiplying fractional gluconeogenesis by EGP. Body glycogen stores were lowered at the start of the intervention with an exhaustive glycogen-lowering exercise test.


EGP was lower in the H condition than in the N condition (181 +/- 9 compared with 226 +/- 9 g/d; P < 0.001), whereas fractional gluconeogenesis was higher (0.95 +/- 0.04 compared with 0.64 +/- 0.03; P < 0.001) and absolute gluconeogenesis tended to be higher (171 +/- 10 compared with 145 +/- 10 g/d; P = 0.06) in the H condition than in the N condition. EE (resting metabolic rate) was greater in the H condition than in the N condition (8.46 +/- 0.23 compared with 8.12 +/- 0.31 MJ/d; P < 0.05). The increase in EE was a function of the increase in gluconeogenesis (DeltaEE = 0.007 x Deltagluconeogenesis – 0.038; r = 0.70, R(2) = 0.49, P < 0.05). The contribution of Deltagluconeogenesis to DeltaEE was 42%; the energy cost of gluconeogenesis was 33% (95% CI: 16%, 50%).


Forty-two percent of the increase in energy expenditure after the H diet was explained by the increase in gluconeogenesis. The cost of gluconeogenesis was 33% of the energy content of the produced glucose.

Although this was only 1.5 days long they did deplete glycogen through excercise and zero carbs for a day and a half should be long enough to lower glycogen to ketogenic levels.

Overfeeding Studies

There are quite a few interesting overfeeding studies. The typical format of these studies is to take subjects and first determine the caloric intake to keep them in energy balance (weight stable). The study will then increase one of the three macronutrients (fat, carbohydrate or protein) and then look at the effects. Often studied are fat accumulation, body composition changes or blood lipids. The change is then attributed to the changed macronutrient.

Both fat and carbs are shown to increase weight and make body composition worse. Protein has been shown to not increase weight and increased protein improves body composition.

The problem I have with the study methodology is that the changes can’t all be attributed to the increased macronutrient alone since the increased macronutrients interacts with the other baseline macronutrients. 

Take as an example a baseline diet which provides 25% of calories from protein, 50% from carbohydrates and 25% from fat. For a 2000 calorie a day person that’s 500 calories from protein (125g), 1000 calories from carbohydrates (250g) and 500 calories from fat (55.6g).

Adding 500 calories a day of fat, for instance would change the fat from 500 calories to 1000 calories (111g) while leaving the carbohydrates and protein at the same amounts. So if there’s an increase in body fat how much of a change in body fat can be attributed to the fat alone? How much of the increase in weight is due to the interaction between fat and, say, carbohydrates? Perhaps there’s a carbohydrate/fat limit where if you exceed the amount of carbs/fat it causes much more fat storage due to the combination of the two?

Low Carb Diet Reduces the Variables

The Low Carb Diet essentially reduces the three [macronutrient] variables to two. The calories from carbohydrates are typically 5% on a very low carb diet. So the only two macronutrients left are protein and fat. Yet, even this is no guarantee for weight loss. There are people (think Jimmy Moore) who eat on the very low protein and high fat end. There are others (think Ted Naiman) who eat on the higher protein and lower fat end.

Jimmy and Ted

Clearly, what Jimmy is doing isn’t working well for Jimmy and what Ted is doing is working quite well for Ted. Jimmy is an n=1 for overeating fat. Ted is an n=1 for eating more protein. However, Ted controls for total calories and Jimmy seems to have no clue how many calories he eats in a particular day.

The difference may be exercise. It may be diet. I have a hard time finding a picture of a higher protein advocate who looks like Jimmy but I can find plenty of keto personalities who eat a lot of fat and look more like Jimmy (the Two Keto Dudes comes to mind).

A Fear of Protein?

Jimmy and others have been afraid of protein with the fear that eating protein causes the protein to turn to chocolate cake (Jimmy is infamous for making the comparison to chocolate cake at one point). I’ve looked at this subject in many posts in this BLOG (Protein does not turn into chocolate cake). 

Ted says he spends most of his day trying to convince diabetics that they should eat more protein. It is true that protein does raise blood sugar by a small amount in a diabetic but the benefits outweigh that small rise and if a person is not a diabetic protein will lower blood sugar (Glucose Response to Protein).

Problem with Protein Studies

Protein studies are used to determine protein requirements. These studies look at nitrogen balance which is either negative (the person isn’t getting enough nitrogen from their diet) or positive (the person is getting enough nitrogen from their diet). 

The problem is that protein studies are based on so-called “balanced” diets where carbohydrates are available to make the amount of glucose required by the body (Low Carbs and Gluconeogenesis). These studies don’t include the effects of gluconeogenesis (GNG). If you are eating low carb then protein provides the substrate materials (from your diet) for (GNG). For diabetics their body is already really good at making glucose via GNG (Gluconeogenesis – Later Thoughts). 

If you barely eat enough protein to meet the minimum (nitrogen replacement) requirements then your body will get it’s GNG needs from fat. Suppose that the body requires 120g of carbohydrates per day for the brain and other essential organs. If you eat 20g of carbohydrates a day that’s 100 short. If half the protein gets converted to glucose and your body requires 200g of protein to provide that glucose. (Note these are very rough numbers but the idea applies).

So, if you are on a low carbohydrate diet you need more protein than just your replacement needs. You also need protein to meet your GNG needs.

Many Ways to Lose Weight

There are quite a few ways to lose weight. Most of them involve eating less calories than you burn. You can lose weight with Low Fat or Low Carb diets. You can even lose weight with a Low Protein diet. All of these work if you are at a caloric deficit. High fat and high carbs at the same time don’t work at the same time unless your goal is weight gain.

Also, there’s an interaction with the macronutrient type. Some macronutrients encourage fat gain. Truthfully, fat is always stored easily as fat – but only accumulates in a caloric surplus. You burn off what you eat if you are in fat balance. If you eat less fat you lose body fat. If you eat more fat you will gain body fat.

Even people who eat a carnivore diet are eating a large portion of their calories as fat. As an example: Ribeye Steak from Walmart has 22g of protein and 20g of fat in an 4 oz serving. That’s 88 calories from protein and 180 calories from fat. Or 33% of calories from protein and 67% of calories from fat.

Consuming large amounts of fat is unavoidable in the weight maintenance portion of Low Carb diets. There’s a top limit on the amount of protein that you can/should eat. As an example, if you are eating 1 g of protein per lb of body weight and you weigh 200 lbs that’s 200 gram of protein or 800 calories. The rest of your daily caloric needs will then come from fat.  If you are eating 2000 calories a day that’s 1200 calories from fat.

The problem is that many people, like Jimmy Moore, eat at a maintenance or higher level of calories and macros when they need to be in a weight loss phase. Jimmy eats low protein and carbs so it’s not protein or carbs that are making Jimmy fat. The extra fat that Jimmy eats accumulates as fat when he eats more calories from fat regardless of whether he avoids carbohydrates or not. Fat doesn’t magically vanish when you eat it and it doesn’t require much energy to store -it is about 95% efficient to store fat (Eat Too Much Fat – Get Fat).

Maximizing Weight Loss

The only way for someone like Jimmy to lose weight is to get enough protein and limit dietary fat. If Jimmy has a goal weight of 200 lbs he should eat 200 grams of protein spread over four meals a day of 50 grams per meal  (Protein Gurus – Part 2). That maximizes Muscle Protein Synthesis and provides enough substrate to maintain his blood glucose. Jimmy should then eat enough fat to cover the amount he won’t be eating from his body. Jimmy has at least 100 lbs of fat mass and could easily have a 3000 calories a day deficit. It wouldn’t be at all pleasant but he could do it.

If you want to find out what you can do on a maximum fat loss diet, check out our Keto calculator.

Improved Overfeeding Studies

So how would you improve an overfeeding study? I would isolate the macronutrients and absolutely minimize the other macronutrients. Do a lean protein study (essentially a PSMF study) with variable protein levels. I’d do a carbohydrate variation study with minimal protein and fat. I’d do a fat level study with minimal carbs and protein. All of them in isolation. Wouldn’t be a very balanced diet at 90%, 5%, 5%. Couldn’t be too long a term. May not pass ethics boards. But it could tease out the interactions between the macronutrients. 

Glucose Response to Protein

I wrote a post a while back comparing my blood sugar response to protein compared to a non-diabetic friend’s response (Blood Sugar Responses Compared). In that n=2 study I noted that my blood sugar goes up a bit when I consume protein but my non-diabetic associate’s blood sugar goes down.

Turns out this difference has been well known for nearly a century. A while back I reviewed a paper by Conn from 1936 (Protein vs Carbs). That paper (J Clin Invest. 1936 Nov; 15(6): 665–671. THE GLYCEMIC RESPONSE TO ISOGLUCOGENIC QUANTITIES OF PROTEIN AND CARBOHYDRATE. Jerome W. Conn and L. H. Newburgh.) which compared the blood sugar response of two non-diabetics against fifteen diabetics.

Turns out there was a difference between the diabetics and the non-diabetics which matched my own n=2 results. Here’s the blood sugar response of the non-diabetics.

And here’s the blood sugar response of the diabetics.

The blood sugar of the non-diabetics dropped when lean beef was eaten. The blood sugar of the diabetics went up a small amount when lean beef was eaten. Could this be an interesting screening test for diabetics?

The OGTT (Oral Glucose Tolerance Test) is one way to determine if someone is a diabetic. They are given a large glucose drink and their blood sugar is monitored over the next couple of hours. The peak value of the diabetic above is 340 mg/dl. The peak value of the non-diabetic is around half of that at about 170 mg/dl. Clearly there’s a difference there between the diabetic and the non-diabetic.

A second difference is the time that the blood sugar takes to return to normal. In the non-diabetic they are back to their baseline at about 2 hours. The diabetic is still high four hours later.

My favorite explanations of the difference have to do with first phase insulin response being delayed in diabetics and diabetics don’t stop GNG as quickly as non-diabetics. The absolute value of the fall or rise from protein isn’t all that much compared to glucose. The point of the Conn paper was that the peak value is what matters for a diabetic. Even though half of the protein was believed to be converted to glucose

Either way, as long as I continue to have this blood sugar response to protein I still have at least one of the side-effects of diabetes.

Fructose – Part 2

Here’s another great paper on the role of Fructose (Lisa C Hudgins; Why do sweets fatten our livers?, The American Journal of Clinical Nutrition, Volume 96, Issue 4, 1 October 2012, Pages 685–686).

Here is another study (Sevastianova K. Effect of short-term carbohydrate overfeeding and long-term weight loss on liver fat in overweight humans
Am J Clin Nutr. 2012 Oct;96(4):727-34. Epub 2012 Sep 5.).

Carbohydrate overfeeding for 3 wk induced a >10-fold greater relative change in liver fat (27%) than in body weight (2%). The increase in liver fat was proportional to that in DNL. Weight loss restores liver fat to normal.

These data indicate that the human fatty liver avidly accumulates fat during carbohydrate overfeeding and support a role for DNL in the pathogenesis of NAFLD.