Blood Sugar and Fasting

A while back, I noticed that my Blood Sugar peaks around the second day of extended fasting. George Cahill did the seminal work measuring blood markers during starvation (Cahill, George. Fuel Metabolism in Starvation.). Here’s an interesting chart from that study that explains the sources of glucose during starvation.

This demonstrates the increase in blood sugar around day 2-3. Diabetics are particularly adept at GNG. Eventually though, even that reduces as the body becomes physiologically Insulin Resistant.

The chart can provide some idea of what happens in a ketogenic diet. Although someone on a ketogenic diet is eating enough food, their exogenous glucose is greatly reduced due to the low carbohydrate content of the diet. Glycogen stores lower next. When the glycogen stores get low the body then upregulates Glyconeogenesis (GNG).

This could also explain why when I see an increase in blood sugars on one morning I often see a drop in weight the following morning. The body is signalling that it is switching fuel to up-regulated GNG due to dropped Glycogen stores. Although these two sources are of the same magnitude in Cahill’s chart above they could well be less equally matched in a diabetic. It is possible that GNG in a diabetic outpaces the ability to pull from Glycogen stores.

 

Fasting and Gluconeogenesis

In my previous post (Low Carbs and Gluconeogenesis) I took a look at the low carb diet and Gluconeogenesis (GNG). The study found that GNG was increased by 14% in low carb diets. For folks who view GNG as the enemy that is challenging. After all, why go on a diet which makes your GNG even worse?

But, did you know that fasting increases GNG even more? This study looked at fasting and GNG (Landau BR, Wahren J, Chandramouli V, Schumann WC, Ekberg K, Kalhan. SC. 1996 Contributions of gluconeogenesis to glucose production in the fasted state. J Clin Invest. 98:378–385.):

The contribution of gluconeogenesis to glucose production was 47+/-64% after 14 h, 67+/-64% after 22 h, and 93+/-62% after 42 h of fasting.

It would be wrong to think this means we should get up in the middle of the night to eat in order to prevent GNG. We should not fear GNG since it is necessary. Our bodies produce the amount of Glucose that our bodies need for those parts of the body which require Glucose. When we are on Low Carb diets we produce Glucose in response to demand.

A more interesting question is why GNG is overdriven in Type 2 Diabetics. This is the paper for that subject (Song S, Andrikopoulos S, Filippis C, Thorburn AW, Khan D, Proietto J. Mechanism of fat-induced hepatic gluconeogenesis: effect of metformin. Am J Physiol Endocrinol Metab. 2001 Aug;281(2):E275-82.).

The high-fat diet increased endogenous glucose production (21.9 +/- 4.4 vs. 32.2 +/- 4.8 micromol x kg(-1) x min(-1), P < 0.05) and alanine gluconeogenesis (4.5 +/- 0.9 vs. 9.6 +/- 1.9 micromol x kg(-1) x min(-1), P < 0.05).

Excess supply of dietary fat stimulates alanine gluconeogenesis via an increase in fructose-1,6-bisphosphatase protein levels

Looks like substrate availability can increase GNG – when the substrate is fat.

References

 

Fat as Glucose (Fuel)

This article cites a number of studies which show the ways that fat gets converted to glucose on a Low Carb diet (We Really Can Make Glucose From Fatty Acids After All! O Textbook, How Thy Biochemistry Hast Deceived Me!).

The common objection to this is that insulin levels are low when eating fat.

Thus, when insulin levels fall and ketone levels rise, as occurs when our carbohydrate intake is low, our cells increase their supply of CYP2E1 and thereby activate the conversion of fatty acids to glucose.

And more details:

methylglyoxal inhibits the breakdown of glucose … when this pathway is activated, we not only convert fatty acids to glucose, but methylglyoxal concentrations rise and inhibit the breakdown of glucose.

Thus, when glucose runs low and we begin subsisting primarily on fatty acids for fuel, we have a coordinated effort to both spare glucose and to make more of it.

Here’s a study of the subject (

Christoph Kaleta, Luís F. de Figueiredo, Sarah Werner, Reinhard Guthke, Michael Ristow, and Stefan Schuster. In Silico Evidence for Gluconeogenesis from Fatty Acids in Humans. PLoS Comput Biol. 2011 Jul; 7(7): e1002116.). If we could not make glucose from fatty acids then we would not be able to survive long fasts because there are parts of our bodies which absolutely require glucose.

Analyzing evidence concerning the detected pathways lends support to their importance during times of starvation, fasting, carbohydrate reduced and ketogenic diets and other situations in which the nutrition is low on carbohydrates. Moreover, the energetic investment required for this pathway can help to explain the particular efficiency of carbohydrate reduced and ketogenic diets such as the Atkins diet.

More:

Although the brain can use ketone bodies in these situations, it still needs a certain amount of glucose, which has critical implications upon starvation and similar conditions.

Another Line of Evidence

An interesting writeup (Glucose from fatty acids: RQ of 0.454) on the generation of glucose from fatty acids(originally from Heinbecker. Studies on the Metabolism of Eskimos., 1928). The Eskimo woman has a very low RQ value on day 3.5 of her fast.

An RQ below 0.69 suggests the generation of oxygen rich molecules from fatty acids. An RQ of 0.454 suggests a huge amount of (probable) gluconeogenesis from fat is going on.

 

Low Carb Diet and Type 1 Diabetics – Part 2

Part 1 took a look at a Systematic Review of this subject.

A new study (May 2018) on the subject of Low Carb and Type 1 Diabetes (Leow ZZX1, Guelfi KJ1, Davis EA2,3,4, Jones TW2,3,4, Fournier PA1. The glycaemic benefits of a very-low-carbohydrate ketogenic diet in adults with Type 1 diabetes mellitus may be opposed by increased hypoglycaemia risk and dyslipidaemia. Diabet Med. 2018 May 8. doi: 10.1111/dme.13663.).

Abstract

AIMS:

To investigate whether very-low-carbohydrate high-fat diets, typical of ketogenic diets, can improve glycaemic control without causing any ill health effects in adults with Type 1 diabetes.

METHODS:

In this observational study, 11 adults with Type 1 diabetes (seven men, four women, mean ± sd age 36.1± 6.8 years, mean ± sd duration of diabetes 12.8 ± 10.3 years), who followed a ketogenic diet (< 55 g carbohydrate per day) for a mean ± sd of 2.6 ± 3.3 years (β-hydroxybutyrate 1.6 ± 1.3 mmol/l), underwent sampling and analysis of fasting blood, and were fitted with a blinded continuous glucose monitor for 7 days to measure glycaemic variability.

RESULTS:

The mean ± sd HbA1c levels were 35±4 mmol/mol (5.3±0.4%), and participants spent 74±20 and 3±8% of their time in the euglycaemic (4-8 mmol/l) and hyperglycaemic (>10 mmol/l) ranges, respectively, with little daily glycaemic variability (sd 1.5±0.7 mmol/l; coefficient of variation 26±8%). Blood glucose levels were <3.0 mmol/l for 3.6% of the time, and participants experienced a median (range) of 0.9 (0.0-2.0) daily episodes of hypoglycaemia.

Total cholesterol, LDL cholesterol, total cholesterol/HDL cholesterol ratio, and triglycerides were above the recommended range in 82%, 82%, 64% and 27% of participants, respectively; however, HDL cholesterol levels were within the recommended range for all participants. Participants displayed no or little evidence of hepatic or renal dysfunction.

CONCLUSION:

This study provides the first evidence that, ketogenic diets in adults with Type 1 diabetes are associated with excellent HbA1clevels and little glycaemic variability, but may also be associated with dyslipidaemia and a high number of hypoglycaemic episodes.

A failure of this abstract is that it was an observational study which didn’t have a control group. Hence, the objection about hypoglycemia lacks a comparison.

Yes, there is a chance of going too low but the very fact that the participants had “little glycaemic variability” reduces the chance of hypoglycemia rather than increases the chance. How were these participants trained? When the details of the study are released we may find out more.

Also, as I have noted on many occasions it is not unusual to have low blood sugar levels while on the ketogenic diet with no ill effects. The presence of ketone bodies as fuel reduces the dependence on blood glucose.

The other complication was the cholesterol numbers. The total cholesterol and total cholesterol to HDL ratio is a function of the LDL cholesterol so this is really one issue not two particularly since this was the value most affected. This BLOG has numerous articles about LDL cholesterol on the ketogenic diet. This is a well understood subject.

Overall, this is an encouraging study for Type 1 Diabetics who want to control their HbA1c values more closely.

 

Low Carb Diet and Type 1 Diabetics

Part 2 takes a look at newer studies.

Here’s a 2018 systematic review  which looked at Type 1 Diabetics and the Low Carb Diet (Jessica L. Turton, Ron Raab, Kieron B. Rooney. Low-carbohydrate diets for type 1 diabetes mellitus: A systematic review. PLoS ONE 13(3): e0194987). They looked through a lot of studies and narrowed down to:

A total of nine studies were eligible and included for this review.

The nine studies were:

two randomised controlled trials , four pre-post intervention studies two retrospective case-series, and one case-report.

There was considerable differences between the nine studies:

Results for our primary outcome (HbA1c) were available from eight of nine studies reviewed. Results for secondary outcomes of interest were inconsistently reported. Two studies reported the effect of a low-carbohydrate diet on frequency of severe hypoglycaemia, five studies reported total daily insulin, three studies reported BMI, and one study reported mean daily blood glucose.

Here’s the detailed data (click to see large image).

The results were disappointing for HbA1C.

Four studies reported non-significant changes in HbA1c with a low-carbohydrate diet and three studies reported statistically significant reductions (P < 0.05).

However:

Of the five studies that reported daily insulin usage, two TLCD studies  demonstrated statistically significant reductions in total daily insulin within carbohydrate restriction groups (P < 0.05) with one study also reporting a statistically significant difference between the low-carbohydrate group and high-carbohydrate comparator (P < 0.05). Levels of significance could not be calculated or obtained in three studies due to inadequate sample size and lack of raw participant data.

The reduction in Insulin use is important since that could forestall Insulin Resistance in the Type 1 diabetic. It’s a serious problem when the Type 1 Diabetic becomes resistant to the very medication that they need to live. As the paper put it:

The excessive use of insulin that is often required to achieve glycaemic control in type 1 diabetes increases susceptibility to severe hypoglycaemia and may lead to some measure of hyperinsulinemia. Hyperinsulinemia is associated with; excessive weight gain, development of the metabolic syndrome, inflammation and atherosclerosis, Alzheimer’s Disease and cancer. Findings of the present review suggest that low-carbohydrate intakes may assist in reducing or preventing hyperinsulinemia in type 1 diabetes by decreasing the absolute amount of insulin required for tight glycaemic control.

The conclusion of the study was:

This systematic review presents all available evidence for low-carbohydrate diets in the management of type 1 diabetes mellitus. The existing body of evidence is limited and more primary studies evaluating the short and long-term effects of low-carbohydrate diets on type 1 diabetes management outcomes are necessary to support its use in practice.

 

 

Long Term Adherence to Low Carb for Diabetics?

I don’t personally find long term adherence to a low carb diet to be difficult. It will be two years next month for me on Low Carb. The rewards outweigh any desire to change away from the low carb diet. In fact, the only pressure has been to maintain my weight on Low Carb since I keep losing. I never thought I would weight 165 lbs and I’ve been in this range for months.

But, there is evidence that many people who are in trials are less motivated to keep the benefits of the low carb diet past a year. Here’s a study which makes that point (Ole Snorgaard, et.al. Systematic review and meta-analysis of dietary carbohydrate restriction in patients with type 2 diabetes. BMJ Open Diabetes Res Care. 2017; 5(1): e000354.).

We identified 10 randomized trials comprising 1376 participants in total. In the first year of intervention, LCD was followed by a 0.34% lower HbA1c (3.7 mmol/mol) compared with HCD (95% CI 0.06 (0.7 mmol/mol), 0.63 (6.9 mmol/mol)).

The greater the carbohydrate restriction, the greater the glucose-lowering effect (R=−0.85, p<0.01).

At 1 year or later, however, HbA1c was similar in the 2 diet groups.

The effect of the 2 types of diet on BMI/body weight, LDL cholesterol, QoL, and attrition rate was similar throughout interventions.

Does Low Carb Itself Only Work for a Year?

There’s nothing about the Low Carb diet itself which means that if you follow the Low Carb diet for a year the benefits end. My own HbA1C before Low Carb ranged from around 7-9 and now it is 5.2 at 18 months after I started Low Carb. Low Carb didn’t stop for me at a year.

My 90 day average blood sugar is 92 per my meter.

“Diet is Temporary”

Rather, it is lack of long term adherence to the diet which is the problem. If a diabetic thinks that they can do Low Carb and all their problems will go away without any potential for re-occurrence they are missing the point of how they got messed up to start with. Re-introduce a high carb load and the diabetic symptoms will quickly return.

Transition to Maintenance

People take the advice that they should increase their carbohydrates once the intervention ends and they just can’t do that. The Low Carb diet has to be followed for as long as a person wants to be non-diabetic. The transition strategy to higher carbs needs to be “just say no” rather than “try and find your carb tolerance”.

Motivated by a Study

On some level this is a problem with the nature of a study since the participants have a different set of motivations than someone who undertakes a Low Carb diet by their own choice. People who do a study are motivated by the study. A diabetic who finds low carb and reverses their diabetes has an entirely different motivation.

Study Participants

Many times these studies are very selective in the population they are studying.  Inclusion criteria is often to be newly diagnosed and un-medicated. That’s a less motivated crowd. They often have no serious symptoms (at least that they can see) and are less motivated to stay non-diabetic.

Study participants are rewarded for participating in studies not long term adherence. Once the study is over their motivation ends.

Too Easy to Pop a Pill

At the start of diabetes it is really simple to just pop a pill. And the HbA1c will react quite nicely to the pill. At least for a while.

What they don’t tell you is that you will eventually be on Insulin. I used to be in a small Bible study group with older men. There were around 6-8 of us and all of us except once guy were Type 2 diabetics. We all shared the same trajectory. We all started with Metformin which worked for a couple of years. Then our blood sugar numbers got worse. And we were prescribed additional oral medications. Eventually, we were all put on Insulin. Once of the guys commented one day that they never tell you when they put you on Metformin that it would eventually result in you getting put on Metform.

One Significant Takeaway

It seems obvious to me but the study found that the greater the carbohydrate restriction the greater the reduction in HbA1c value. This is worth noting all by itself. Here’s the figure from the study:

 

The cross over point is somewhere around 40% of energy. Assuming a 2000 calorie diet that’s 800 calories or 200 grams of carbohydrates. Above that point things get worse.

Equally the maximum benefit of around 0.8% reduction in HbA1c was found at 15% of energy from carbs. Again assuming a 2000 calorie diet that’s 300 calories or 75 grams of carbohydrates. That’s still high by my own standards.

 

Picking The Right Diet for Diabetics

The standard sort of recommendation for diets for diabetics is the “plate method”.

A 2017 new study compared the effectiveness of the “plate method” to a Very Low Carb diet (Laura R Saslow, PhD, et.al. An Online Intervention Comparing a Very Low-Carbohydrate Ketogenic Diet and Lifestyle Recommendations Versus a Plate Method Diet in Overweight Individuals With Type 2 Diabetes: A Randomized Controlled Trial. J Med Internet Res. 2017 Feb; 19(2): e36.). The results were:

At 32 weeks, participants in the intervention group reduced their HbA1c levels more (estimated marginal mean [EMM] –0.8%, 95% CI –1.1% to –0.6%) than participants in the control group (EMM –0.3%, 95% CI –0.6% to 0.0%; P=.002). More than half of the participants in the intervention group (6/11, 55%) lowered their HbA1c to less than 6.5% versus 0% (0/8) in the control group (P=.02).

Participants in the intervention group lost more weight (EMM –12.7 kg, 95% CI –16.1 to –9.2 kg) than participants in the control group (EMM –3.0 kg, 95% CI –7.3 to 1.3 kg; P<.001). A greater percentage of participants lost at least 5% of their body weight in the intervention (10/11, 90%) versus the control group (2/8, 29%; P=.01).

Participants in the intervention group lowered their triglyceride levels (EMM –60.1 mg/dL, 95% CI –91.3 to –28.9 mg/dL) more than participants in the control group (EMM –6.2 mg/dL, 95% CI –46.0 to 33.6 mg/dL; P=.01).

Dropout was 8% (1/12) and 46% (6/13) for the intervention and control groups, respectively (P=.07).

  • Lower HbA1c = VLC win
  • Weight Loss = VLC win
  • Triglyceride reduction = VLC win
  • Dropout rate = VLC win

Here’s the link to the “plate method” in case anyone still wants to try the ADA recommended diet (demonstrated as ineffective to reverse diabetes above).

A critique of this study (Andrew Nathan Reynolds, BSc, MSc, PhD, et.al. Comment on “An Online Intervention Comparing a Very Low-Carbohydrate Ketogenic Diet and Lifestyle Recommendations Versus a Plate Method Diet in Overweight Individuals With Type 2 Diabetes: A Randomized Controlled Trial”. J Med Internet Res. 2018 May; 20(5): e180.) was published which complained that the intervention counselled the Low Carb participants more than the ADA plate method. Since the ADA plate method was ineffective compared to the Low Carb diet, the correct critique of the study should not be against the Low Carb diet but against the ineffective4 plate method.

 

Curing Diabetes

I wrote the following to respond to a post about Jason Fung on Carb Sane (Diabetes Un-Funged). Her central thesis is that exogenous Insulin doesn’t cause Insulin Resistance.

I was a T2DM for 13 years (and probably undiagnosed for 8 years before that).

Two years ago, I went from 100 units a day of Insulin (Medtronics Pump) to zero in two weeks following Fung’s methods (Low Carb and Intermittent Fasting) with great blood sugar levels. I did Low Carb in the past and it helped me get a decent HbA1C but not out of the diabetic range. Fast forward 22 months and I am down 120 lbs (current weight is 165). My HbA1C was 5.2 a few months ago. No longer on HBP meds (I was on them for 20 + years). All of this while following Fung’s methods (Low Carb and Intermittent Fasting).

As to the progression of Insulin and loss of blood sugar control points in your article. In my own case I went from 40 units of Insulin with good control to 100 units with poorer control (higher HbA1C) in 4.5 years. The more I tried to control my blood sugar with Insulin the higher the amount of Insulin I required kept getting.

Worse yet the real surrogate of Insulin Resistance is the ratio of grams of carbs to units of Insulin. Anyone who has been on Insulin for a long time can testify that this ratio degrades with time. At the start, 1 unit of Insulin would cover 15 grams of carbohydrates and 4.5 years later one unit would only cover 4 grams of carbs. Clearly (at least to me) this is evidence of progressive insulin resistance).

Even if you don’t agree with Fung’s reasons his method is essentially the same as yours (Low Carb). Problem for me was that without having an intermittent fasting window I would have just had lower Insulin requirements – not a cure, but a decent treatment. I got to HbA1C of 6.6 with Low Carb and Insulin.

And it wasn’t about weight loss since most of what someone loses in the first week or two is water weight. I think it was more about leaning out the liver and then leaning out the fat around the pancreas than anything else…

Incidentally, this wasn’t about titrating the dosage of Insulin over the four and a half years. The “honeymoon period” is well known among people who start using diabetes meds – including Insulin. It isn’t long until more is required as the body becomes more resistant to the insulin.

Another line of evidence is the studies showing that hyperinsulinemia precedes diabetes and obesity often by decades.

The Great Noakes-McDonald Debate

One of my new favorite podcasts is the Sigma Nutrition Radio Podcast.

Podcast 210 was a debate between Dr. Tim Noakes and Martin McDonald. It was conducted in a gentlemanly way. Given the personality of Tim Noakes it is hard to imagine it not being handled that way.

The subject was Insulin Resistance and the effectiveness of the Low Carb diet compared to other interventions. Both sides had good points but to my way of thinking Dr. Noakes clearly won the debate.

Both sides pointed to studies (linked on the page above).

How Type 2 Diabetics Gain Weight on Insulin

This study looks at how a Diabetic is affected strongly by taking Insulin (A. Franssila-Kallunki, L. Groop. Factors associated with basal metabolic rate in patients with Type 2 (non-insulin-dependent) diabetes mellitus. Diabetologia; October 1992, Volume 35, Issue 10, pp 962–966.). The study looked at:

66 Type 2 (non-insulin-dependent) diabetic and 24 healthy age- and weight-matched control subjects…

The interesting part is that some of the diabetics were looked at both before and after insulin therapy.

Eight Type 2 diabetic patients were re-studied after a period of insulin therapy.

In the following analysis, take note that the group put on Insulin therapy was a subset of the original group of Diabetics so their numbers were different (more exaggerated) from the rest of the Diabetics group.

Weight Gain on Insulin

The group on the Insulin treatment saw their BMI increase from 28.2 to 29.6 kg/m^2.

Basal Metabolic Rate

The control and Diabetics groups were weight matched. Surprisingly, the BMR in the Diabetics was 13% higher than the control group:

Basal metabolic rate was higher in Type 2 diabetic patients than in control subjects (102.8 ± 1.9 J · kg LBM−1-min−1 vs 90.7 ± 2.8 J · kg LBM−1;min−1; p<0.01)

Insulin treatment reduced the BMR of the Diabetics (115.5 ± 5.6 to 103.1 ± 5.7). It is question begging whether the lowered BMR caused the BMI increase with Insulin.

Diabetics Produce More Glucose

Not surprisingly the Type 2 Diabetics were producing glucose from their livers at significantly higher rates than the control group.

 The basal rate of hepatic glucose production was higher in Type 2 diabetic patients than in control subjects (1044.0 ± 29.9 vs 789.3 ± 41.7 μmol/min; p <0.001)

Insulin therapy decreased glucose production (1133 ± 92 to 983 ± 80). In theory this is good. A possible explanation of the effect of Insulin is that it took more insulin to overcome the Insulin Resistance of the liver. Insulin therapy isn’t a great long term solution, though, since the liver will eventually become even more Insulin Resistant and require ever increasing levels of exogenous Insulin.

Insulin Therapy Reduced Fat Oxidation Rate

The fat oxidation of the Diabetics was reduced when Insulin therapy was added:

Lipid oxidation was increased in Type 2 diabetic patients compared with control subjects (1.68 ± 0.05 vs 1.37 ± 0.08 μmol · kg LBM−1 · min−1‘; p <0.01) and decreased significantly after insulin therapy (p<0.05).

The lipid oxidation rate fell from 2.1 ± 0.1 to 1.4 ± 0.1 with the addition of Insulin therapy. A key phrase in the discussion section is:

lipid oxidation accounted for the major part of the BMR

So, putting someone on Insulin reduces their fat oxidation rate. If Type 2 Diabetes is a problem of fat build-up then Insulin therapy isn’t helping. It’s making Diabetics fatter. Yes, it is driving down Serum Glucose levels in the short term.

Fasting Insulin

Of note is the difference in the Fasting Serum Insulin levels between the Diabetics (64 ± 5) and the control group (37 ± 4).

The subset of the Diabetics put on Insulin therapy had higher Fasting Insulin levels than the lumped group of all diabetics. With the addition of exogenous Insulin therapy the Fasting Serum Insulin levels in the Diabetic (subset) increased from 84 to 132.

That would, of course, indicate that the part of the Diabetics group that was not put on Insulin had a much lower fasting Insulin level. This is interesting given that the error bar was ±5 so the group put on Insulin therapy at 84 +± 11 was many standard deviations out of the entire group.

The paradox here is that even with higher fasting insulin levels the fat oxidation rate in the diabetics indicates that the additional fasting insulin levels didn’t seem to stop the diabetics from being able to burn fat. The paradox is that the fat oxidation rate decreased with Insulin Therapy which would indicate the opposite conclusion.

This fits the hypothesis that Insulin Resistance in the liver is a primary driver rather than insulin resistance in adipose cells.

Calories out is much more complicated than just a number on a paper.