Sucralose and Insulin

Here’s a study which shows sucralose affect Insulin (Diabetes Care. 2013 Sep;36(9):2530-5. doi: 10.2337/dc12-2221. Epub 2013 Apr 30. Sucralose affects glycemic and hormonal responses to an oral glucose load. Pepino MY, Tiemann CD, Patterson BW, Wice BM, Klein S.).

Compared with the control condition, sucralose ingestion caused

1) a greater incremental increase in peak plasma glucose concentrations (4.2 ± 0.2 vs. 4.8 ± 0.3 mmol/L; P = 0.03),

2) a 20 ± 8% greater incremental increase in insulin area under the curve (AUC) (P < 0.03),

3) a 22 ± 7% greater peak insulin secretion rate (P < 0.02),

4) a 7 ± 4% decrease in insulin clearance (P = 0.04), and 5) a 23 ± 20% decrease in SI (P = 0.01).

There were no significant differences between conditions in active glucagon-like peptide 1, glucose-dependent insulinotropic polypeptide, glucagon incremental AUC, or indices of the sensitivity of the β-cell response to glucose.

If you are trying to get your Insulin Resistance under control this is bad news.

A second study confirms the Insulin response to sucralose (Eur J Clin Nutr. 2015 Feb;69(2):162-6. doi: 10.1038/ejcn.2014.208. Epub 2014 Oct 1.
Sucralose enhances GLP-1 release and lowers blood glucose in the presence of carbohydrate in healthy subjects but not in patients with type 2 Diabetes. Temizkan S, Deyneli O, Yasar M, Arpa M, Gunes M, Yazici D1, Sirikci O, Haklar G, Imeryuz N, Yavuz DG.).

In healthy subjects, the total area under the curve (AUC) of glucose was statistically significantly lower in the sucralose setting than in the water setting (P=0.002). There was no difference between the aspartame setting and the water setting (P=0.53). Total AUC of insulin and c-peptide was similar in aspartame, sucralose and water settings. Total AUC of GLP-1 was significantly higher in the sucralose setting than in the water setting (P=0.04). Total AUC values of glucose, insulin, c-peptide and GLP-1 were not statistically different in three settings in type 2 diabetic patients.

 

Metabolic Syndrome Progression

Metabolic Syndrome is a diagnostic criteria but it’s also a progression of the comorbidities. Before I was diagnosed with Type 2 Diabetes I had all five of the above elements.

I work with a couple of guys who don’t realize where they are on the curve. They are both mid 30s and both fit the criteria for diagnosis. They are not yet diagnosed with diabetes but they are on their way to it.

One of them thinks he can outrun his bad diet. Both of them think that they can keep drinking high carb beer. They don’t realize it’s slowly killing them. They enjoy it too much to quit and the above criteria are just numbers on a page to them.

As much as I know and as much as I have tried to talk to these guys they just won’t bite into Low Carb.

 

Fat and Insulin Resistance at Insulin Injection Sites

I had an insulin pump for over four years. I learned a lot about Insulin from using the pump.

One of the things that I learned about Insulin injection is that insulin injection points need to be moved after a while. The reason is that the area around the injection becomes Insulin Resistant and insulin isn’t as effective in that area. Eventually, a whole part of the body becomes unusable and may remain that way for years.  I could no longer pump into the area to the sides of my navel. It gets harder and harder to find a place to pump Insulin. There are limited areas to pump. Some are pretty hard to reach, uncomfortable or just plain impractical.

The other thing I learned is that there’s localized fat deposited in the same area as the Insulin injection point was placed. This fact has been noted in the literature for almost 70 years (Renold AE, Marble A, Fawcett DW. Action of insulin on deposition of glycogen and storage of fat in adipose tissue. Endocrinology. 1950;46(1):55–66.).

SOON after the discovery of insulin, clinical observers reported the occurrence … hypertrophies (Eeg-Olofsson, 1930; Rowe and Garrison, 1932) of subcutaneous adipose tissue at the site of repeated insulin injections. A number of case reports and statistical studies have since been published. … lipodystrophy without evidence of inflammation has not been reported following injection of substances other than insulin. The production of insulin lipodystrophies in animals has been attempted by Reed, Anderson, and Mendel (1930), Marble and Smith (1942), Goldner (1943) and Oesterreicher (1947) with conflicting results.

In the search for an explanation of the effect of insulin on the adipose tissue of diabetics, various factors not concerned with the actual metabolic action of insulin have been suggested but supporting experimental evidence has been lacking (Marble and Smith, 1942).

This is interesting to me because of excess skin. My fat was enlarged by Hyperinsulinemia both from diet and exogenous Insulin.

 

HyperInsulinemia – Finding the Moving Target

My BLOG posts on hyperinsulinemia.

A related BLOG post by an MD (Hyperinsulinemia: Should You Be Tested?).

My initial target was hacking my diabetes. That was even the subtitle of my original BLOG (Hacking my T2DM). For years, I took the medications that the doctors gave me and my diabetes got worse. In the end I was on 100+ units Insulin delivered via a pump and I was getting worse. I thought there must be a better target since the doctor’s approach wasn’t helping me.

Diabetes and Insulin Resistance

In seeking answers, I found that the diabetes related to Insulin Resistance. So I chased after curing my Insulin Resistance via the Low Carb diet. In doing so my diabetes was apparently cured.

Certainly the low carb diet has greatly helped my Insulin Resistance, but the question remained of whether my diet has cured my Insulin Resistance and there’s indications that I am not completely cured (Insulin Resistance Test).

Aspects of Insulin Resistance

Turned out that Insulin Resistance has a bunch of subtle aspects. There’s hepatic (in your liver) Insulin Resistance, peripheral (in your muscles) insulin resistance, physiological insulin resistance, etc. Each of these play a role in diabetes and each are affected in various ways by the Low Carb diet.

Somebody may have written a good write-up on all of this but I haven’t yet seen it. Everyone seems to have a piece of the story. Perhaps a BLOG post sorting it out would be helpful?

Fatty Liver and Diabetes

Recently, I’ve been circling around a more nuanced view of the problem and have been looking more closely at the role of the fatty liver and glycogen stores.

Your body stores glucose in the liver as glycogen. Once those glycogen stores are filled, excess carbohydrates then fill up the liver fat. . Fat then overflows into other internal organs, particularly the pancreas. Eventually the pancreas isn’t able to make enough Insulin to keep up with the resistant areas. That’s when you end up on insane levels of Insulin.

How Does a Low Carb Diet Work?

Low carb reverses fatty liver quickly by first dropping glycogen stores. It only takes a day or two of eating very low carbs to reduce your glycogen stores to minimal levels.  The liver then mobilizes its own fat for energy. This leads to a leaned liver within a week or less. This leads to less fat in the pancreas and restores normal insulin production in the pancreas.

In addition, the reduction in carbohydrates leads to a reduction in blood glucose and insulin levels. The lower glucose load allows the pancreas to keep up. This is part of why the Low Carb diet is effective with diabetes so quickly.

Obesity fits into this in a strange way since increasing insulin sensitivity (decreasing Insulin Resistance) allows cells to take up more glucose. But a low carb diet reduces the glucose from the diet. Under a low carb diet most of the glucose the body needs comes from Gluconeogenesis (GNG) (glucose made by the liver from stuff other than glucose). So GNG which is a problem under a high carb diet because it contributes to the amount of glucose in the body, then becomes what provides the necessary glucose to survive under a low carb diet.

What Causes What?

But all of this raises the question of what causes what. Current dogma mostly blames energy surplus as the problem. You are fat because you eat too much and getting fat makes you Insulin Resistant, diabetic, etc.

Since the Low Carb cure reduces weight it’s hard to tease out which effect leads in terms of the effectiveness of the cure. I know in my own case that I got off all Insulin within two weeks and I hadn’t lost much weight yet.

The Real Target

I’ve come to view Hyperinsulinemia as the central issue in the development of the cluster of issues known as Metabolic Syndrome (hypertension, hyperlipidemia, obesity, Type 2 Diabetes).  Others have recently presented the same insight. One crucial paper on the subject is (Erion, K.A. & Corkey, B.E. (2017). Hyperinsulinemia: a Cause of Obesity? Curr Obes Rep (2017) 6: 178.).

Purpose of Review

This perspective is motivated by the need to question dogma that does not work: that the problem is insulin resistance (IR).

The prequel to severe metabolic disease includes three interacting components that are abnormal: (a) IR, (b) elevated lipids and (c) elevated basal insulin (HI). HI is more common than IR and is a significant independent predictor of diabetes.

We hypothesize that

(1) the initiating defect is HI that increases nutrient consumption and hyperlipidemia (HL);

(2) the cause of HI may include food additives, environmental obesogens or toxins that have entered our food supply since 1980; and

(3) HI is sustained by HL derived from increased adipose mass and leads to IR.

We suggest that HI and HL are early indicators of metabolic dysfunction and treating and reversing these abnormalities may prevent the development of more serious metabolic disease.

Not only are high levels of Insulin the key driver in the processes related to the development of Metabolic Syndrome but they are the key drivers in reversing Metabolic Syndrome.

Taking exogenous Insulin drives hyperinsulinemia.

Eating too many carbs drives hyperinsulinemia like nothing else can do.

Reversing hyperinsulinemia via a combination of low carb diets and fasting does the best possible of any treatment.

Another view showing evidences on both sides (Shanik MH1, Xu Y, Skrha J, Dankner R, Zick Y, Roth J. (2008). Insulin resistance and hyperinsulinemia: is hyperinsulinemia the cart or the horse? Diabetes Care. 2008 Feb;31 Suppl 2:S262-8.).

We examine situations where insulin itself appears to be a proximate and important quantitative contributor to insulin resistance.

1) Mice transfected with extra copies of the insulin gene produce basal and stimulated insulin levels that are two to four times elevated. The mice are of normal weight but show insulin resistance, hyperglycemia, and hypertriglyceridemia.

2) Somogyi described patients with unusually high doses of insulin and hyperglycemia. Episodes of hypoglycemia with release of glucose-raising hormones, postulated as the culprits in early studies, have largely been excluded by studies including continuous glucose monitoring.

3) Rats and humans treated with escalating doses of insulin show both hyperinsulinemia and insulin resistance.

4) The pulsatile administration of insulin (rather than continuous) results in reduced requirements for insulin.

5) Many patients with insulinoma who have elevated basal levels of insulin have reduced (but not absent) responsiveness to administered insulin.

In summary, hyperinsulinemia is often both a result and a driver of insulin resistance.

 

Liver Fat and Low Carb

Here’s a thought that is initially quite scary until you figure out what is going on.

Low Carb Diets increase Liver Fat.

There is a mouse study which shows that Low Carb diets increase liver fat (Curr Opin Clin Nutr Metab Care. 2012 Jul; 15(4): 374–380. Low-carbohydrate ketogenic diets, glucose homeostasis, and nonalcoholic fatty liver disease. Rebecca C. Schugar).

Mice fed the Ketogenic Diet (KD) for 12 weeks were lean, euglycemic, ketotic, and hypoinsulinemic, but were glucose intolerant, and exhibited NAFLD.

MRS revealed that KD-fed mice accumulate hepatic lipid within 3 weeks after initiation of the diet, and the hepatic gene expression signature for DNL (encoded mediators of SREBP-1c, FAS, ACC1, SCD1) was suppressed compared to livers of chow-fed controls.

In contrast, mice fed the WD ultimately accumulate higher IHTG than KD-fed animals, but do so much more slowly, and as expected due to the high sucrose content, induce mediators of DNL.

So, mice fed the western diet accumulated MORE liver fat over time…

Wait, I thought that’s what you are trying to solve by doing a low carb diet? Yep. Here’s the difference. Here’s a pretty simple explanation (Reddit thread).

Fatty liver in humans is primarily caused by hepatic triglycerides that the liver fails (for whatever reason) to remove from the liver via VLDL or oxidize for fuel. So, if you’re insulin resistant, the liver gets regular and massive influxes of carbohydrate, not to mention an increase in hepatic glucose production that is also characteristic of insulin resistance.

Your body has three options with excess carbohydrates; store as glycogen, burn as fuel, or store as fat. When the carbs are in excess, the first two former options are often impossible, so your body opts to attempt to store carbohydrates as fat. However, if this happens faster than your liver can manage, the triglycerides accumulate. This is just how NAFLD works in humans (Clinical Lipidology, 1st edition, ch. 37, pg 448).

 

Taxonomy of Low Carb Studies

I’ve been collecting studies for a while and hosting them on GitHub at OpenKeto/KetoStuff. Here’s the structure of the studies.

Some of the studies can be put into multiple places so I picked one or the other place to put them without much pattern as to why. Classifying the LC Diet as Energy Input is possibly the key insight into this pattern. Also, the Effect of the Ketogenic Diet on Diabetes is under MetS.

With GitHub Desktop you can replicate the entire repository onto your computer or select individual files to download. Copyrights are the individual holders. Studies are reproduced here and were found on the Internet in general.

 

 

Insulin Resistance Test

There’s an Insulin Resistance test, the homeostasis model assessment-estimated insulin resistance (HOMA-IR) but it requires a fasting insulin test  for the calculation which is not a normal part of blood lipid tests. There’s also a surrogate for HOMA-IR called the Triglycerides/glucose index. Here’s a paper on it (B Kang, Y Yang, E Y Lee, H K Yang, H-S Kim, S-Y Lim, J-H Lee, S-S Lee, B-K Suh & K-H Yoon. Triglycerides/glucose index is a useful surrogate marker of insulin resistance among adolescents. International Journal of Obesity volume 41, pages 789–792).

The TyG index was calculated as ln [triglycerides (mg/dl) × fasting glucose (mg dl)/2]. IR was defined using HOMA-IR >95th percentile for age and sex.

The threshold is:

The cut-off of the TyG index for diagnosis of insulin resistance was 8.18.

I created an on-line calculator for this index.

Numbers less than 8.18 are not insulin resistant. My own numbers are:

  • Triglycerides = 118
  • Fasting Glucose = 103
  • TyG = ln(118*103/2) = 8.71

Here’s how do this calculation in EXCEL:

I am still Insulin Resistant.

My numbers from 2015 (before Low Carb) were:

  • Triglycerides = 460
  • Fasting Glucose = 152
  • TyG = ln(114*103/2) = 10.5

So I’m not where I want to be yet, but I’m long ways from where I was.

A Second Study

A second related study (Mohd Nor, N. S., Lee, S. , Bacha, F. , Tfayli, H. and Arslanian, S. (2016), Triglyceride glucose index as a surrogate measure of insulin sensitivity in obese adolescents with normoglycemia, prediabetes, and type 2 diabetes mellitus: comparison with the hyperinsulinemic–euglycemic clamp. Pediatr Diabetes, 17: 458-465.):

Insulin‐stimulated glucose disposal (Rd) declined significantly across the glycemic groups from OB‐NGT to OB‐preDM to OB‐T2DM with a corresponding increase in TyG index (8.3 ± 0.5, 8.6 ± 0.5, 8.9 ± 0.6, p < 0.0001). The correlation of TyG index to Rd was −0.419 (p < 0.0001).

The optimal TyG index for diagnosis of insulin resistance was 8.52 [receiver operating characteristic‐area under the ROC curves (ROC‐AUC) 0.750, p < 0.0001].

A Third Study

Here’s a third study with the same data but particular to diabetes (Prev Med. 2016 May;86:99-105. Triglyceride-glucose index (TyG index) in comparison with fasting plasma glucose improved diabetes prediction in patients with normal fasting glucose: The Vascular-Metabolic CUN cohort.
Navarro-González D, Sánchez-Íñigo L, Pastrana-Delgado J, Fernández-Montero A, Martinez JA.).

We observed a progressively increased risk of diabetes in subjects with TyG index levels of 8.31 or more. Among those with normal fasting glucose at baseline, <100mg/dl, subjects with the TyG index in the fourth quartile were 6.87 times more likely to develop diabetes (95% CI, 2.76-16.85; P for trend<0.001), as compared with the bottom quartile.

The areas under the ROC curves (95% CI) were 0.75 (0.70-0.81) for TyG index, 0.66 (0.60-0.72) for FPG and 0.71 (0.65-0.77) for TG, in subjects with normal fasting glucose (p=0.017).

Energy Expenditure Same on Various Diets

An interesting study (J O Hill J C Peters G W Reed D G Schlundt T Sharp H L Greene. Nutrient balance in humans: effects of diet composition. The American Journal of Clinical Nutrition, Volume 54, Issue 1, 1 July 1991, Pages 10–17).

Abstract

The purpose of this study was to examine the effect of alterations in diet composition on energy expenditure and nutrient balance in humans. Eight adults (three men, five women) ate a high-carbohydrate (60% of calories from carbohydrate) and a high-fat (60% of calories from fat) diet for 7 d each according to a randomized, crossover design. Six subjects were studied for an additional week on a mixed diet (45% of calories from fat).

For each subject, total caloric intake was identical on all diets and was intended to provide the subject’s maintenance energy requirements.

All subjects spent days 3 and 7 of each week in a whole-room indirect calorimeter.

Diet composition did not affect total daily energy expenditure but did affect daily nutrient oxidation by rapidly shifting substrate oxidation to more closely reflect the composition of the diet.

You can burn more fat and not lower your metabolism on a lower carb diet.