Insulin Resistance – Everything You Want to Know and Probably a Lot More

A great write-up on Insulin Resistance (Clin Biochem Rev. 2005 May; 26(2): 19–39. Insulin and Insulin Resistance. Gisela Wilcox).  It is not an understatement that the paper says:

…More than a century after scientists began to elucidate the role of the pancreas in diabetes, the study of insulin and insulin resistance remain in the forefront of medical research, relevant at all levels from bench to bedside and to public health policy

First some definitions:

Insulin resistance is defined where a normal or elevated insulin level produces an attenuated biological response; classically this refers to impaired sensitivity to insulin mediated glucose disposal.

Compensatory hyperinsulinaemia occurs when pancreatic β cell secretion increases to maintain normal blood glucose levels in the setting of peripheral insulin resistance in muscle and adipose tissue.

Insulin resistance syndrome refers to the cluster of abnormalities and related physical outcomes that occur more commonly in insulin resistant individuals. Given tissue differences in insulin dependence and sensitivity, manifestations of the insulin resistance syndrome are likely to reflect the composite effects of excess insulin and variable resistance to its actions.

Metabolic syndrome represents the clinical diagnostic entity identifying those individuals at high risk with respect to the (cardiovascular) morbidity associated with insulin resistance.

Interesting graphic (major pathways and influences on insulin secretion):

Here’s why Low Carb works so well:

Glucose is the principal stimulus for insulin secretion

Pancreatic β cells secrete 0.25–1.5 units of insulin per hour during the fasting (or basal) state, sufficient to enable glucose insulin-dependent entry into cells. This level prevents uncontrolled hydrolysis of triglycerides and limits gluconeogenesis, thereby maintaining normal fasting blood glucose levels. Basal insulin secretion accounts for over 50% of total 24 hour insulin secretion. … In healthy lean individuals circulating venous (or arterial) fasting insulin concentrations are about 3–15 mIU/L or 18–90 pmol/L

At rest we don’t need glucose for our muscles.

Muscle cells do not rely on glucose (or glycogen) for energy during the basal state, when insulin levels are low. Insulin suppresses protein catabolism while insulin deficiency promotes it, releasing amino acids for gluconeogenesis.

Perhaps of importance to low carb eaters a low level of glucose may produce a lower level of protein synthesis due to its similarity with starvation:

In starvation, protein synthesis is reduced by 50%. hilst data regarding a direct anabolic effect of insulin are inconsistent, it is clearly permissive, modulating the phosphorylation status of intermediates in the protein synthetic pathway.

In insulin resistance, muscle glycogen synthesis is impaired

We get fatter via:

Intracellular glucose transport into adipocytes in the postprandial state is insulin-dependent via GLUT 4; it is estimated that adipose tissue accounts for about 10% of insulin stimulated whole body glucose uptake.

As relates to low carb diets:

Insulin stimulates glucose uptake, promotes lipogenesis while suppressing lipolysis, and hence free fatty acid flux into the bloodstream.

As adipocytes are not dependent on glucose in the basal state, intracellular energy may be supplied by fatty acid oxidation in insulin-deficient states, whilst liberating free fatty acids into the circulation for direct utilization by other organs e.g. the heart, or in the liver where they are converted to ketone bodies.

Ketone bodies provide an alternative energy substrate for the brain during prolonged starvation.

Interesting:

…glucose uptake into the liver is not insulin-dependent

Another interesting section:

Whilst in insulin deficiency, e.g. starvation, these processes are more uniformly affected, this is not necessarily the case with insulin resistance. Compensatory hyperinsulinaemia, differential insulin resistance and differential tissue requirements may dissociate these processes. Resistance to insulin’s metabolic effects results in increased glucose output via increased gluconeogenesis (as in starvation), however, unlike starvation, compensatory hyperinsulinaemia depresses SHBG production and promotes insulin’s mitogenic effects. Alterations in lipoprotein metabolism represent a major hepatic manifestation of insulin resistance. Increased free fatty acid delivery, and reduced VLDL catabolism by insulin resistant adipocytes, results in increased hepatic triglyceride content and VLDL secretion. Hepatic synthesis of C-reactive protein, fibrinogen and PAI-1 is induced in response to adipocyte-derived pro-inflammatory cytokines such as TNFα and IL-6. Insulin may also increase factor VII gene expression.

Other factoids:

The insulin resistance syndrome describes the cluster of abnormalities which occur more frequently in insulin resistant individuals. These include glucose intolerance, dyslipidaemia, endothelial dysfunction and elevated procoagulant factors, haemodynamic changes, elevated inflammatory markers, abnormal uric acid metabolism, increased ovarian testosterone secretion and sleep-disordered breathing. Clinical syndromes associated with insulin resistance include type 2 diabetes, cardiovascular disease, essential hypertension, polycystic ovary syndrome, non-alcoholic fatty liver disease, certain forms of cancer and sleep apnoea.

Good write-up on Diabetes:

Compensatory hyperinsulinaemia develops initially, but the first phase of insulin secretion is lost early in the disorder. Additional environmental and physiological stresses such as pregnancy, weight gain, physical inactivity and medications may worsen the insulin resistance. As the β cells fail to compensate for the prevailing insulin resistance, impaired glucose tolerance and diabetes develops. As glucose levels rise, β cell function deteriorates further, with diminishing sensitivity to glucose and worsening hyperglycaemia. The pancreatic islet cell mass is reported to be reduced in size in diabetic patients; humoral and endocrine factors may be important in maintaining islet cell mass

 

 

Overshot My Recomp Goals – Part 8 – Bod Pod Accuracy

In Part 1 reviewed my [20 Apr 2018] Bod Pod test results against my goals of Body Recomposition.

Part 2 looked at some of the problems with having too low a body fat.

Part 3 looked at the consequences of low body fat with regard to fasting.

Part 4 looked at “Can’t I just eat more?”

Part 5 looked at maintenance diets.

In Part 6 set some goals of fat gain and longer term, muscular gain.

In Part 7 looked at skinfold measurements for body fat percentage.

The Bod Pod result of 7.5% seemed way too low, so I’ve been considering getting a DEXA scan to determine my body fat percentage. I did a quick look at the differences between DEXA and Bod Pod and found this study (Physiol Meas. 2004 Jun;25(3):671-8. Comparison of the Bod Pod and dual energy x-ray absorptiometry in men. Ball SD, Altena TS.). The study found:

The purpose of this study was to compare per cent fat estimates by the Bod Pod to those of DXA in a large number of men. Participants were 160 men (32 +/- 11 years). Per cent body fat was estimated to be 19.4 +/- 6.8 and 21.6 +/- 8.4 for DXA and the Bod Pod, respectively. Although the two methods were highly correlated (0.94), the mean difference of 2.2% was significant (p < 0.01). The amount of difference increased as body fatness increased (p < 0.0001). The results of this study indicate that a difference between methods existed for our sample of men. It is uncertain exactly where the difference lies. Practitioners should be aware that even with the use of technologically sophisticated methods (i.e., Bod Pod, DXA), differences between methods exist and the determination of body composition is at best, an estimation.

So if this is right, the DEXA scan typically gives lower values than the Bod Pod.

 

Insulin Levels in the Obese

Another interesting study on the levels of fasting Insulin in obese vs non-obese people (J Clin Invest. 1988 Feb; 81(2): 442–448. Twenty-four-hour profiles and pulsatile patterns of insulin secretion in normal and obese subjects. K S Polonsky, B D Given, and E Van Cauter). Here’s the differences in Insulin levels.

The obese have a much higher basal (background) level.

Insulin secretion rates were consistently elevated in the obese subjects under basal conditions (11.6 +/- 1.2 vs. 5.4 +/- 0.5 nmol/h)

The obese also had a much higher Insulin response.

…in the 4 h after breakfast (139 +/- 15 vs. 63 +/- 5 nmol/4 h, P less than 0.001), lunch (152 +/- 16 vs. 67 +/- 5 nmol/4 h, P less than 0.001), and dinner (145 +/- 18 vs. 65 +/- 6 nmol/4 h, P less than 0.001)…

When Insulin is high it pushes fat and glucose into cells. In the obese it takes more Insulin to push the fat into cells than it does in the normal.

When Insulin is low it allows fat to be mobilized from fat cells.

So what happens when you put a person on Insulin? They get fatter. And they have a harder time losing fat.

If you remove carbohydrates from the diet the Insulin levels drop. After a couple of weeks the basal Insulin levels drops to a level comparable to a normal person.

Another article (TED NAIMAN’S DAM FAT STORAGE INSULINOGRAPHIC EXPLAINED).

Obesity and Insulin Resistance

Here’s an interesting paper on the role of obesity in insulin resistance (J Clin Invest. 2000;106(4):473-481. Obesity and insulin resistance. Barbara B. Kahn, Jeffrey S. Flier.) Here’s one of the interesting figures from that paper which shows storage and mobilization (freeing) of fat from fat cells (adipocytes).

In this graphic, fat gets stored from glucose or fat in the diet. Fat in the diet gets shuttled through the liver. Insulin is the key element in the storage and mobilization of fat. That’s the core to the idea that leaning out the liver will reverse diabetes.

At the base of any strategy is lowering Insulin levels.

From (Nutrients. 2013 Jun; 5(6): 2019–2027. Body Fat Distribution and Insulin Resistance. Pavankumar Patel* and Nicola Abate.):

Insulin resistance is an underlying key pathophysiologic process in the development of cardio-metabolic disorders among obese individuals. Insulin resistance leads to development of an atherogenic dyslipidemic profile, and prothrombotic and proinflammatory states.

Dyslipidemia in insulin resistant individuals is characterized by elevated triglycerides, apolipoprotein B, small dense low density lipoprotein (LDL) particles, and reduced high density lipoprotein (HDL) concentration and smaller HDL particle size. Insulin resistance also leads to elevated blood pressure and glucose intolerance, which in the presence of genetic and environmental factors, can progress to hypertension and type 2 diabetes mellitus

 

Insulin Resistance and Diet Type

Here’s an interesting pilot (small) study (Obesity 2016:24, 79–86. Weight Loss on Low-Fat vs. Low-Carbohydrate Diets by Insulin Resistance Status Among Overweight Adults and Adults With Obesity: A Randomized Pilot Trial. Christopher D. Gardner, Lisa C. Offringa, Jennifer C. Hartle, Kris Kapphahn, and Rise Cherin.).

The study compared two dimensions: high/low insulin resistance against high/low carb diets. This meant that four groups of people were studied.  The study concluded that weight loss was comparable between all four groups.

Substantial weight loss was achieved overall, but a significant diet vs Insulin Resistance status interaction was not observed. Opportunity to detect differential response may have been limited by the focus on high diet quality for both diet groups and sample size.

The Low Carb group ended up eating 22% of calories from carbohydrates which is not ketogenic levels. There were significant improvements in most of the cardiovascular markers in favor of the Low Carb/Insulin Resistant group (See Table 3).

 

How Low in Carbs Should Low Carb Be for Diabetics?

Since I reversed my own diabetes with a Very-Low-Carb diet, I’ve been asked the question, “How many grams of carbs does it take to reverse diabetes?” Or, “How low do I need to go?”

There’s a study (Nutrition & Metabolism, December 2006, 3:22. Low-carbohydrate diet in type 2 diabetes. Stable improvement of bodyweight and glycemic control during 22 months follow-up. Jørgen Vesti, Nielsen, Eva Joensson.) which partially answers the question. This study put people on a relatively low carb diet of 20 % carbohydrates. But was that low enough?

The results of this level of carbohydrates was:

Results

The mean bodyweight at the start of the initial study was 100.6 ± 14.7 kg. At six months it was 89.2 ± 14.3 kg. From 6 to 22 months, mean bodyweight had increased by 2.7 ± 4.2 kg to an average of 92.0 ± 14.0 kg. Seven of the 16 patients (44%) retained the same bodyweight from 6 to 22 months or reduced it further; all but one had lower weight at 22 months than at the beginning. Initial mean HbA1c was 8.0 ± 1.5 %. After 6 and 12 months it was 6.6 ± 1.0 % and 7.0 ± 1.3 %, respectively. At 22 months, it was still 6.9 ± 1.1 %.

This group lost more around 20 lbs. More importantly the group reduced their HbA1c values from 8.0 to 6.9. Unfortunately, this is still not low enough to reverse diabetes.

20% of 2000 calories is 400 calories or 100 grams of carbohydrates. I conclude from this that 100 grams of carbohydrates is too high of a limit to reverse diabetes.

Here’s the relative risk from higher levels of HbA1C:

Zone Diet and Cellular Inflammation

It is the core assumption/belief of the Zone Diet that inflammation is the cause of Insulin Resistance (Zone Diet Paradigm Difference). From the Zone Diet page (Insulin Resistance and Weight Loss. Dr. Sears. Apr 6, 2018):

It is the dietary factors below that over the long term lead to increased cellular inflammation, making it more likely to become insulin resistant.

An imbalance of protein to carbohydrate at each meal.

Excess dietary caloric intake causing oxidative stress.

Excess dietary intake of omega-6 fatty acids.

Excess dietary intake of the saturated fatty acids, especially palmitic acid.

Lack of dietary intake of omega-3 fatty acids.

Lack of dietary intake of polyphenols to activate anti-oxidative genes to reduce oxidative stress.

Lack of dietary intake of polyphenols to promote gut health.

Lack of dietary intake of fermentable fiber to promote gut health.

“Protein to Carbohydrate Imbalance”

This is the central feature of the Zone diet. However, it fails the smell test for me since it’s very unlikely that our ancestors at this way. Certainly our grandparent ate meat and potato every meal but not our deeper ancestors. The potato itself came to the old world from the new world after Columbus. Meat may have been a rarity in more recent years but more a staple in our deeper history. I have doubts that we had both at the same meal at much time in our history.

This particular subject is well covered in the critique of the Zone Diet (J Am Coll Nutr. 2003 Feb;22(1):9-17. The Zone Diet phenomenon: a closer look at the science behind the claims. Cheuvront SN.). (Full-PDF). From the abstract:

The precise 0.75 protein to carbohydrate ratio required with each meal is promoted to reduce the insulin to glucagon ratio, which purportedly affects eicosanoid metabolism and ultimately produces a cascade of biological events leading to a reduction in chronic disease risk, enhanced immunity, maximal physical and mental performance, increased longevity and permanent weight loss. There is presently little scientific support for the connections made between diet, endocrinology and eicosanoid metabolism. In fact, a review of the literature suggests that there are scientific contradictions in the Zone Diet hypothesis that cast unquestionable doubt on its potential efficacy.

I may tackle some of the other listed items above. Or I may not.

 

Aspartame and Syrian Hamsters

From this interesting study (Journal of Food and Nutrition Research. Vol. 4, No. 3, 2016, pp 152-156. Low Intake of Aspartame Induced Weight Gain and Damage of Brain & Liver Cells in Weanling Syrian Hamsters. Magda Ibrahim Hassan, Department of Food Science, Faculty of Agriculture, Cairo University, Giza, Egypt.):

Abstract

This study aims to investigate the health effects of aspartame on weanling male hamsters. 20 Golden Syrian hamsters drank only water (control) or water with 6, 11, and 18 mg aspartame/kg of body weight per day for 42 days. Food intake, weight gain, glucose blood level, and lipid profile were determined at the end of the experiment. The animals were sacrificed and histopathological examination of organs (liver, brain and heart) was done. Results revealed that animals in Aspartame groups (Asp.groups) consumed significantly larger amount of food than the control (13.4±5.9, 8.6±2.5 and 8.8±3.0 vs 4.2±2.5 g/day, in succession). Hamsters in the control group showed higher total cholesterol and HDL levels than hamsters in aspartame 6, 11, 18 groups (160±19 vs 101±13, 130±22, 141±15 mg/dl & 144±9 vs 120±12, 118±13, 99±17 respectively (P<0·05)). The control group showed a glucose concentration below those of aspartame groups, indicating no effect of aspartame on glucose blood level. While, there were no significant differences in the triglycerides and LDL levels between control group and Asp.groups. Histopathological changes were observed, especially in brain and liver cells. Aspartame increases appetite and weight gain of young hamsters. Therefore, authorities (the Joint FAO/WHO Expert Committee on Food Additives (JECFA), the U.S. Food and Drug Administration (FDA), the European Food Safety Authority (EFSA) and the Agence Française de Sécurité Sanitaire des Aliments (French Food Safety Agency – AFSSA)) should reconsider the acceptable daily intake (ADI) of aspartame especially for children, they are more vulnerable than adults.

Another article (Diet soda sweetener may cause weight gain).

Dr. Hodin and team (Inhibition of the gut enzyme intestinal alkaline phosphatase may explain how aspartame promotes glucose intolerance and obesity in mice. Sarah S. Gul,* A. Rebecca L. Hamilton,* Alexander R. Munoz, Tanit Phupitakphol, Wei Liu, Sanjiv K. Hyoju, Konstantinos P. Economopoulos, Sara Morrison, Dong Hu, Weifeng Zhang, Mohammad Hadi Gharedaghi, Haizhong Huo, Sulaiman R. Hamarneh, Richard A. Hodin) had conducted previous research where they fed IAP to mice that were on a high-fat diet. They found that IAP can prevent the onset of metabolic syndrome, as well as reduce the symptoms in animals that already had the condition.

Based on this known relationship between IAP, phenylalanine, and aspartame, researchers hypothesized that consuming aspartame may promote metabolic syndrome because of its inhibition of phenylalanine.

Another study (Appetite, Volume 60, 1 January 2013, Pages 203-207 Appetite. Saccharin and aspartame, compared with sucrose, induce greater weight gain in adult Wistar rats, at similar total caloric intake levels. Fernanda de MatosFeijó, et.al.).

Twenty-nine male Wistar rats received plain yogurt sweetened with 20% sucrose, 0.3% sodium saccharin or 0.4% aspartame, in addition to chow and water ad libitum, while physical activity was restrained. Measurements of cumulative body weight gain, total caloric intake, caloric intake of chow and caloric intake of sweetened yogurt were performed weekly for 12 weeks. Results showed that addition of either saccharin or aspartame to yogurt resulted in increased weight gain compared to addition of sucrose, however total caloric intake was similar among groups. In conclusion, greater weight gain was promoted by the use of saccharin or aspartame, compared with sucrose, and this weight gain was unrelated to caloric intake.

CrossFit and Nutrition – Part 4 – CrossFit and the Zone Diet

There’s a claim made by CrossFit that the Zone diet is optimal for their athletes. Glassman wrote (CFJ Issue 21: Zone Meal Plans, May 01, 2004):

Our clinical experience proves the Zone Diet, by Dr. Barry Sears is the best nutritional model for optimal performance…

The Zone Diet amplifies and accelerates the benefits of the CrossFit regimen. CrossFit’s best performers are Zoning. When our second tier athletes commit to “strict” adherence to Zone parameters they quickly surpass their peers.

This claim has been reviewed (The Zone Diet and Athletic Performance. Sports Medicine, April 1999, Volume 27, Issue 4, pp 213–228. Samuel N. Cheuvront.)

Applying the Zone’s suggested protein needs and macronutrient distributions in practice, it is clear that it is a low carbohydrate diet by both relative and absolute standards, as well as calorie deficient by any standard. Reliable and abundant peer reviewed literature is in opposition to the suggestion that such a diet can support competitive athletic endeavours, much less improve them.

The notion that a 40/30/30 diet can alter the pancreatic hormone response in favour of glucagon is also unfounded. The Zone is a mixed diet and not likely to affect pancreatic hormone release in the same way individual nutrients can. Although the postprandial insulin response is reduced when comparing a 40% with a 60% carbohydrate diet, it is still a sufficient stimulus to offset the lipolytic effects of glucagon.

Many of the promised benefits of the Zone are based on selective information regarding hormonal influences on eicosanoid biology. Contradictory information is conveniently left out. The principle of vasodilating muscle arterioles by altering eicosanoid production is notably correct in theory. However, what little human evidence is available does not support any significant contribution of eicosanoids to active muscle vasodilation. In fact, the key eicosanoid reportedly produced in the Zone and responsible for improved muscle oxygenation is not found in skeletal muscle. Based on the best available scientific evidence, the Zone diet should be considered more ergolytic than ergogenic to performance.

Robb Wolf has written a response to this paper (The Zone and Athletic Performance). I like Robb’s response to one question there:

Coach Glassman has called Atkins “The Zone for Sedentary people”.

We ONLY need carbs for intense activity. Glycogen drives most crossfit activities but it is a battle for some to take in adequate carbs to drive that activity AND still be under the insulin radar. I simply do a bit more strength work in preference to the high volume met-cons. I can recover from this workload with fewer carbs. I may not set the CF world on fire but it works well for me.

Here’s a very short study (J Strength Cond Res. 2002 Feb;16(1):50-7. The acute 1-week effects of the Zone diet on body composition, blood lipid levels, and performance in recreational endurance athletes. Jarvis M1, McNaughton L, Seddon A, Thompson D.).