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).

Liver at the Center of Metabolic Syndrome

The liver is at the center of Metabolic Syndrome (Yki-Järvinen, Hannele. Nutritional Modulation of Non-Alcoholic Fatty Liver Disease and Insulin Resistance. Nutrients 7.11 (2015): 9127–9138. PMC. Web. 22 May 2018.) states the reason why this is relevant.

If the liver is fatty due to causes of insulin resistance such as obesity and physical inactivity, it overproduces glucose and triglycerides leading to hyperinsulinemia and a low high-density lipoprotein (HDL) cholesterol concentration.

How do you tell if you have a Fatty Liver?

Trouble is blood tests don’t tell you most of the time.

NAFLD is usually asymptomatic and most patients have normal transaminases (ALT <30–40 U/L for men and <20–30 U/L for women)

See also (J Res Med Sci. 2016; 21: 53. The effects of low carbohydrate diets on liver function tests in nonalcoholic fatty liver disease: A systematic review and meta-analysis of clinical trials. Fahimeh Haghighatdoost,

… we conducted a meta-analysis of clinical trial data to summarize the effects of LCDs on liver function tests in NAFLD.

Low Carb Diet consumption in subjects with NAFLD led to a significant reduction in IHLC, but did not significantly affect the concentration of liver enzymes.

Metabolic Syndrome Development

Pathophysiology of “Metabolic NAFLD”, which causes and consequences resemble those of the insulin resistance/metabolic syndrome (MetS).

Overeating and physical inactivity predispose to both conditions.

Excess glucose, fructose and amino acids are converted to triglyceride (TG) in the liver via de novo lipogenesis (DNL), which pathway is increased in NAFLD.

Alterations in gut microbiota in obesity increase gut permeability to bacterial components such as lipopolysaccharide (LPS), which may contribute to inflammation in both adipose tissue and the liver.

Overeating leads to adipose tissue expansion, hypoxia, increased fibrosis and cell death. Dead adipocytes are surrounded by macrophages, which produce cytokines such as tumor-necrosis alpha and chemokines such as monocyte chemoattractant protein-1. This impairs the ability of insulin to inhibit lipolysis i.e., inhibit release of free fatty acids (FFA) and leads to deficiency of the insulin-sensitizing cytokine adiponectin. The latter two changes promote synthesis of intrahepatocellular TG.

The ability of insulin to suppress glucose and VLDL production is impaired resulting in mild hyperglycemia and hyperinsulinemia, hypertriglyceridemia (TG↑) and a low HDL cholesterol concentration (HDL chol↓).

The fatty liver also overproduces many other factors such as the liver enzymes alanine aminotransferase (ALT), aspartate aminotransferase (AST) and gamma-glutamyltransferase (GGT), C-reactive protein (CRP) and coagulation factors.

This paragraph really summarizes it well:

Hypocaloric, especially low carbohydrate ketogenic diets rapidly decrease liver fat content and associated metabolic abnormalities. However, any type of caloric restriction seems effective long-term. Isocaloric diets containing 16%–23% fat and 57%–65% carbohydrate lower liver fat compared to diets with 43%–55% fat and 27%–38% carbohydrate. Diets rich in saturated (SFA) as compared to monounsaturated (MUFA) or polyunsaturated (PUFA) fatty acids appear particularly harmful as they increase both liver fat and insulin resistance. Overfeeding either saturated fat or carbohydrate increases liver fat content.

Low carb works much better once again.

Type 2 Diabetes Cured in Less Than Two Months

An interesting small study which fed subjects a very low fat diet and reversed their Type 2 Diabetes in a couple of months (Kitt Falk Petersen, Sylvie Dufour, Douglas Befroy, Michael Lehrke, Rosa E. Hendler, Gerald I. Shulman. Reversal of Nonalcoholic Hepatic Steatosis, Hepatic Insulin Resistance, and Hyperglycemia by Moderate Weight Reduction in Patients With Type 2 Diabetes. Diabetes Mar 2005, 54 (3) 603-608).

To examine the mechanism by which moderate weight reduction improves basal and insulin-stimulated rates of glucose metabolism in patients with type 2 diabetes, we used 1H magnetic resonance spectroscopy to assess intrahepatic lipid (IHL) and intramyocellular lipid (IMCL) content in conjunction with hyperinsulinemic-euglycemic clamps using [6,6-2H2]glucose to assess rates of glucose production and insulin-stimulated peripheral glucose uptake.

The participants were fed a low calorie, low fat diet.

Eight obese patients with type 2 diabetes were studied before and after weight stabilization on a moderately hypocaloric very-low-fat diet (3%).

These were full blown diabetic patients.

The diabetic patients were markedly insulin resistant in both liver and muscle compared with the lean control subjects. These changes were associated with marked increases in IHL (12.2 ± 3.4 vs. 0.6 ± 0.1%; P = 0.02) and IMCL (2.0 ± 0.3 vs. 1.2 ± 0.1%; P = 0.02) compared with the control subjects.

IHL is fat in the liver. The IHL went from 12.2% to 0.6% in the diabetics with the treatment.

A weight loss of only ∼8 kg resulted in normalization of fasting plasma glucose concentrations (8.8 ± 0.5 vs. 6.4 ± 0.3 mmol/l; P < 0.0005), rates of basal glucose production (193 ± 7 vs. 153 ± 10 mg/min; P < 0.0005), and the percentage suppression of hepatic glucose production during the clamp (29 ± 22 vs. 99 ± 3%; P = 0.003).

That is a fairly small weight loss but it shows that loss of fat from the liver drops the production of glucose from the liver significantly.

These improvements in basal and insulin-stimulated hepatic glucose metabolism were associated with an 81 ± 4% reduction in IHL (P = 0.0009)

These diabetics lost 81% of their liver fat!

but no significant change in insulin-stimulated peripheral glucose uptake or IMCL (2.0 ± 0.3 vs. 1.9 ± 0.3%; P = 0.21).

This showed it wasn’t peripheral Insulin Resistance that was the problem, but rather fat in the liver. It also wasn’t other fat (IMCL).

In conclusion, these data support the hypothesis that moderate weight loss normalizes fasting hyperglycemia in patients with poorly controlled type 2 diabetes by mobilizing a relatively small pool of IHL, which reverses hepatic insulin resistance and normalizes rates of basal glucose production, independent of any changes in insulin-stimulated peripheral glucose metabolism.

The average course of treatment was 7 weeks. After the treatment their Fasting Insulin levels were almost 1/3 of the original numbers.

Low carb, of course, can quickly achieve the same results but this does point to the liver fat as the root cause of diabetes. I did this in two weeks with Low Carb and Intermittent Fasting.

Bariatric patients who are scheduled surgery are often told that they need to lose liver fat before their surgery. From (How to Shrink Your Liver Before Weight Loss Surgery).:

Studies have shown that losing weight before surgery and avoiding carbohydrates and fats in the weeks leading up to surgery can reduce the size of your liver through a process known as “ketosis,” which is when your body starts to use its fat stores because it has run out of fuel (calories). Excess fat in the liver appears to be one of the first places the body turns to for this added fuel.

Or you can just stay on the Low Carb diet…

A Second Related Study

Here’s a second related study (Noud A. van Herpen Vera B. Schrauwen-Hinderling Gert Schaart Ronald P. Mensink Patrick Schrauwen. Three Weeks on a High-Fat Diet Increases Intrahepatic Lipid Accumulation and Decreases Metabolic Flexibility in Healthy Overweight Men. The Journal of Clinical Endocrinology & Metabolism, Volume 96, Issue 4, 1 April 2011, Pages E691–E695).

Twenty overweight men were randomly allocated to low- or high-fat groups (age, 54.0 ± 2.3 and 56.4 ± 2.5 yr; body mass index, 29.3 ± 0.6 and 28.3 ± 0.5 kg/m2, respectively). Both groups started with a 3-wk low-fat diet [15% energy (En%) as protein, 65 En% as carbohydrates, 20 En% as fat], after which half of the subjects switched to a 3-wk isocaloric high-fat diet (15 En% protein, 30 En% carbohydrates, 55 En% fat). After 3 and 6 wk, IHL and IMCL content were assessed by 1H magnetic resonance spectroscopy and a muscle biopsy, and insulin sensitivity was studied using a hyperinsulinemic-euglycemic clamp. An additional liver scan was performed after 1 wk in the high-fat group.

Note this was not a low carb study because both diets were relatively high in carbohydrates. However, the results are interesting.

IHL decreased by 13% in the low-fat group and increased by 17% in high-fat group (P = 0.047). IMCL content was unaffected (P = 0.304). Insulin sensitivity was unaffected. At wk 3, IHL correlated negatively with insulin sensitivity (r = −0.584; P = 0.009, all subjects combined). Metabolic flexibility, defined as change in respiratory quotient upon insulin stimulation, was decreased after 3 wk of the high-fat diet (change in respiratory quotient was +0.02 ± 0.02 vs.−0.05 ± 0.1 in low-fat vs. high-fat group, P = 0.009).

The change in RQ was very small which shows that the carb/fat burning mixture was not much changed. There was enough carbs present to cause the liver to get fatter.


Keto Podcasts

I listen to quite a few Keto Podcasts. They can be informative and in some cases entertaining. Here’s some of them.

  • The Paleo Solution Podcast – It might seem like an odd first choice but I really like Robb Wolf’s style. He’s one smart paleo cookie. He has quite a bit of keto content and has done keto for much of his adult life.
  • 2 Keto Dudes – There’s a lot to like with these two software developers turned keto dudes. They’ve had a similar journey to mine with overcoming Type 2 Diabetes and their interview format is flexible enough for them to have guests that aren’t exactly in line with their higher-fat views. I’d like to see these guys get closer to goal weight but their reluctance to do Protein Sparing Modified Fasts (PSMF) is really slowing down their progress.
  • Keto for Normies – Her voice can be grating and his can sound like a meathead but their hearts are in the right place. They aren’t afraid to try things like PSMF or Carnivore and report on their successes or failures.
  • The Primal Blueprint Podcast is hosted by Mark Sisson, author of a famous low-carb paleo blog Mark’s Daily Apple.
  • Ben Greenfield FitnessBen Greenfield is another really sharp guy with some good insights into keto and athletic performance.
  • Keto Savage – This is the guy who ate 4000 calories a day and gained body fat.
  • Keto Geek – A good science keto show.
  • Ketodontist – An orthodontist/dentist who lives keto and has some great interviews as well.
  • Keto Talk with Jimmy Moore – It is with great reluctance that I list this podcast. Mostly I am listing it because Jimmy Moore tends to have some pretty good guests. But Jimmy’s dramatics are a bit to take at times.

The same sets of guest often make the rounds on each of these shows. They all seem to have the same list of keto guests such as Dave Feldman (Cholesterol Code), Marty Kendall (Optimising Nutrition), Shawn Baker (Carnivore Diet), Ted Naiman (Burn Sugar Not Fat),  Robert Sikes (Keto Savage), Luis Villasenor/Tyler Cartwright (KetoGains). It does also entertain me that the podcasters often interview other podcasters.

I haven’t deliberately omitted any podcasts that I know of. There’s some I have not listened to yet so if I find a new one, I will add it to this list.


Hyperinsulinemia – Chicken or Egg?

Which comes first – obesity or Hyperinsulinemia? Does fat get locked in our cells due to higher fasting insulin levels? Or is it the fact that we are fat that raises our fasting insulin levels?

From (Crofts, C., Zinn, C., Wheldon, M., Schofield, G. 2015. Hyperinsulinemia: A unifying theory of chronic disease?. Diabesity 1(4): 34-43.):

It is agreed that hyperinsulinemia precedes hyperglycemia, by up to 24 years. There is a strong argument that hyperglycemia indicates pancreatic β-cell attrition; essentially end-stage organ damage.We contend that the under-recognition of hyperinsulinemia is an important clinical issue because there are no standard diagnostic reference values, is most accurately diagnosed with dynamic glucose and insulin testing, and has few (pharmaceutical) management options.

One of the posited reasons for hyperinsulinemia is fructose.

Fructose is metabolized in liver into ATP and/or triglycerides in a process that is competitive with, and preferential to, glucose. If excessive fructose is consumed, glucose will not be metabolized causing hyperglycemia and subsequent hyperinsulinemia.

A helpful insight:

Hyperinsulinemia is independent to insulin resistance: Hyperinsulinemia is excessive insulin secretion, while insulin resistance is impaired glucose uptake.

Given the intertwined nature between insulin resistance and hyperinsulinemia as depicted above, it can be assumed that the majority of people with insulin resistance are also hyperinsulinemic.

Here’s another subject that is interesting:

There is debate as to whether hyperinsulinemia precedes, or are a consequence of fatty liver

From the citation noted (Dig Liver Dis. 2010 May;42(5):320-30.  From the metabolic syndrome to NAFLD or vice versa? Vanni E,

Recent data indicate that hyperinsulinemia is probably the consequence rather than cause of NAFLD and NAFLD can be considered an independent predictor of cardiovascular disease. Serum free fatty acids derived from lipolysis of visceral adipose tissue are the main source of hepatic triglycerides in NAFLD, although hepatic de novo lipogenesis and dietary fat supply contribute to the pathogenesis of NAFLD.

Here’s more on the fat question:

Hypertrophic adipose tissues activate inflammatory and stress pathways and decreases insulin response. This results in increased cytokine production including TNF-α, vascular endothelial growth factor and leptin, while adiponectin expression is decreased. These actions contribute to decreased glucose and lipid uptake, leading to further reductions to adiponectin secretion and adipogenesis as well as contributing to further insulin resistance. Decreased glucose uptake means there is less glycerol within the adipocyte to esterify free fatty acids, allowing them to infiltrate and accumulate in other tissues.

Sounds like a viscous cycle!


RQ, Hyperinsulinemia and Nighttime Eating

Interesting study done in a metabolic ward (Obesity (Silver Spring). 2011 Feb;19(2):319-23. doi: 10.1038/oby.2010.206. Epub 2010 Sep 23. Higher 24-h respiratory quotient and higher spontaneous physical activity in nighttime eaters. Gluck ME, Venti CA, Salbe AD, Votruba SB, Krakoff J.).

We investigated whether 24-h RQ was higher in individuals who exhibited nighttime eating behavior. Healthy nondiabetic Pima Indians (PI; n = 97, 54 male/43 female) and whites (W; n = 32, 22 male/10 female) were admitted to our Clinical Research Unit. After 3 days of a weight maintaining diet, 24-h energy expenditure (24-h EE), 24-h RQ, rates of carbohydrate (CHOX) and lipid oxidation (LIPOX), and spontaneous physical activity (SPA) were measured in a metabolic chamber whereas volunteers were in energy balance and unable to consume excess calories. Individuals subsequently ate ad libitum from a computerized vending machine for 3 days with amount and timing of food intake recorded. F

ifty-five individuals (36%; 39 PI, 16 W) were NE, who ate between 11 PM and 5 AM on at least one of the 3 days on the vending machines. There were no differences in BMI or percentage body fat between NE and non-NE. After adjusting for age, sex, race, fat-free mass, fat mass, and energy balance, NE had a higher 24-h RQ (P = 0.01), higher CHOX (P = 0.009), and lower LIPOX (P = 0.03) and higher 24-h SPA (P = 0.04) compared to non-NE.

There were no differences in adjusted 24-h EE or sleep RQ between the groups. Individuals with nighttime eating behavior have higher 24-h RQ, higher CHOX and lower LIPOX, a phenotype associated with increased food intake and weight gain.

Night eating and higher RQ (carb oxidation rates). Calorie matched (fed from controlled vending machine). They ate at night and therefore their glycogen levels didn’t drop enough to switch to fat burning. Hyperinsulinemia?


Protein and Metabolic Syndrome

Another study (Obes Facts. 2017 Jul; 10(3): 238–251. Effect of a High-Protein Diet versus Standard-Protein Diet on Weight Loss and Biomarkers of Metabolic Syndrome: A Randomized Clinical Trial. Ismael Campos-Nonato, Lucia Hernandez, and Simon Barquera) on protein and the Metabolic Syndrome. The study was a:

Randomized controlled trial in 118 adults aged 47.4 ± 11.5 years and meeting the established criteria for MeS were randomized to prescribed hypocaloric diets (500 kcal less than resting metabolic rate) providing either 0.8 g/kg body weight (standard protein diet (SPD)) or 1.34 g/kg body weight (higher protein diet (HPD)) for 6 months.

Was there a downside to higher protein diet?

There were 105 subjects (51 for SPD and 54 for HPD) who completed the trial. Overall weight loss was 5.1 ± 3.6 kg in the SPD group compared to 7.0 ± 3.7 kg in the in HPD group. Both groups lost a significant percent of centimeters of waist circumference (SPD −6.5 ± 2.6 cm and HPD −8.8 ± 2.6 cm). There was no statistical difference Except for the varying weight losses the two groups did not show any further differences overall. However in the subgroup judged to be adherent more than 75% of the time with the prescribed diets, there was a significant difference in mean weight loss (SPD −5.8% vs. HPD −9.5%) after adjusting for baseline BMI.

Both groups demonstrated significant decreases in waist circumference, glucose, insulin, triglycerides, and VLDL cholesterol, but there were no differences between the groups. There were no changes in blood tests for liver or renal function.

Good result for higher protein.

Metabolic Syndrome – Am I Cured?

The Adult Treatment Panel III of the National Cholesterol Advisory Panel defines Metabolic syndrome as the “constellation of lipid and non-lipid risk factors of metabolic origin” (Journal of the American College of Cardiology
Volume 44, Issue 3, 4 August 2004, Pages 720-732 Journal of the American College of Cardiology. NCEP Report. Implications of Recent Clinical Trials for the National Cholesterol Education Program Adult Treatment Panel III Guidelines. Scott M.Grundy,, Coordinating Committee of the National Cholesterol Education Program). Their diagnostic criteria for metabolic syndrome require three of the following:

  • Abdominal obesity
    • Men: waist circumference >40 inches (102 cm )
    • Women: waist circumference >35 inches (88 cm)
  • Fasting glucose ≥ 110 <126 mg/dL (6.1–7.0 mmol/L)
  • Blood pressure ≥ 130/80 mmHg
  • Triglycerides >150 mg/dL (>1.7 mmol/L)
  • HDL cholesterol
    • Men <40 mg/dL (<1.0 mmol/L)
    • Women <50 mg/dL (<1.3 mmol/L)

Here’s my current numbers:

  • My waist circumference is now 33″ so that’s good.
  • My fasting glucose is 100 so that’s good.
  • My blood pressure is good.
  • My triglycerides are 114 so that’s good.
  • My HDL was 51 so that’s good.

 No more Metabolic Syndrome!

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.


…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



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