Is Insulin Resistance A Result Of Impaired Beta Oxidation Or Excessive Beta Oxidation?

[Peater Piper]

I think one of the problems with this contradiction you are seeing is that people often report the actions in the whole body, in a specific tissue (like liver), or in a cellular preparation, as the same. As we all know, muscle burns more fatty acids at rest than liver or the brain, and how they are affected by substrate availability and the hormonal signals is different as well. So at the whole body level, what you describe could be the effect and that is confusing. It's still possible, however, that the livers of those prediabetic people are having trouble using glucose, and that could be balanced out by muscle burning more glucose than fat compared to the healthy individuals. I think what the liver does (or doesn't do) is probably the most important for diabetic symptoms.

The author's actually mentioned the liver. They didn't think NAFLD would have set in yet, but didn't actually perform any tests. However. the relatives of the diabetics responded similarly to the controls when tested with a high carbohydrate meal. I would have expected either increased glucose due to the liver not shutting down gluconeogenesis, or elevated insulin, if the liver is starting to fatten up.

 

[Kyle M]

The author's actually mentioned the liver. They didn't think NAFLD would have set in yet, but didn't actually perform any tests. However. the relatives of the diabetics responded similarly to the controls when tested with a high carbohydrate meal. I would have expected either increased glucose due to the liver not shutting down gluconeogenesis, or elevated insulin, if the liver is starting to fatten up.

So they measured glucose utilization and/or production at the liver level in these people? I didn't think that was possible. If they tested the whole body, then there may have been a change in the liver but that the resulting higher or lower blood sugar could be compensated for by increased or decreased non-liver uptake. Like a pH buffer, every living system has a little less response to a chemistry change than a non-living system would.

 

[Peater Piper]

So they measured glucose utilization and/or production at the liver level in these people? I didn't think that was possible. If they tested the whole body, then there may have been a change in the liver but that the resulting higher or lower blood sugar could be compensated for by increased or decreased non-liver uptake. Like a pH buffer, every living system has a little less response to a chemistry change than a non-living system would.

No, they weren't that detailed, I'm just saying I would expect when they were tested with a high carbohydrate meal to either see elevated glucose levels or insulin levels if the liver is becoming a problem. Here's what they did:

Subjects attended the clinical research facility on three separate visits, and each visit was at least 3 days but no more than 14 days apart. On the first visit, subjects fasted for 10 h overnight, and body weight was measured in a hospital gown and height measured by a stadiometer. Insulin sensitivity was then measured by 2-h hyperinsulinemic-euglycemic clamp (50 mU/m2 per min), according to previously described methods (21). Briefly, two intravenous cannula were inserted, one for infusion of regular insulin (Novo Nordisk, Baulkham Hills, NSW, Australia) and glucose (Baxter, Old Toongabbie, NSW, Australia), and the other was placed in the contralateral hand for blood withdrawal with the hand placed in a heating pad. A variable infusion of exogenous glucose was given to maintain glucose concentrations at 5.0 mmol/l. After the clamp, body composition was measured by dual X-ray absorptiometry (Lunar DPX; Lunar Radiation, Madison, WI). At visits 2 and 3, subjects attended the clinical research facility at 8 a.m. to measure various factors in response to a meal after a prolonged fast (20 h). These visits were identical except for the type of meal consumed. At each visit, subjects were weighed, and an intravenous cannula was inserted into the antecubital vein. A blood sample was taken (−60), and subjects rested in the supine position for 30 min. Resting metabolic rate and respiratory quotient (RQ) were determined over a 30-min period (Deltatrac; Datex, Helsinki, Finland). A vastus lateralis muscle biopsy was then performed to obtain ∼200 mg of tissue, and the samples were immediately blotted for blood, and any visible fat was removed from the sample. Samples were snap-frozen at −80°C. One female subject from the group of subjects with a family history of type diabetes refused muscle biopsy. After the muscle biopsy, a 0–time point blood sample was taken, and subjects were fed a standard 1,000-kcal meal that was high in either fat (76%) or carbohydrate (76%). The meals were held constant for protein (15%) and were randomly assigned to visit 2 or 3. Detailed meal composition is given in Appendix 1, which can be found in an online appendix (available at http://dx.doi.org/10.2337/db06-1687). Additional blood samples were taken at 30, 60, 120, 180, and 240 min after the meal was completed. A second muscle biopsy was taken at 180 min after the meal, and the metabolic rate and RQ were assessed for 30 min from 210 to 240 min.

The thing is, these aren't considered prediabetics. They're supposedly healthy relatives with a strong genetic potential to become diabetic, but they're supposed to be healthy at this point and matched to controls without a family history of diabetes. The most notable differences came from gene expression following the high fat meal, observed through muscle biopsies.

Metabolically healthy skeletal muscle is characterized by its ability to switch rapidly between glucose and fat oxidation in response to homeostatic signals. Obese insulin-resistant individuals and individuals with type 2 diabetes are metabolically inflexible (23). However, it is not clear whether metabolic inflexibility is a cause or a consequence of insulin resistance and type 2 diabetes. Therefore, we examined a human model where insulin resistance and diabetes had not yet developed and challenged this system by a prolonged fast followed by either high-fat or -carbohydrate meals. First, we showed that the insulin-sensitive relatives of individuals with type 2 diabetes had an impaired ability to increase fatty acid oxidation 4 h after a single high-fat meal. We also showed general differences in the activation of genes involved in lipid metabolism in response to either high-carbohydrate or -fat meals, and in particular we showed reduced expression of adipoR1 and -2 in response to high-fat meal, suggesting nutrient-specific regulation of these receptors. Third, we showed differential changes in the expression of PGC1α, FAT/CD36, and ACC2 between control subjects and those with a family history of type diabetes in response to the high-fat meal. This study suggests that metabolic flexibility may be involved in the development of insulin resistance in genetically susceptible individuals and that defective regulation of PGC1α and FAT/CD36 may be involved in this response.

The ability to switch on fat oxidation in response to an increase in dietary fat is variable between subjects and may translate to a positive fat balance and weight gain over time (24). Furthermore, an impaired ability to oxidize fatty acids is postulated to increase intramyocellular triglycerides and other lipid intermediates in the cell, which interfere with insulin signaling (25,26). In the current study, we observed that basal fat oxidation was similar between control subjects and those with a family history of type diabetes, but the latter had an impaired ability to switch on fat oxidation after a single high-fat meal. This was observed in the absence of detectable differences in insulin sensitivity by the clamp or of differences in postprandial FFAs or triglycerides in response to the meal, which accompany decreased insulin sensitivity (4). Therefore, we speculate that impaired fatty acid oxidation is a primary defect in the development of insulin resistance in individuals with a strong genetic predisposition for developing type 2 diabetes. However, we did not measure insulin resistance by low-dose clamp, and the subjects with a family history of type diabetes did trend toward an increased insulin response after the high-carbohydrate meal, which may be indicative of insulin resistance. On the other hand, other studies have shown that hepatic insulin resistance is not present at this stage in human relatives of individuals with type 2 diabetes (27,28), and all other indicators of insulin resistance, such as fasting insulin, homeostasis model assessment, or metabolic flexibility to carbohydrate ingestion, were not different between groups. Furthermore, it is likely that the 20-h fast was sufficient to “stress the system,” potentially allowing an early metabolic defect to become apparent after a high-carbohydrate meal when not apparent by the clamp. Because no differences were observed in serum FFAs, this study also suggests that fatty acid uptake into skeletal muscle was not altered in nondiabetic relatives of individuals with type 2 diabetes. This has previously been reported to be similar or increased in obese rodent models and humans (12,29) and may eventually result in increased triglyceride storage within skeletal muscle (3). Also of note, a small but significantly higher glucose response was observed in relatives of individuals with type 2 diabetes in response to the high-fat meal. However, this was in the normal physiological range, and we suggest that if it were clinically important, it would have invoked an insulin response, but that it may indicate a higher “gluconeogenesis set” to fat input in this population.

We then examined potential mechanisms in skeletal muscle that may account for the impairments in fatty acid oxidation that were observed after the prolonged fast and refeed. The prolonged fast was designed to represent a metabolic challenge to skeletal muscle, requiring a sustained increase in the reliance on lipid and protein metabolism. Previous studies of refeeding after prolonged fasting in lean healthy subjects have found marked heterogeneity in the transcriptional response in PDK4 and lipoprotein lipase (LPL), suggesting that individual differences in genetic profile may play an important role in adaptive molecular responses (20). In the current study, PDK4 expression was not different between groups. However, the change in PGC1α, FAT/CD36, and ACC2 expression in response to the high-fat meal was significantly lower in relatives of individuals with type 2 diabetes compared with control subjects. PGC1α is a transcriptional coactivator that controls genes involved in oxidative phosphorylation and fatty acid metabolism, and it is lower in insulin-resistant individuals (30–32).

 

[Kyle M]

1000 kcal meal 76% fat, oof. Reference 23 is interesting, it dovetails with my results in mice, where the linoleic acid fed mice were glucose intolerant or insulin resistant (depending on other particulars like sex). I found some references showing different fatty acids affect this flexibility differently, by blocking inhibiting of CPT1 by malonyl CoA, and by changing activity of CPT1 in liver.

 

[LeeLemonoil]

If what the quoted post is true, does niacianamide act in a similar manner?
Increasing oxidation/NAD levels while preventing FFA overload in the mitochondria. Otherwise isn’t B3 too often a risk to impair beta-oxidation?

Sorry, this surely has been discussed before but I can’t really find it right now

impaired beta oxidation is caused by an elevated level of fatty acids inside the mitochondria

oxygen is needed to complete the process of beta oxidation and in times of intense stress or (chronic stress caused by ongoing elevated FFA levels) the oxygen demand by the mitochondria isnt met and the fatty acids pile up inside the cell and in doing so inhibit the oxidation of glucose and the oxidation of themselves .

so if i was to take a stab in the dark taurine and caffeine are lifting the gate on that stress to allow the demand for oxygen to be met more efficiently , temporarily restoring beta oxidation reducing the level of fatty acids inside the cell and allowing glucose and fatty acid metabolism to continue until oxygen supply becomes short and impairs oxidation again

and this is why mildronate is so effective.. it stops the entry of long chain fatty acids entering the mitochondria by inhibiting gamma-butyrobetaine dioxygenase(no carnitine to transport the LCFA).

so the take home note is basically what haidut said , nothing wrong with beta oxidation... the problem would be chronic lipolysis