Anabolism Gone Awry: Muscle Fibres, Glucose Tolerance and Insulin Sensitivity
Chronic overconsumption of carbohydrates results in high blood sugar levels (hyperglycemia) and resistance/insensitivity to the hormone insulin. Normally insulin is responsible for directing glucose into skeletal muscles for storage as glycogen, but the capacity for storing glycogen is limited. If the muscles erect "no vacancies" signs, insulin is unable to efficiently dispose of glucose, and hyperglycemia (along with glycative damage and other delights) ensues.

Despite this, some people (e.g. elite athletes and those who behave like them) are able to indulge in generous quantities of carbohydrate with much less hazard than members of the general public. This is because their regular, demanding physical endeavours result in the depletion of large amounts of their existing glycogen stores, hence creating vacancies for more glucose and keeping the muscles sensitive to insulin.

Insulin is important for storing glucose in the muscles as glycogen; it is not important for fuelling the muscles with fat. Many muscle fibres can function perfectly well using for fuel the fatty acids stored in intramuscular triglycerides. Reliance on intramuscular triglycerides for fuel is in some quarters regarded as a terrible thing leading to insulin resistance, but fasting and caloric restriction are popularly regarded as being "good things", and fasting results in insulin resistance and in a sluggish uptake of glucose when the latter is suddenly administered over three hours as part of a hyperinsulinaemic-euglycaemic clamp (much as happens when insulin-challenged subjects have been pre-adapted to diets high in palmitic acid or fructose). Does this mean that those who righteously advocate lifelong dietary restraint (on the basis of experiments in non-human species) are all going to develop the metabolic syndrome? Sadly not. Insulin resistance is only a hazard when there's a lot of glucose to be disposed of. When there isn't a lot of glucose to be disposed of, the muscle fibres involved in regular, everyday functions utilize fatty acids (from the diet or, in the case of fasting, from reserves of body fat) and pay no heed to insulin, thereby sparing glucose for the brain and their host from falling into a coma. Some muscle fibres are able to make very little use of fatty acids, but these are not normally used in regular, everyday functions.

Muscle fibres are sometimes divided simply into categories of "fast-twitch" (type II) and "slow-twitch" (type I) in accordance with their velocity, but the faster ones are often sub-divided into the moderately fast (type IIa) and the very fast (type IIb or IIx) and occasionally also into the faster-than-Usain-Bolt-headbanging-to-DragonForce (type IIb or IIx, the labels seeming to be applied inconsistently). A type IIc muscle fibre is also sometimes referred to. Logic would suggest that this be the name for a muscle fibre that is faster than the IIbs, but confusing the inquisitive is a more prioritized motive, and therefore IIc is the name for a type of muscle fibre intermediate between type I and type IIa.

All the muscles on the body have a mixture of different types of muscle fibres, and some muscle fibres are in a "transitory" state between two others, but the proportions differ between muscles and individuals. The slower a muscle fiber is, the weaker it is, the more stamina it has, the more able it is to rely on fat for fuel, and the less need it has of glycogen and insulin. The faster a muscle fibre is, the stronger it is, the less stamina it has, and the more anaerobic and glycolytic (dependent on the anaerobic use of glycogen and/or ATP/phosphocreatine for energy) it is. Fat can only be used aerobically (oxidatively, with oxygen) for fuel; glucose can be used aerobically or anaerobically (without oxygen). The type I fibres function aerobically; the type IIc and IIa fibres are all-purpose fibres that can function aerobically or anaerobically; the fastest ones are predominantly (but not completely exclusively) anaerobic.

The fastest muscle fibres (type IIb/IIx), functioning anaerobically, are best characterized by being compared to lions (so long as you can imagine lions that hunt dextrose monohydrate rather than wildebeest). They are lazy, greedy, horny bastards who spend most of their time sleeping, eating and having sex. They incur the impotent resentment of their fellow citizens by not producing any of the calories that they consume, and by not bothering to partake in the fortification of the settlement. Then, at the eleventh hour, when the enemy is advancing and their panic-stricken fellow citizens are performing stretching exercises in a futile effort to prepare themselves for combat, the lions rise from their slumber and punish the enemy for interrupting by obliterating them with a single, nonchalant swipe of their forearms.

Since the fastest muscle fibres have a greater capacity to grow bigger in response to training and are primarily dependent on anaerobic fuel sources, it is obvious that they are more adept at storing glycogen and that those possessing greater quantities of them are more insulin sensitive and can safely scoff more carbohydrate than the rest of the population. It is also obvious that those having a high proportion of slow type I fibres will be insulin resistant, carbohydrate intolerant and more prone to conditions such as diabetes and the metabolic syndrome.

Obvious, but wrong.

Surprisingly, type IIb muscle fibres, despite having a higher activity of glycogen-utilizing glycolytic enzymes (in "lean", "obese" and type-2 diabetic subjects alike), are typically less insulin sensitive due to factors including less vasodilation (and/or more vasoconstrictive sympathetic nervous system activity), larger cells coupled with fewer insulin receptors and a lower content of glucose-transporting GLUT4 and (in some but not all cases, as outlined below) fewer capillaries, and (possibly) the fatty acid composition of phospholipid membranes. Membranes with a higher quantity of unsaturated fatty acids are more fluid and more sensitive to insulin. The fact that the body takes care to desaturate palmitic and stearic acids into monounsaturated palmitoleic and oleic acids via the stearoyl-CoA desaturase (SCD) enzymes suggests that it doesn't wish for its membranes to be overly impermeable, but the fact that it downregulates SCD activity in response to a higher content of polyunsaturated fatty acids suggests that neither does it wish for its membranes to be overly permeable. Eating lots of PUFAs is the way in which membranes are made the most unsaturated and permeable; the way in which they are made the most saturated and least permeable is, counter-intuitively, by consuming a high-carbohydrate, low-fat diet and stimulating the process of "de novo lipogenesis", which slows down the palmitic-stearic-oleic production line and results in greater quantities of palmitic acid in bodily cells than if more had been consumed directly - but the relationship between palmitic acid and insulin resistance is a subject for another article.

As expected, type IIb muscle fibres also have a lower activity of oxidative (fat-and-lipid-utilizing) enzymes, and type-2 diabetics and "obese" subjects sport a relatively higher lipid content and a relatively lower oxidative enzyme activity in all muscle fibres. Type-2 diabetics exhibit a high ratio of intramyocellular lipid to oxidative enzymes (correlated with insulin resistance) in type I muscle fibres, a low glycogen content (correlated with hyperglycaemia) in type IIa muscle fibres, and a high ratio of glycogen to oxidative enzymes (correlated with insulin resistance) in type IIb muscle fibres. Many highly conditioned athletes also have a high quantity of intramyocellular lipid - a "paradox" that is offset by their training-induced high oxidative capacity - and moderate, progressive exercise enhances the oxidative capacity of old, "obese", insulin resistant men and women as well as increasing their intramyocellular lipid content. It also increases the proportion of slower type I muscle fibres, an alteration that often occurs, among the general population, alongside improved insulin sensitivity. Intense, supposedly "anaerobic" interval training (which actually places massive demands on both categories of energy system) increases the oxidative capacity of the faster muscle fibres, naturally enough, because "anaerobic endurance" is something of an oxymoron. 

Percentage of type I fibres and capillary density were positively correlated (and percentage of type IIb fibres was negatively correlated) with insulin sensitivity among a cohort of 70-year-old Swedish men. Similar associations are seen among the young. Low birth weight is thought to reflect an "adverse fetal milieu" and is linked with the later development of glucose intolerance, insulin resistance and diabetes; accordingly, male subjects with a low birth weight exhibited (at the age of 19, being compared to control subjects matched for age, fitness, body-fat and glucose tolerance) a higher percentage of type IIb/IIx fibres (correlated, albeit weakly, with sluggish insulin-stimulated glycolysis, low GLUT4 protein and lower fasting glucose levels) and a lower percentage of type IIa fibres (weakly correlated with efficient insulin-stimulated glycolysis and higher fasting glucose levels). They also exhibited more capillaries in type IIa and type I muscle fibres, but those fibres also tended to be enlarged, meaning that capillary density didn't differ. Interestingly (though probably coincidentally), the size (but not the numeric percentage) of type I fibres correlated with both VO2 max (the acid test of oxidative metabolic efficiency) and the percentage of fat borne in the abdominal region (the latter usually a strong indication of glucose intolerance and insulin resistance).

Auxiliary findings with regard to the link between high proportions of the fastest muscle fibres and glyco-insulinemic woes are by no means uniform. In the last example a greater quantity of capillaries (in the not-so-fast fibres) was cancelled out by their greater size; in this example, 13 (out of 29) 48-year-old Swedish men with impaired glucose tolerance who managed to develop diabetes over a 15-year period despite partaking in an intervention programme were seen to have more capillaries per muscle fibre in the type IIb fibres, a phenomenon that was theorized to be an insulin-stimulated compensation for the capillaries' poor diffusion capacity. Differences between these subjects and the ones above include their age, the fact that the greater number of capillaries per muscle fibre was observed in the fastest muscle fibres rather than the not-so-fast ones, and the fact that the muscle samples were extracted from the gastrocnemius (rear calf) muscles rather than (as in all the other examples before and after) the vastus lateralis component of the quadriceps (front thighs). Since capillary density appears to adapt in diverse ways to reduced glucose tolerance, it is no surprise that it did not differ between first-degree relatives of type-2 diabetics (who displayed a decreased VO2 max and a decreased rate of glucose disposal along with a higher proportion of type IIb muscle fibres) and control subjects. Capillary density was positively correlated with VO2 max and glucose disposal together, but not with glucose disposal alone.

Youngish women with Turner's syndrome (a condition pre-disposing to diabetes, although all the subjects were free of it and had no family history of it) presented larger (but not a higher percentage of) type IIa muscle fibres (type IIb/IIx fibres didn't differ from controls, and neither did capillary density). Women with Cushing's syndrome (a condition, not named after Brian Cushing, characterized by abdominal and visceral obesity) presented a high proportion of type IIb muscle fibres (32% versus 30% type I - a very rare profile, especially in women) that was theorized to be due to elevated levels of corticosteroids (e.g. cortisol). Despite their high proportions of anaerobically functioning muscle fibres, levels of glycogen synthase in those muscles were very low. In another example, post-menopausal women with impaired glucose tolerance or type-2 diabetes presented larger (but not a higher percentage of) type IIa and IIb/IIx muscle fibres, although the size of type IIa fibres correlated (among glucose-tolerant and -intolerant subjects combined) with insulin sensitivity (despite a greater diffusion distance among the glucose-intolerant subjects), and the capillary density of type I fibres correlated with glucose intolerance two hours after a challenge. It was suggested that capillary density is in fact a good indication of glucose intolerance, despite the reverse being linked with clamp insulin resistance. In real life, of course, an adaptation that quickens insulin's transport of glucose to the muscles will not continue to work once the muscles are overloaded with glycogen. Glycogen synthase and GLUT4 contents did not display any very interesting patterns.

It doesn't end there. A shift towards more type IIb muscle fibres in the lower limbs has been linked with the lower exercise tolerance of patients with chronic heart failure. A similar shift - thanks to the wholesale loss of type I fibres - has been seen among patients with complete cervical spinal cord lesions (although the remaining musculature appears to have been fighting a heroic rearguard action to maintain a glucose transport system)!

Insulin is thought to have a role in the expanded size of type II muscle fibres. No kidding. Forty days of insulin administration to old-aged patients with poorly controlled type-2 diabetes resulted in increases of the cross-sectional areas of the type IIa and IIb (but not IIc) muscle fibres by 32% and 38%, and in lowered blood glucose, HbA1c and triglyceride levels along with an increased body mass and arm circumference. Lucky bastards, eh? As would be expected, given insulin's role in glycolysis, there was a reduced level of an enzyme (3-hydroxyacyl-CoA dehydrogenase) related to fatty acid oxidation within the muscles.

The information above makes it pretty clear that, all things being equal, the type IIb muscle fibres (the most glycolytic) are the least sensitive to the hormone (insulin) responsible for delivering glucose for storage as glycogen. Also, the type I muscle fibres, which could get by perfectly well with minimal insulin, appear to be super-sensitive to it!

All things never are equal, however. Among strength, speed and power athletes, and those who employ similar training modes for recreation, it is reasonable to expect some adaptations that are favourable to insulin sensitivity. Vigorous stimulation of the muscles will increase blood flow and (presumably) upregulate the expression of insulin's little helpers (e.g. GLUT4), as well as increasing the quantity of glycolytic and/or oxidative enzymes (depending on the specific metabolic challenge) and maybe the quantity of insulin receptors within the muscles. Vigorous training can also result (given sufficient calories) in the hypertrophy of the muscle fibres, especially the type II ones, as seen (without the assistance of training) in the old-aged diabetics given exogenous insulin mentioned above. While this could increase the diffusion area, it will also increase the glycogen storage capacity and raise the threshold for insulin resistance in conjunction with a greatly increased turnover of glycogen in the relevant muscles. Remember: if regular subjects do partake in some sort of exercise, it is normally moderate, long-duration jogging, cycling, swimming etc. which places very few demands on the type IIb muscle fibres and which results in very little glycogen turnover in those fibres, so that a high proportion of type IIb fibres in those subjects will make them both less tolerant of moderate, long-duration forms of exercise and unreceptive to insulin in a significant portion of (barely used) musculature. Type IIb fibres may be less insulin sensitive generally, but all muscle fibres ought to be more than adequately insulin sensitive when blood is flowing from a training stimulus and when glycogen is low (as it will be periodically in a muscle receiving regular training stimuli). All of this is rational-sounding but mostly theoretical. What does actual research show?

Perhaps surprisingly, it is reported that capillaries do not proliferate in weightlifters and powerlifters (and do so only slightly in bodybuilders) and that heavy resistance training reduces oxidative enzymes and does not increase anaerobic enzymes despite enhancing glycogen storage capacity. Also reported is a striking similarity between the muscle fibre compositions and capillary densities of elite weight- and power-lifters and those of non-athletes, in contrast to the capillary-rich fibres of endurance athletes. Weightlifters are also reported to have a lower rate of glucose metabolism per unit of muscle mass than long-distance runners during an euglycemic clamp, but their muscle mass was much greater and their rate of glucose metabolism per unit of body weight was identical to that of the runners and an astronomical 4045% that of untrained control subjects! This supports what I wrote in the paragraph above: type IIb muscle fibres may be the least insulin sensitive, all things being equal, but well-trained type IIb muscle fibres will still be more than adequately "insulin sensitive" - even if their apparent sensitivity is actually a reflection of the activity of insulin's little helpers.

Resistance training certainly can increase the expression of GLUT4, which decreases during de-training or immobilization and increases during training or rehabilitation. Moderate resistance training - 4-6 sets of 12 unilateral knee extensions, three times per week for 10 weeks, at an intensity of 60% of maximal isometric torque - returned GLUT4 levels in the vastus lateralis to normal in a control group whose levels had diminished while wearing a cast over the right leg for two weeks. GLUT4 levels were maintained during immobilization, and increased during rehabilitation, in a group given a total of 5-20g of creatine monohydrate per day (the controls received the same amount of maltodextrin). Three-day-per-week one-legged "strength" training (3 sets of 10 leg presses, leg extensions and leg curls using 50% of the subjects' estimated 1-rep-max for the first two weeks, followed by two weeks of 4 sets of 8-12 reps using 70-80% of 1RMs on the same exercises, followed by two weeks of the same with the loads adjusted upwards to induce failure within 8-12 reps) by type-2 diabetic and control subjects resulted, in both groups, in increased quantities of GLUT4, glycogen synthase and insulin receptors in skeletal muscle.

Both of the above studies used training parameters that don't really count as "strength training" (but which are still perfectly reasonable representations of resistance training in its broader sense). Elsewhere, it is reported (unfortunately only the abstract is available) that c. 5 hours per week of mixed "strength/power" and "aerobic" exercise produced decreases in fasting insulin, insulin resistance, glucose, hemoglobin A1c and "glycogen synthase kinase-3-alpha-beta" in middle-aged diabetics with faster muscle fibres (as judged by myosin heavy chain profiles), but only decreased fasting glucose and HbA1c in those with slower isoforms. "Glycogen synthase kinase-3-alpha-beta" inhibits the activity of glycogen synthase (I think).

Resistance training also improves apparent insulin sensitivity by increasing blood flow. Flow-mediated dilation did not increase, but post-occlusion blood flow did, among young males undergoing a five-day-per-week "body-part" regime using weight machines. "Progressive resistance training" increased a measure (vascular response) of endothelial function in type-2 diabetics. In non-diabetic patients who had previous suffered a myocardial infarction (heart attack), resistance training or "aerobic" exercise (all exercise involves at least a little bit of aerobic metabolism, and some modes of resistance training involve a massive amount), or both combined, improved flow-mediated dilation to identical degrees. "Dynamic strength training" (actually 12 weeks of one-hour, 3-days-per-week circuit-style weight-machine training performing 1-2 sets of 12-15 reps of various exercises using 60-70% of the 1RM) can enhance a measure of insulin sensitivity in "obese" males (ages 28-63) through restoring the balance (normally shifted in favour of the latter in "obese" subjects) between the beta-adrenergic receptors (which promote subcutaneous abdominal adipose tissue lipolysis) and the alpha-2A-adrenergic receptors (which inhibit it).

"Heavy resistance training" was reported earlier to reduce muscle oxidative capacity and not to increase muscle glycolytic capacity. By contrast, short-burst interval training (e.g. 4-10 30-second sprints on a cycle ergometer, separated by rest intervals of as long as 2.5-4 minutes) can increase (in a remarkably time-efficient way) both oxidative and glycolytic enzyme activities. This mode of training, often referred to as "anaerobic", ironically makes muscles more adept at functioning aerobically as well! Similar multi-purpose metabolic challenges are encountered in many sports and in strongman medley events.

It is clear, therefore, that the pursuance of training modes involving vigorous stimulation of the type IIb/IIx muscle fibres is not a health hazard, despite potentially resulting in a muscular phenotype that strongly (but mostly superficially) resembles that seen in several conditions characterized by insulin resistance and glucose intolerance. Some of these conditions seem like states of anabolism that have gone awry due to the lack of an appropriate training stimulus. The fastest muscle fibres are less insulin sensitive, but heavy resistance training increases their glycogen turnover and can increase their glycogen storage capacity, which, by itself, ought (all else being equal) to roughly compensate for the reduced insulin sensitivity - as in the case of weightlifters exhibiting rates of glucose metabolism per unit of bodyweight equal to that of long-distance runners. On top of that, modes of moderately heavy resistance training have increased blood flow, the expression of GLUT4, the activity of glycolytic enzymes and the quantity of insulin receptors, and modes of short-burst interval training have simultaneously enhanced both aerobic and anaerobic metabolic efficiency in record-breaking time! These factors should super-compensate for any lack of insulin sensitivity in the type IIb/IIx muscle fibres, although it may be that the adaptations stemming from the oxymoronic "anaerobic endurance" challenge imposed on the fastest fibres during this type of training make them more insulin sensitive by ultimately converting them into more multi-purpose type IIa fibres: for example, sprinters including interval training along with strength training in their regime have exhibited a post-training predominance of type IIa fibres resulting from the conversion of intermediate fibres into the IIa form from both directions. Depending on the specific mode, training that stimulates the type IIb/IIx muscle fibres will either provide some compensation for their lack of insulin sensitivity or turn them towards a more insulin sensitive form.

Written: January 2010