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Pathophysiology of Insulin Resistance and Noninsulin Dependent Diabetes Submitted by Anonymous on

One of modern society’s most prevalent health problems is type 2 diabetes, or non-insulin dependent diabetes mellitus, NIDDM. It is estimated that approximately 15 million individuals in the U.S. have NIDDM, 85% of whom are obese. Unlike type I diabetes, or insulin dependent diabetes, which generally manifests itself early in life, type 2 diabetes normally afflicts people later in life, with an age of onset generally later than 30 years. Also unlike with type 1 diabetes, most NIDDM patients retain at least some capacity to secrete insulin until the disease reaches a late stage. Instead, what characterizes the disease is an impaired insulin secretory response to glucose and decreased insulin effectiveness, or insulin resistance. Clinically, insulin resistance is most simply described as a failure of insulin to stimulate normal glucose uptake into its target tissues of muscle and fat. The disease is complex however, and the majority of NIDDM patients initially suffer from hypersecretion of insulin. This is the body’s way of compensating for the defective insulin signaling in skeletal muscle that limits glucose uptake. Current thinking is that over a period of many years eventually the hypersecretion of insulin coupled with hyperglycemia from insulin resistance leads to the exhaustion of the pancreatic islet cells which are responsible for insulin secretion, and the eventual failure of the insulin secretory process.

Athletes and bodybuilders have developed a keen interest in insulin resistance, particularly in ways to make muscle more sensitive to the effects of insulin. There are primarily two reasons for this developing interest, other than the obvious concern about reducing the likelihood of developing NIDDM. One belief is that by increasing the muscle’s ability to take up glucose more readily, glycogen stores can be repleted more quickly. The other area of concern is weight management, or more specifically bodyfat reduction. Insulin is a fat storage-promoting hormone. If drugs or supplements can be used that facilitate glucose uptake into skeletal muscle, the reasoning goes, the body will be required to secrete less insulin, and this will reduce fat deposition.


The cause and effect relationship between obesity and NIDDM is debated, but there are a number of observations that shed light on how obesity could lead to NIDDM. One is that the connection between obesity and NIDDM is stronger in people exhibiting abdominal subcutaneous and visceral obesity versus peripheral obesity (1). Visceral obesity refers to fat accumulation in the intraperitoneal region around the organs, whereas peripheral obesity refers to fat accumulation in places where most people find it the least attractive: in the hips, love handles, etc. Ironically, the fat we can’t see that is stored intrapreritoneally, as well as abdominal subcutaneous fat (the combination is often termed central fat), may be the least healthful.

Central obesity can promote hyperinsulinemia, hyperglycemia, and insulin resistance in a number of ways. For one thing, central adipocytes are larger than peripheral adipocytes, and they have higher levels of enzymes that can break down fats and allow them to enter the bloodstream as free fatty acids (FFA). The portal circulation also connects central adipose tissue to the liver, so the released free fatty acids can act on the liver in several ways. Normally insulin limits production of glucose by the liver, the process known as gluconeogenesis. Free fatty acids block this inhibitory effect of insulin, so the liver puts out inappropriately high levels of glucose, contributing to hyperglycemia. The elevated FFA also slow the metabolic breakdown of insulin by the liver, contributing to hyperinsulinemia (2).

Besides their action on the liver, free fatty acids are also thought to inhibit insulin signaling in muscle tissue (3). This contributes greatly to hyperglycemia, with the pancreas putting out more insulin in an attempt to compensate. Adipocytes also secrete insulin like growth factor (IGF-1). Lest this sounds like a good thing, the IGF-1 acts in a negative feedback way on growth hormone (GH) secretion (4). GH has lipolytic action, stimulating the enzyme hormone sensitive lipase, which mobilizes fat so it can be used as fuel. GH also lowers activity of lipoprotein lipase, the enzyme responsible for the storage of free fatty acids in fat cells. Additionally, GH elevates metabolic rate, perhaps in part by elevating levels of thyroid hormone (T3). To compound matters, hyperinsulinemia has been shown to reduce GH secretion in response to growth hormone releasing hormone (GHRH) in both normal and obese humans (5).

Circulating free fatty acids, elevated in obesity, are also thought to be responsible for the suppression of GH seen in obesity. It is generally accepted that circulating FFA rapidly partition into the plasma membranes of pituitary somatotrophs, the cells which secrete GH. This is believed to alter the function of proteins embedded in the plasma membrane, perturbing intracellular signaling and inhibiting GH release (6).

Another chemical, specifically a cytokine, called tumor necrosis factor alpha, or TNF alpha, also correlates strongly with insulin resistance and may be an early marker for the onset of type 2 diabetes (7). TNF alpha is secreted in relatively large amounts by the adipocytes of obese persons. TNF alpha has been shown to interfere with insulin signaling in muscle and adipose tissue, and may in this way contribute to insulin resistance (8)

Leptin, which acts as a satiety or hunger-suppressing hormone, is released from fat cells and is thought to serve as a signal to reduce food intake. Leptin is expressed more in subcutaneous fat than in visceral fat, so in visceral obesity less leptin may be available to suppress eating, leading to further obesity. Moreover, the hyperinsulinemia of NIDDM is also believed to lead to leptin resistance, abrogating the normal action of leptin to suppress appetite (9).

Besides the aforementioned leptin and TNF-alpha, adipocytes secrete a number of other compounds that may have a bearing on the development of diabetes. The observation that adipocytes are active secretaory organs is part of an emerging picture of fat cells in which they are much more than just passive storage sites for fat. The compounds they secrete have complex actions that work not only on fat cells themselves, but also on other tissues throughout the body.

Resistin, first described in 2001 (10), originally looked very promising as a compound potentially linking obesity with diabetes. Animal studies showed resistin levels are decreased by the anti-diabetic drug rosiglitazone, and increased in diet-induced and genetic forms of obesity. Administration of anti-resistin antibody improves blood sugar and insulin action in mice with diet-induced obesity. Further, treatment of normal mice with recombinant resistin impairs glucose tolerance and insulin action. Insulin-stimulated glucose uptake by adipocytes is enhanced by neutralization of resistin and is reduced by resistin treatment.

Unfortunately, in humans, the relationship between resistin, obesity, and insulin resistance is much less clear. Some research has shown that in human adipose tissue resistin seems to be present at much lower levels than in rodents, and has a considerably different amino acid sequence. There also seems to be a much weaker correlation between resistin levels and obesity.

Adiponectin is another putative candidate linking obesity with diabetes. Like resistin, adiponectin is secreted from adipocytes. Plasma adiponectin concentration is reduced in obese animals and humans and in patients with type 2 diabetes mellitus. Adiponectin appears to stimulate fatty acid oxidation, decreases plasma triglycerides, and improves glucose metabolism by increasing insulin sensitivity. Like resistin, adiponectin levels respond to treatment with antidiabetic drugs. In humans treatment with the drug troglitazone increased serum adiponectin levels by 300% (11).

During prolonged exercise, interleukin-6 (IL-6) is released from skeletal muscle. Current thinking is that IL-6 is a glucose-sensing agent that registers declining levels of muscle glycogen, promotes glucose production by the liver, and improves glucose uptake in skeletal muscle. IL-6 levels increase dramatically when exercise is performed in a glycogen-depleted state. Basal serum IL-6 is higher in type II diabetics. Muscle-derived IL-6 may also work to inhibit the effects of pro-inflammatory cytokines such as TNF, thereby protecting against insulin resistance (12). Confusing matters somewhat is the observation that IL-6 downregulates adiponectin (13), seemingly at odds with IL-6’s role as a glucose sensitizing agent. However, one way in which adiponectin regulates blood glucose levels is by inhibiting hepatic glucose production. This is consistent with low levels of adiponectin in NIDDM, which is characterized by hyperglycemia. Since one putative role of IL-6 is to increase glucose availability, it is possible that the downregulation of adiponectin by IL-6 is a mechanism to increase glucose availability to skeletal muscle by increasing hepatic glucose production.

So, in summary, Type 2 diabetes is characterized by reduced sensitivity of muscle tissue to insulin, leading to hyperglycemia, as well as reduced insulin secretion and eventual failure of insulin secretion altogether. Obesity is thought to be a central player in the development of diabetes, leading to derangement in glucose and insulin metabolism via a number of proposed mechanisms.


Perhaps the most intriguing theory about how NIDDM originated, and why it has become prevalent in modern society, was one originally formulated by James Neel in 1962 (14).

Neel suggested “that the diabetic genotype is, to employ a somewhat colloquial but expressive term, a “thrifty” genotype, in the sense of being exceptionally efficient in the intake and utilization of food”. Neel regarded early humans as generally having lived under conditions of feast or famine. When faced with feasting, individuals who possessed a “quick insulin trigger” to use Neel’s term released large amounts of insulin to facilitate more efficient storage of food and minimize urinary glucose loss. We now live in a period where food is relatively abundant (at least in developed countries), people are generally sedentary, and the diet contains large quantities of fat and high glycemic index carbohydrates. Postprandial hyperinsulinemia, once a genetic benefit, now leads to insulin resistance, beta cell failure, and eventual NIDDM. One thing to note here is that according to Neel’s theory, muscle insulin resistance is acquired as a result of chronic hyperinsulinemia.

Hypersinsulinemia is believed to interfere with cellular glucose uptake either by a direct effect on the insulin receptor or a disruption of the intracellular insulin-signaling pathway (15).

Cahill (16) and Reaven (17) have looked at the evolution of NIDDM differently. They regard insulin resistance as the fundamental genetic adaptation, rather than an acquired characteristic. Their logic holds that preservation of skeletal muscle mass was the priority for early man. Muscle insulin resistance conserves glucose for use by the central nervous system, decreasing the amount of muscle protein that must be converted into glucose during periods of food deprivation. Hyperinsulinemia may be the direct mechanism for this. Studies have shown that physiologic hyperinsulinemia promotes skeletal muscle anabolism either by stimulating protein synthesis or inhibiting protein breakdown, and stimulating amino acid uptake by muscle (18). Skeletal muscle proteolysis appears to be reduced in NIDDM, consistent with the hypothesis that insulin resistance was selected in order to preserve muscle mass (41). At the same time, resistance to glucose uptake does not extend to amino acid uptake in NIDDM, so contrary to what might be expected, there is no impairment of amino acid transport in cells (42). This is not entirely surprising since glucose and amino acids use different families of transporters to enter cells.

As farming developed and food became relatively more abundant, the development of diabetes was probably held in check by the fact that people remained active, and early crops produced food of a relatively low glycemic index. It was not until the modern era, the abundance of highly processed carbohydrates, and the onset of obesity that the symptoms of insulin resistance and NIDDM began to manifest themselves through the mechanisms described above.

Miller and Colagiuri (19) offer a third explanation for the current high incidence of NIDDM. According to their “carnivore connection” hypothesis, our primate ancestors subsisted on a diet that was rich in carbohydrates, and as a consequence our brains and reproductive systems evolved a requirement for glucose as a source of fuel. The climate changes that accompanied the ice ages beginning about two million years ago forced a relatively high protein diet (from animal meat) on early humans. As we have discussed, hyperglycemia is a hallmark of insulin resistance; insulin resistance would help maintain high blood glucose levels in the face of a shortage of carbohydrates. To quote the authors:

We propose that the low-carbohydrate carnivorous diet would have disadvantaged reproduction in insulin-sensitive individuals and positively selected for individuals with insulin resistance. Natural selection would therefore result in a high proportion of people with genetically determined insulin resistance (19).

An attractive aspect of this theory is that it explains why societies that have switched from a hunter-gatherer lifestyle to an agricultural one relatively recently have higher incidences of type 2 diabetes than do societies with a long history of agriculture, such as northern Europeans. The latter have had longer to readapt genetically to a diet once again high in carbohydrates.

Not surprisingly, there is much evidence both to support and refute each of these three theories. Neel’s ideas have been criticized on the basis of archeological evidence suggesting that famine was actually less common in prehistoric times than it was after the development of agriculture. Cahill and Reaven have been questioned because their theory depends on the unproven assumption that type 2 diabetics retain sensitivity to the antiproteolytic effects of insulin, while at the same time losing sensitivity to the glucose disposing effects of insulin. Miller and Colagiuri have been criticized based on the observation that primates are omnivores more than strict vegetarians, and the diets of our primate ancestors may not have been as carbohydrate rich as the authors assume.


In contrast to the above “thrifty genotype” theories, Hales & Barker have proposed that the fetal environment plays a vital role in determining the likelihood of developing NIDDM. Their so-called “thrifty phenotype” theory posits the following chain of events leading up to diabetes in adulthood: (1) the growth of the fetus (and possibly infant) is altered by its nutritional environment (which may include maternal diet-dependent changes in maternal hormones); (2) The fetus adapts to this environment by being nutritionally ‘thrifty’, resulting in decreased fetal growth, islet function and ?-cell mass (low glucose levels require low insulin levels), and other hormonal and metabolic adaptations. In essence, the developing fetus sacrifices organ development, in particular pancreatic development, to ensure adequate energy supplies for the brain to develop (3)—an individual so constituted suffers adverse consequences in adult life if he/she experiences good or supranormal nutrition; (4) both poor insulin secretion and insulin resistance can result from these adaptive processes; (5) the adverse consequences include loss of glucose tolerance and hypertension.

Needless to say, the proponents of the various “thrifty genotype” theories and the “thrifty phenotype” theory have amassed evidence to support their theories and refute those of their rivals. For example, thrifty phenotype proponents argue that since NIDDM generally develops in the post reproductive years, it would not be controlled by natural selection so could not be genetic in origin. The thrifty phenotype theory also can explain why the most westernized societies where obesity is rampant and diet is conducive to the development of NIDDM have rates of the disease far lower than in countries with developing economies: natives of the former countries are much less likely than the latter to suffer from fetal malnourishment. On the other hand this argument can be turned around by genetic theory advocates who note that obesity is increasing along with NIDDM in the West while there is nothing to suggest fetal nutrition is deteriorating.

One attractive feature of the thrifty phenotype theory is that it can be tested in animals. When pregnant rats are fed an isocaloric, protein poor diet their offspring have low birth weight, reduced islet cell mass and vascularization, and an impaired insulin response to glucose. These first generation rats in turn go on to have diabetic pregnancies, and their offspring, exposed to hyperglycemia in utero go on to develop diabetes as adults. The reduced islet cell mass and consequent diminished response of insulin secretion to glucose posited by this theory is also in accord with research showing that reduced insulin secretion is quantitatively more important than insulin resistance in muscle and fat in the development of reduced tolerance to glucose (40).



Consistent with the hypotheses of Neel and others, the body has developed nutrient sensing pathways that may alter metabolism to regulate the storage of energy substrates when nutrient levels are high. One such recently characterized pathway is the hexosamine biosynthetic pathway (HBP). Glucose entering the HBP is ultimately converted to UDP-N-acetylglucosamine, which is believed to play a role in modifying the activity of a number of transcription factors involved in the expression of genes whose transcribed proteins affect energy substrate utilization. HPB activation acts seemingly in a paradoxical way both to induce satiety via leptin secretion and promote fat burning in brown adipose tissue in animals, while at the same time slowing the body’s overall metabolic rate. In animal studies this latter effect seems to win out, with a net slowing of the body’s resting metabolic rate (20). The slowing of metabolic rate by HPB activation is accomplished by inhibiting the expression of mitochondrial proteins involved in oxidative phosphorylation and substrate oxidation in skeletal muscle. In other words, energy utilization is slowed in skeletal muscle, allowing excess nutrients to be stored.

Other than possibly contributing to obesity and thereby indirectly promoting insulin resistance, there are other mechanisms where increased glucose flux through the HBP may directly lead to insulin resistance. One fate for dietary glucose is storage as glycogen. The key enzyme responsible for glycogen formation is glycogen synthase. In a normal (non-diabetic) individual, a carbohydrate meal normally results in an increase in insulin secretion. Insulin in turn activates glycogen synthase, promoting storage of a part of the ingested carbohydrates as glycogen. In type 2 diabetes glycogen synthase is resistant to stimulation by insulin. One proposed mechanism for this is increased glucose flux through the HBP. An end product of the HBP, N-acetylglucosamine, has been shown capable of binding to glycogen synthase and significantly reducing its ability to catalyze the conversion of glucose to glycogen (21). So again, we see an adaptation where nutrient intake activates mechanisms for the efficient storage of excess calories as fat. The calories that are not stored as glycogen or used immediately for fuel are shunted into fat storage.

One interesting approach to gain further insight into HBP modulation of substrate storage is to engineer strains of mice that overexpress the rate-limiting enzyme for hexosamine synthesis, glutamine: fructose-6-phosphate amidotransferase (GFA) in tissues including skeletal muscle, liver, fat, and pancreatic beta cells (which recall are responsible for insulin secretion) (22). In these animals, the overactivation of the HPB leads to muscle insulin resistance, excess insulin secretion by the pancreas and excess synthesis of fatty acids by the liver. All these can be considered mechanisms to promote the storage of excess calories, consistent with the thrifty phenotype of Neel, and/or the preservation of muscle mass via hyperinsulinemia ala Cahill and Reaven.

The abovementioned skeletal muscle insulin resistance in transgenic animals overexpressing GFA was shown to result from an inhibition of GLUT4 translocation from intracellular vesicles to the plasma membrane (23). Normally, insulin acts via binding to its receptor to promote migration of the glucose transporter GLUT4 to the cell surface, where it picks up glucose and shuttles it into the cell. This process is inhibited in the presence of an oveactive hexosamine biosynthetic pathway.

We also mentioned above that overactivation of the HBP in transgenic animals leads directly to hyperinsulinemia with subsequent development of peripheral insulin resistance (24). As previously mentioned, hyperinsulinemia is a consistent hallmark of early type 2 diabetes. Arguing from the viewpoint of the “thrifty genotype”, hyperinsulinemia may simply be the body’s way of compensating for insulin resistance, the fundamental phenotype of the Cahill/Reaven model, where insulin resistance was selected in order to preserve muscle mass during times of low food availability. On the other hand there are data, such as presented in (22) showing that hyperinsulinemia can lead directly to insulin resistance. This model is consistent with Neel’s original idea.

In any case, although hyperinsulinemia is characteristic of the early stages if NIDDM, eventually the beta cells fail. This is thought to be a result of the chronic hyperglycemia associated with the disease. After chronic exposure to hyperglycemia, insulin gene transcription and glucose-stimulated insulin secretion are suppressed. Although the exact mechanism is unknown, hyperglycemia has been shown to induce the production of reactive oxygen species at concentrations high enough to be toxic to beta cells (24). Keeping with our theme of the role of the HBP in the development of diabetes, this pathway has been shown to induce beta cell deterioration via the generation of reactive oxygen species (24).

We discussed above how obesity, particularly visceral obesity, contributes to NIDDM through the action of elevated levels of circulating free fatty acids (FFA). High FFA have been implicated in stimulating the HBP (26). Free fatty acids and glucose exert a mutually inhibitory action on the use of one versus the other for fuel. When FFA are readily available as energy substrates, their metabolism leads to high levels of acetyl-CoA within the cellular mitochondria. This acts as a signal to slow the use of glucose as fuel. Specifically, the high concentrations of acetyl-coA inhibit the activity of the enzyme pyruvate dehydrogenase, a rate-limiting enzyme for the complete oxidation of glucose. Additionally, the elevated acetyl-CoA leads to high levels of citrate in the mitochondria. Citrate in turn deactivates another enzyme involved in glycolysis (the use of glucose for fuel), phosphofructokinase. The end result is that dietary glucose is shunted away from use as fuel when FFA levels are high. This expands the pool of glucose available for entry into the HBP, with all the associated deleterious consequences discussed above.


Adenosine 5′-monophosphate-activated protein kinase (AMPK) has been characterized as one of the body’s master metabolic switches. The primary function of AMPK is thought to be as a sensor of ATP status, shutting off ATP consuming processes like lipogenesis and switching on ATP producing processes (like fatty acid oxidation) when ATP levels are low. A kinase is an agent that phosphorylates specific target proteins. AMP kinase is activated by high AMP and low ATP and acts as an energy sensor, regulating such diverse processes as lipolysis and lipogenesis, skeletal muscle fatty acid oxidation, cholesterol synthesis, glucose uptake by adipocytes and muscle tissue, and regulating preproinsulin (insulin precursor) gene expression and insulin secretion in pancreatic islet beta-cells. High concentrations of ATP antagonize the effects of AMP, so it is probably best to say that AMPK responds to the ratio AMP/ATP rather than to absolute values of either.

Since derangements in many of these processes are present in NIDDM, it has been suggested that defects in AMPK signaling could contribute to the disease. If so, AMPK could be a potential target for antidiabetic drugs. For example, in the liver, AMPK activation causes an increase in fatty acid oxidation and inhibition of glucose production. Unrestrained hepatic glucose production is a hallmark of NIDDM. A defect in AMPK signaling in the liver could be responsible at least in part for this. Perhaps even if AMPK signaling were normal in type 2 diabetes, it might be possible to stimulate the signaling pathway to improve symptoms nevertheless.

One agent in particular, AICAR (5-amino-imidazole carboxamide riboside) has been studied extensively for its ability to activate AMPK. It has shown the ability to increase glucose transport in vivo in animals, as well as in vitro in muscle tissue from both normal and diabetic human subjects. In one study exposure of type 2 diabetic skeletal muscle to a combination of insulin and AICAR increased glucose transport and cell-surface GLUT4 content to levels achieved in control subjects.

It has also been observed that AMPK is important in non-insulin mediated glucose uptake by skeletal muscle during contraction. Many of the current treatments for NIDDM focus on improving insulin mediated glucose uptake. But as mentioned, beta cell failure is the end result of NIDDM. If the AMPK regulated non-insulin mediated glucose uptake seen in exercising muscle could be duplicated in resting muscle with drugs, this could represent another potential therapeutic avenue that would not be thwarted by eventual beta cell failure. Here again AICAR or an analog may be promising.

AICAR is a potential drug for the future, but metformin is an antidiabetic drug that is already widely prescribed to treat type 2 diabetes. Its primary mode of action is to reduce hepatic glucose production, thereby improving hyperglycemia, but it is also thought to enhance glucose transport into skeletal muscle as well. Some recent research has shown that metformin may work to improve glucose uptake and glycogen storage in human skeletal muscle by activating AMPK. The increase in AMPK activity was likely due to a change in muscle energy status because ATP and phosphocreatine concentrations were lower after metformin treatment, and we have seen that the trigger to activate AMPK is low ATP status.


PPARg is a member of a family of ligand activated transcription factors. It is found in both white and brown adipose tissue and is involved in the transcriptional activation of an array of adipose tissue specific genes. But perhaps its most important roles are to promote the development of adipose tissue and to inhibit leptin gene expression. In this sense it may be a “thrifty gene”: during times of food shortage, PPARg would tend to promote fat storage; during times of plenty, or in modern times associated with high fat diets, it seems to promote obesity. As we have seen above, obesity may be the most important risk factor for developing NIDDM. So in this way, PPARg may be important to the development of diabetes.

Perhaps no research better illustrates the potential connection between PPARg and the development of insulin resistance than that carried out by Kubota et al (27). These researchers developed heterozygous mice lacking one PPARg gene, but expressing another. (Wild type mice carry two copies of the gene, one inherited from each parent.) The heterozygous mice are designated PPAR+/-; wild type are PPAR+/+. The PPAR+/- strain exhibited reduced adiposity and reduced adipocyte size when placed on a high fat diet, as well as an increase in leptin. They also showed reduced food intake and increased energy expenditure, likely as a result of increased leptin levels. These mice were protected from the development of insulin resistance as well. In contrast, wild type mice with the normal complement of PPARg exhibited adipocyte hypertrophy and obesity on a high fat diet. The increased adiposity would tend to increase systemic levels of TNF-alpha, FFA, and the other adipokines described above, potentially leading to insulin resistance and diabetes.

It is thought that during development and childhood PPARg is responsible primarily for the differentiation of preadipocytes into relatively small adult adipocytes that do not secrete large amounts of the insulin resistance promoting adipokines we discussed above. Later in adulthood, PPARg activation in conjuction with a high fat diet appears to promote adipocyte hypertrophy, obesity, and insulin resistance. This would help explain the apparent paradoxical action of the class of antidiabetic drugs known as the thiazolidinediones, which act to improve insulin sensitivity by acting as PPAR gamma agonists and actually increase the number of fat cells in the body. A large number of relatively small fat cells seem to improve insulin sensitivity, while hypertrophied fat cells have the opposite effect. Interestingly, PPARg antagonists such as the experimental agent SR-202, which have the opposite effect as the thiazolidinediones in that they inhibit adipocyte differentiation, reduce the ability of mice to accumulate fat. This leads to drop in plasma levels of TNFalpha, which as we discussed above is believed to be a key cytokine in promoting insulin resistance (28).


Do any of the agents used as ergogenic aids by athletes and bodybuilders cause insulin resistance? Over the years there have been a number of studies done on how androgens affect glucose sensitivity, some of them conflicting. Virtually all studies show that low testosterone causes insulin resistance. One of the most recent studies done in humans showed that supraphysiological testosterone had no effect on insulin sensitivity but nandrolone actually improved it (29). The doses were 300 mg/week.

In another recent study 600 mg of testosterone enanthate per week had no effect on glucose sensitivity in normal adult men (30). This is the highest dose that I’ve seen used in any studies. However, when 500 mg of testosterone was administered to obese men, glucose tolerance decreased, while 250 mg increased glucose tolerance (31). Obesity could be having an effect here, as the previously mentioned negative studies were done in non-obese individuals.

Hyperandrogenism is often associated with insulin resistance in women. Whether this is merely an association or an actual causal relationship is debated. In agreement with the latter hypothesis, when normal women were administered methyltestosterone, insulin sensitivity deteriorated (32). This could have widespread implications for women’s health as androgen administration becomes more common in the treatment of menopausal symptoms and sexual dysfunction

In other studies in animals, there appears to be a “window” of testosterone levels around the normal range that optimize insulin sensitivity (33).

So you can see why there is some confusion. We don’t know what happens when androgen doses exceed 600 mg/week (It is hardly uncommon for bodybuilders to use doses of anabolic steroids far in excess of 600 mg/wk.), and studies in animals have given results in conflict with those done in men, but in agreement with studies performed in women. And the particular compound used seems to make a difference.

One anabolic agent that unquestionably is capable of causing (temporary) insulin resistance is recombinant human growth hormone, hGH. This side effect of hGH is discussed in detail in the M & M # 14 article on GH use to treat obesity, so I will refer interested readers to that piece for more information.

Hyperthyroidism is associated with elevated plasma glucose, and when rats are given high doses of thyroid hormone both fasting glucose and plasma glucose in response to a glucose load are elevated (34). This hyperglycemia does not appear to be the result of any thyroid hormone induced defect in insulin signaling, but rather decreased insulin secretion in response to glucose. The deceased insulin secretion is most likely a result of thyroid hormone induced apoptosis (programmed cell death) of pancreatic beta cells (35). A second factor contributing to the hyperglycemia seen in hyperthyroidism is increased gluconeogenesis (36). So technically, the elevated plasma glucose seen when supraphysiological doses of T3 or T4 are administered is not due to insulin resistance, but rather to lowered insulin production and increased glucose production from glucogenic substrates.

Caffeine, another common ergogenic aid, decreases insulin sensitivity in healthy subjects. This is most likely due to increased plasma epinephrine and FFA levels associated with caffeine ingestion (37).

Athletes, and in particular bodybuilders, consume a high proportion of protein in their diets. It turns out a protein enriched diet may impair glucose metabolism. Elevated plasma amino acid levels impair glucose uptake, most likely by direct inhibition of muscle glucose transport and/or phosphorylation with a resulting reduction in rates of glycogen synthesis (38).

Finally, in what may be the greatest irony of all for an athlete, eccentric resistance exercise induces a transient whole body insulin resistance. This may result from elevated levels of TNFalpha associated with the muscle damage arising from strenuous eccentric exercise (39). Recall that TNFalpha interferes directly with insulin signaling, in particular with impaired insulin-stimulated IRS-1-associated PI 3-kinase activity. It should be noted however that over the long term both aerobic and resistance exercise training improve glucose sensitivity.


We have attempted to address what are thought to be the major pathophysiological features of insulin resistance and type 2 diabetes, as well as possible theories about the genetic origin of the disease, and the potential role of the body’s energy sensing mechanisms in the development of diabetes. The treatment has been far from exhaustive; only the better-characterized aspects of the pathophysiology of the disease have been presented. We have emphasized understanding the development of the disease within the context of the different models of NIDDM, which stress the importance of the inheritance of thrifty genes, such as PPARg, which tend to promote fuel storage and lead to insulin resistance under conditions of a modern lifestyle, but were beneficial to our ancestors.


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