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Fullness of Fat Storage Capacity: An Alternative to Adipocyte Insulin Resistance


John M. Poothullil, MD, FRCP

Brazosport Memorial Hospital

201 Oak Drive South, #106

Lake Jackson, TX 77566


Key Words: adipocyte insulin resistance, insulin resistance, obesity, type 2 diabetes, fat stores





Obesity and type 2 diabetes are considered to be insulin-resistant states. Insulin resistance is diagnosed when glucose transport is reduced and hepatic glucose production is increased in the presence of normal or elevated plasma insulin levels. Exposure of muscle and the liver to elevated levels of free fatty acid combined with signals from adipocytes could explain the appearance of general insulin resistance. It is proposed that adipocytes stuffing could be responsible for the appearance of adipocyte insulin resistance and increased plasma free fatty acids.



Insulin promotes differentiation of preadipocytes to adipocytes, stimulation of glucose transport in adipocytes, and synthesis and retention of triglyceride in mature adipocytes. The presence of normal or elevated plasma free fatty acid (FFA) in the presence of fasting hyperinsulinemia is taken as clear evidence of insulin resistance of adipose tissue in obesity and type 2 diabetes.1-5

Fatty acids found commonly in the western diet stimulate glucose transport by a mechanism that involves translocation and activation of the same glucose transporters as those used by insulin.6 Enhanced glucose transport due to the specific effect of fatty acids would increase triglyceride formation in adipocytes.7 Adipocytes in culture exposed to fatty acids within the range of the normal physiologic fasting serum fatty acid concentration displayed increased glucose transport after short-term treatment, and reduced glucose transporters and impaired insulin stimulated transporter activity after prolonged exposure.8,9 This observation is taken as evidence for the existence of a defect in insulin- resistant adipocytes.

Dysfunction of intracellular pathways after insulin signaling is suggested to be responsible for adipocyte insulin resistance.8-11 However, the molecular mechanism responsible for insulin resistance in adipocytes of obese individuals is not understood. In addition, we need information regarding the mechanism for the release of FFA from adipose tissue of lean individuals, considering that the severity of insulin resistance is the same in lean and obese subjects with type 2 diabetes.12,13

This manuscript suggests that the degree of fullness of fat storage capacity could explain the presence of resistance of adipocytes to insulin and is responsible for the inappropriate release of FFA from adipose tissue seen in insulin resistant states.



Adipocytes hypertrophy during the initial stages of the development of obesity.14,15 However, adipocytes do not have an unlimited capacity for expansion.14,15 Reaching a critical fat cell size is thought to be necessary to initiate events that result in increased fat cell number.16,17 Regional differences in the fat cell size distribution profile suggest that locally produced growth factors are involved in the regulation of adipocyte hyperplasia.18 Although there are differences between fat depots in different parts of the body, enlarged adipocytes, especially those in the 140- to 180-m diameter size range, secrete growth factors that induce preadipocyte proliferation.19 The association of large adipocytes with paracrine factors that induce the proliferation of preadipocytes suggests that adipocytes are sensitive to the degree of fullness, implying a potential limit to adipocyte storage capacity.

Adipogenesis occurs as a consequence of normal cell turnover and from the need for more storage space during weight gain.20 The need for new fat cells could occur throughout life. Preadipocytes from infants to adults can be induced to differentiate to adipocytes.21,22 However, aging is associated with a decline in cellular replicative capacity in the adipocyte precursor system.23 This suggests a potential limit to the expansion of fat storage capacity as one gets older.



Adipose sensitivity to insulin, as measured by its effect on the rate of glucose oxidation, was closely related to the adipose cell size.24 The larger the adipose cells, the less insulin sensitive they were. Adipose tissue of obese subjects, with enlarged cells showed a diminished response to insulin. After weight loss and reduction in adipose cell size, insulin sensitivity of the adipose tissue of obese individuals was restored to normal.24 These findings suggest that the size of the adipocyte is involved in the development of "insulin resistance." The correlation between the adipocyte cell size and reduced insulin responsiveness indicates that the amount of lipid within the cell may influence its metabolic efficiency. Restoration of insulin sensitivity of the adipose tissue of obese individuals after weight loss and reduction in adipose cell size24 is consistent with this possibility.



Dissolved glucose is always present in the extracellular fluid and is readily available to all cells. Except in very few select sites, such as renal proximal tubules, one or more members of the closely related GLUT family of glucose transporters mediate glucose transport. The pattern of expression of the GLUT transporters in different tissues is related to the role of glucose metabolism in different tissues. Aerobic exercise training is shown to be associated with an increase in GLUT transporters in the skeletal muscle of young healthy humans,25 previously sedentary middle aged men,26 individuals with impaired glucose tolerance,27 and individuals with type 2 diabetes.28 This suggests that utilization of glucose determines transport of glucose.

Insulin causes translocation of glucose transporters from intracellular storage sites to the plasma membrane.29,30 In insulin-resistant individuals, it is found that enlarging adipocytes with a normal capacity for glucose transporter synthesis have reduced number of recruitable glucose transporters.12,31 This and the diminished insulin-stimulated translocation of glucose transporters seen in adipocytes of obese individuals and of type 2 diabetics31,32 are consistent with the possibility of an adaptive mechanism based on reduced need for intracellular glucose. The observed impairment of a glucose transport mechanism after prolonged exposure of adipocytes in culture to fatty acids8,9 supports this possibility.

Adipose tissue plays a minor role compared with skeletal muscle in whole body glucose disposal. However, "stuffing" the adipocyte with triglyceride may interfere with its storage functions. Insulin stimulates the synthesis of intravascular lipase, which liberates fatty acids from triglyceride for uptake into fat cells. Inside the fat cell, fatty acids are incorporated into triglyceride by esterification with glycerolphosphate formed from glucose, which is transported into the cell under the influence of insulin. Inability of adipocytes to accommodate more triglyceride would allow entry of FFA released by intravascular lipase into the circulation. Thus, unlike Randle's theory of resistance of intracellular lipase to insulin,33 limited capacity to store triglyceride could explain the inappropriate release of FFA from adipose tissue seen in insulin-resistant states.



The primary basis for the diagnosis of general insulin resistance is the differences in an individual's response to insulin-mediated glucose uptake by peripheral (muscle) tissues. The association of obesity and type 2 diabetes is the major basis for the link between obesity and insulin resistance. Although all the mechanisms by which obesity causes systemic insulin resistance remain unknown, obesity is positively correlated with plasma FFA concentration.34 Increase in FFA concentration is shown to be associated with decreased insulin-stimulated glucose uptake.35,36 Accumulation of Acetyl CO-A and other intermediate products of FFA oxidation could interfere with glucose oxidation in muscle.33,37-40 In addition, increased plasma FFA could stimulate hepatic gluconeogenesis41 and increase insulin secretion.42 A high degree of correlation exists between concentrations of plasma glucose and that of FFA in individuals with type 2 diabetes.1 In short, elevated FFA levels are thought to be responsible for a significant portion of general insulin resistance seen in obesity and type 2 diabetes.43

The appearance of insulin resistance in peripheral tissues could be mediated by an adipocyte-secreted signaling molecule called resistin, the blockage of which improves blood sugar and insulin action.44 Resistin has been found to modulate insulin-stimulated glucose transport in cultured adipocytes. Blockage of resistin potentiates insulin-stimulated glucose uptake, and exposure of adipocytes to resistin reduces insulin-stimulated glucose uptake.44 Taken independently, these data suggest that resistin could be the signal that links obesity to general as well as adipocyte insulin resistance. However, taken together, it stands to reason that if adipocytes secrete a signaling molecule to induce increased peripheral usage of FFA, there could be a corresponding signal to reduce storage of the same fuel. This is consistent with the role of adipocytes as a source of a variety of polypeptides that may affect the action of insulin in other tissues. For example, leptin, secreted by adipocytes, is involved with the regulation of adipose tissue mass.45

Central adiposity could be an important factor in the genesis of insulin resistance. Exposure of the liver to elevated FFA levels coming from intra-abdominal fat stores could cause reduced clearance of insulin, resulting in hyperinsulinemia.46,47 Although some have not been able to verify this,48-50 the hypothesis presented is consistent with this possibility. It is possible that the primary defect in insulin-resistant states is the inability to match the rate of recruitment of preadipocytes, especially in the location of visceral fat depots, to the rate of conversion of energy-containing nutrients to fat.



The (PPAR) family of nuclear receptors represents one of the central regulators of the expression of the main genes controlling adipocyte differentiation.51-53 PPARg (the adipocyte-specific isoform) expression is increased in omental fat in obese subjects compared to that seen in omental fat in lean and moderately overweight subjects.54 This is thought to be related to the expansion of visceral adipose mass observed in obese subjects.54



PPARg can be activated by agents of the thiazolidinedione family. Thiazolidinediones induce conversion of fibroblast cells into triglyceride-storing adipocytes.55,56 In clinical studies, thiazolidinediones are found to promote conversion of preadipocytes to adipocytes in subcutaneous but not in visceral, adipose tissue.57-59 An explanation for this site-specific effect on differentiation of human preadipocytes by thiazolidinediones is not available. However, this is consistent with a reduced availability of thiazolidinedione-sensitive preadipocytes in visceral fat locations, perhaps due to prior recruitment during weight gain.

Clinical studies on thiazolidinediones lasting a relatively short term (3 to 4 months) show improved insulin sensitivity in subjects with type 2 diabetes without associated weight gain.59,60 However, long-term (6 to 12 months) clinical studies with thiazolidinediones have resulted in significant weight gain.57,61-63 This suggests that a significant number of persons treated with these drugs actually gain weight while improving HbA1c levels. It is possible that increased insulin sensitivity seen after the administration of thiazolidinedione is secondary to greater conversion of preadipocytes to fat cells, greater storage of more triglycerides and resulting decrease in the rate of fatty acid release, and redistribution away from visceral adiposity. The finding that non-thiazolidinedione PPARg agonists also show an anti-hyperglycemic effect along with weight gain64 is consistent with this possibility.

The administration of thiazolidinedione has been imagined to increase insulin sensitivity of muscle and liver, either directly through the low levels of PPARg expressed in these tissues or indirectly through (TNFa) produced in fat. However, it is not clear how large an increase in insulin sensitivity these could generate.53



Fifteen percent to 20% of individuals who develop insulin resistance are nonobese. There is no evidence to suggest that the mechanism of insulin resistance of adipocyte is different in nonobese subjects with type 2 diabetes compared with that in obese subjects. Yet, there is no information regarding the mechanism for the release of FFA from adipose tissue of lean individuals with type 2 diabetes. The finding that the severity of insulin resistance is the same in lean and obese diabetic subjects12,13 is consistent with the possibility of adipocyte storage capacity being more important than body fatness in the genesis of insulin resistance. Based on the hypothesis presented, lean individuals could develop elevated FFA levels after gaining weight considered acceptable according to weight tables because of reduced capacity to store triglyceride compared with obese individuals. Improved insulin sensitivity seen following increased adipogenesis after treatment with thiazolidinediones in nonobese individuals57 supports this position.

Obesity is strongly correlated with insulin resistance as evidenced by significant increase in glucose transport, reduction in free fatty acid levels, and decrease in plasma insulin level seen after weight loss.65,66 However, many individuals will not develop insulin resistance despite profound obesity. A very large capacity to accommodate additions in fat mass could explain this finding. Adipocyte size and number are greater in obese than in lean individuals.67,68 The ability to match fat cell acquisition with fat accumulation could explain normoglycemia in the presence of hyperinsulinemia seen in some obese individuals who do not develop insulin resistance.69 At the other end of the spectrum could be the entity called lipoatrophy characterized by complete absence of subcutaneous fat tissue. Although the factors responsible for the decrease in fat tissue are unknown, this condition is associated with hyperglycemia, hypertriglyceridemia, and elevated FFA in the presence of normal or elevated serum insulin levels.70

The hypothesis presented is not at odds with the finding that fat accumulation in muscle could contribute to insulin resistance at that site.71 Nor is it in opposition to the prevailing understanding of the role of impaired islet cell secretion in the etiology of hyperglycemia of type 2 diabetes.



Muscles are capable of using large amounts of fatty acids for energy. Use of this capacity could result in decreased utilization of glucose. The switch to FFA for energy could spare large amounts of glucose since carbohydrates are usually used preferentially by muscles. High levels of FFA and endocrine signals from adipocytes could be responsible for the apparent defect in glucose transport and utilization. It is proposed that adipocyte stuffing could be responsible for the appearance of adipocyte insulin resistance and increased plasma FFA.



The author thanks Antony M. Poothullil, MD, for carefully reading the manuscript and for helpful discussion.




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