Insulin Resistance and Hyperinsulinemia Is Hyperinsulinemia the Cart Or the Horse?

Home , Hyperinsulinemia, Hyperinsulinism, Pulsatile insulin

SECTION III

Insulin Resistance and Hyperinsulinemia Is hyperinsulinemia the cart or the horse?

1 MICHAEL H. SHANIK, MD RACHEL DANKNER, MD, MPH4 middle tertile showed an intermediate 2 5 YUPING XU, MD YEHIEL ZICK, PHD prevalence (Fig. 1). 2,6 JAN Sˇ KRHA, MD, DSC3 JESSE ROTH, MD Insulin resistance is defined as a reduced responsiveness of a target cell or a whole organism to the insulin concentra- Insulin resistance, recently recognized as a strong predictor of disease in adults, has become the tion to which it is exposed. It should be leading element of the metabolic syndrome and renewed as a focus of research. The condition recognized that in vivo insulin resistance exists when insulin levels are higher than expected relative to the level of glucose. Thus, insulin is tethered to hyperinsulinemia. In con- resistance is by definition tethered to hyperinsulinemia. The rising prevalence of medical con- trast to the prevailing view that assigns a ditions where insulin resistance is common has energized research into the causes. Many causes dominant role to insulin resistance, we and consequences have been identified, but the direct contributions of insulin itself in causing or examine in this article the possible role of sustaining insulin resistance have received little sustained attention. We examine situations where insulin itself appears to be a proximate and important quantitative contributor to insulin hyperinsulinemia, especially in the basal resistance. 1) Mice transfected with extra copies of the insulin gene produce basal and stimulated state, in sustaining, expanding, or initiat- insulin levels that are two to four times elevated. The mice are of normal weight but show insulin ing the insulin resistance. Particularly re- resistance, hyperglycemia, and hypertriglyceridemia. 2) Somogyi described patients with un- markable will be the severity of the insulin usually high doses of insulin and hyperglycemia. Episodes of hypoglycemia with release of resistance (and the magnitude of insulin glucose-raising hormones, postulated as the culprits in early studies, have largely been excluded secretory defects) brought about by mod- by studies including continuous glucose monitoring. 3) Rats and humans treated with escalating est (twofold) elevations in basal insulin doses of insulin show both hyperinsulinemia and insulin resistance. 4) The pulsatile adminis- concentrations in mice with transgenic tration of insulin (rather than continuous) results in reduced requirements for insulin. 5) Many overexpression of insulin. Twofold eleva- patients with insulinoma who have elevated basal levels of insulin have reduced (but not absent) tions in basal insulin levels are common responsiveness to administered insulin. In summary, hyperinsulinemia is often both a result and a driver of insulin resistance. in patients with insulin resistance associated with obesity or type 2 diabetes. We Diabetes Care 31 (Suppl. 2):S262–S268, 2008 review other examples where basal hyperinsulinemia initiates and significantly contributes to insulin resistance. Hope- nsulin resistance has been assigned a drome, the deadly quartet, and more fully, this information will provide new central place in the metabolic distur- commonly, the metabolic syndrome. insight into our understanding of obesity I bances associated with obesity and More recently, Reaven et al. focused and type 2 diabetes. type 2 diabetes. Early studies (referred to on insulin resistance as the key feature. In later under historical notes, including the a prospective study of 208 people over HORMONE REGULATES citation to work by Modan et al.) were 4–11 years, Facchini et al. (2) showed TISSUE SENSITIVITY — A hor- crystallized and brought to fruition by that insulin resistance was a powerful in- mone acutely stimulates its target cell and Reaven (1), who proposed in 1988 that dependent predictor of a wide range of simultaneously resets the responsiveness the cluster of insulin resistance (and by serious illnesses, including stroke, type 2 of the target cell to subsequent doses of definition, hyperinsulinemia), impaired diabetes, cardiovascular disease, hyper- hormone. Homologous desensitization, glucose tolerance, abnormalities of tension, and even cancer. Subjects in the the ability of a stimulatory ligand to de- plasma lipids, and hypertension were part upper tertile of insulin resistance showed sensitize its target cells to its action, is of a single syndrome, Syndrome X. It has a very high prevalence of these illnesses, widespread. Let us examine two extreme also been called the insulin resistance syn- the lowest tertile had very few, and the examples where persistently high hormone levels totally desensitize the target cell ●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●● to subsequent action by that hormone. From the 1Division of Endocrinology, North Shore–Long Island Jewish Health System, Lake Success, New Patients with choriocarcinoma who 2 York; the Feinstein Institute for Medical Research, North Shore–Long Island Jewish Health System, Manhas- have very high levels of human chorionic set, New York; the 3Department of Internal Medicine 3, 1st Faculty of Medicine, Charles University, Prague, Czech Republic; the 4Cardiovascular Epidemiology Unit, Gertner Institute for Epidemiology and Health gonadotropin (hCG) may show no signs Policy Research, Tel-Hashomer, Israel; the 5Department of Molecular Cell Biology, Weizmann Institute of of excess gonadotropins (3) and are unre- Science, Rehovot, Israel; and the 6Department of Internal Medicine, Albert Einstein College of Medicine, sponsive to injected human chorionic go- New York City, New York. nadatropin (4). Extracts of the tumor do Address correspondence and reprint requests to Jesse Roth, MD, 149-37 Powells Cove Blvd., Whitestone have biologically active hormone. After NY 11357. E-mail: [email protected]. The authors of this article have no relevant duality of interest to declare. cure of the tumor, patients are responsive This article is based on a presentation at the 1st World Congress of Controversies in Diabetes, Obesity and to injected human chorionic gonada- Hypertension (CODHy). The Congress and the publication of this article were made possible by unrestricted tropin. educational grants from MSD, Roche, sanofi-aventis, Novo Nordisk, Medtronic, LifeScan, World Wide, Eli A more familiar example is with go- Lilly, Keryx, Abbott, Novartis, Pfizer, Generx Biotechnology, Schering, and Johnson & Johnson. Abbreviations: GnRH, gonadotropin-releasing hormone; IRS, insulin receptor substrate. nadotropin-releasing hormone (GnRH). DOI: 10.2337/dc08-s264 Under normal circumstances, GnRH is se- © 2008 by the American Diabetes Association. creted in a pulsatile fashion. When this

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sponse to glucose, followed by a pro- longed hyperinsulinemic phase. Are these disturbances due to insulin resistance at the level of the ␤-cell? Might we expect an insulin secretory defect in any condition associated with generalized hyperinsulinemia and insulin resistance? In this section, we will summarize data showing that insulin resistance limited to the pancreatic ␤-cell is capable of causing major disturbances in insulin secretion. Genetic ablation of the insulin receptor only in the pancreatic ␤-cell of mice causes a defect in insulin secretion that is similar to that observed in type 2 diabetes (10). The mice show a loss in first-phase insulin secretion in response to glucose, Figure 1—The number of clinical events observed, as a function of insulin resistance tertile at but not to arginine, similar to that seen in baseline. CA, cancer; CHD, coronary heart disease; HT, hypertension; SSPG, steady-state plasma humans with type 2 diabetes. The mice glucose (determined by continuous infusion of somatostatin, insulin, and glucose during a 75-g with ␤-cell–specific insulin receptor oral glucose tolerance test). Plasma glucose and insulin concentrations were drawn every 10 min ␤ during the last 30 min of the infusion. The average of the last four measurements was used to define knockout ( IRKO) exhibit progressively the SSPG. There were 28 events in the highest tertile (SSPG Ͼ7.8 mmol/l), 12 in the intermediate impaired glucose tolerance over 6 tertile (SSPG Ͼ 4.4 Ͻ 7.8 mmol/l), and none in the most insulin-sensitive tertile (SSPG Ͻ4.4 months. The mechanism of this effect is mmol/l). From Facchini et al. (2) complex, but the reduction in ␤-cell mass and islet number appear to be minor (Ta- pattern of secretion is mimicked by exog- extra copies of the human insulin gene ble 1) (11). The important role of the in- enous injections, fertility can be induced (9). The transfected mice had elevated sulin response pathway in the function of in patients who have a disruption in basal plasma insulin levels that were re- the normal pancreatic ␤-cell is demon- GnRH release and/or function. When the spectively two and four times higher than strated by these studies. Insulin resistance hormone is given persistently, fertility normal. They had normal weight and nor- at the level of the ␤-cell, coupled with and its other effects are blocked. Indeed, mal fasting glucose levels, but they dis- peripheral insulin resistance, might pro- this feature of the hormone is used thera- played elevated postprandial glucose vide a unifying hypothesis to explain the peutically in patients with idiopathic pre- associated with an exaggerated insulin re- pathophysiology of type 2 diabetes in cocious puberty. With continuously sponse to glucose (Fig. 2). The mice also humans. elevated levels of GnRH, the precocious showed diminution in hyperglycemia In a complementary study, deletion of puberty is inhibited. Removal of the hor- during an insulin tolerance test (Fig. 3). the IGF-I receptor only in ␤-cells resulted mone is followed rapidly by a recrudes- The hyperinsulinemia-induced insulin in hyperinsulinemia (both fasted and fed) cence of the pubescent process (5). resistance was associated with reduced in- and glucose intolerance without a reduc- In both cases, the high hormone lev- sulin receptor binding as well as signifi- tion in ␤-cell mass (12). Likewise, a els produce essentially complete unre- cant hypertriglyceridemia that was mouse model lacking functional recep- sponsiveness to the hormone. The correlated with the degree of hyperinsu- tors for both insulin and IGF-I in ␤-cells insensitivity is reversed by removing the linemia. We conclude that hyperinsulin- only (␤DKO) exhibited a normal level of excess hormone. In the case of insulin re- emia in the basal state leads to generalized islet cells up to 5 days, indicating that the sistance, responsiveness of target cells is insulin resistance associated with distur- insulin and IGF-1 pathways are not essen- considerably diminished but never com- bances in glucose metabolism and insulin tial for islet cell development (13). How- pletely lost. An acute rise in insulin is secretion. That these mice were thin, did ever, this same mouse model exhibited a stimulatory, but persistently elevated lev- not develop antibodies to insulin, and had significant decline in the levels of islet els of insulin desensitize the target cells normal fasting glucose simplified the in- cells at 2 weeks. Furthermore, 3 weeks through multiple mechanisms, including terpretation of the findings. after birth, they developed diabetes. effects at the level of the insulin receptor Taken together, these data as well as data (6) and at several sites beyond the recep- from other related knockout models sug- tor (7,8). A sustained elevated level of in- INSULIN RESISTANCE gest that insulin and IGF-1–dependent sulin, immaterial of its origin, typically DISRUPTS INSULIN pathways are not critical for ␤-cell devel- leads to generalized insulin resistance. SECRETION — Type 2 diabetes is of- opment, but reduced action of these hor- The ability of insulin to desensitize target ten associated with basal hyperinsulin- mones in the ␤-cells produces defects cells to its own effects is best illustrated in emia, reduced sensitivity to insulin, and in insulin secretion and possibly even a group of mice that have chronic overex- disturbances in insulin release. In trans- diabetes. pression of insulin. genic mice, basal hyperinsulinemia and reduction in target cell sensitivity to insu- REVIEW OF PRIMARY TRANSGENIC lin were associated with a disturbance in HYPERINSULINEMIA IN HYPERINSULINEMIA — Mice insulin release from the ␤-cell. There was VIVO — Starting in 1938, Somogyi re- were stably transfected with 0, 8, or 32 a delayed onset of insulin secretion in reported patients with poorly controlled

DIABETES CARE, VOLUME 31, SUPPLEMENT 2, FEBRUARY 2008 S263 Insulin resistance and hyperinsulinemia

excluded antecedent hypoglycemia as the cause, have shed doubt on his original ex- planation (15). We suggest that insulin- induced insulin resistance is the most likely mechanism. Insulin resistance is associated with continuous exposure to high levels of insulin. Regardless of whether the insulin resistance or the basal hyperinsulinemia came first, the hyperinsulinemia itself might perpetuate the insulin resistance. Several in vivo studies, in which insulin was administered at high levels (similar to those found in insulin-resistant states), have confirmed that basal hyperinsulinemia can lead to insulin resistance. In- creasing doses of NPH insulin in rats decreased the number of insulin receptors on target tissues with a corresponding de- crease in cell sensitivity to insulin (16). By using a similar technique of administering gradually increasing doses of NPH insulin to rats, both downregulation of the insulin receptors and postreceptor defects were demonstrated (17). Rizza et al. (18) found that continuous (40-h) hyperinsulinemia in humans significantly reduced glucose utilization and overall glucose metabolism at submaximally and maxi- mally effective plasma insulin concentrations. These studies indicate that hyperinsulinemia at levels similar to those observed in many insulin-resistant states can produce insulin resistance.

PULSATILE INSULIN MINIMIZES DESENSITIZATION — Studies comparing continuous versus pulsatile administration of insulin have further supported the hypothesis that continuous hyperinsulinemia can cause insulin resistance. In healthy subjects, pulsatile delivery of insulin had a more robust hypoglycemic effect than continuous delivery (19–21). This phenomenon has also been shown in subjects with diabetes (21–23) as well as in an animal model of diabetes (24). The efﬁcacy of many hormones is Figure 2—Glucose tolerance tests in transgenic hyperinsulinemic (thin) mice. After an overnight greater when secreted in an oscillatory or fast, animals were injected intraperitoneally with glucose (2 mg/g body wt). Blood samples were pulsatile fashion. Luteinizing hormone, taken at time points up to 120 min after injection for measurements of plasma glucose (A) and GnRH, growth hormone, and adrenocor- plasma insulin (B). Points each represent the mean Ϯ SE of nine or more individual measurements. ticotropic hormone exhibit pulsatile pat- Adapted from Marban and Roth (9). terns of release. The theoretical advantage of intermittent release is to minimize desensitization, thereby enhancing the ac- hyperglycemia who were receiving unex- phenomenon to episodes of hypoglyce- tion of the hormone. Similar to other pectedly large doses of insulin in whom mia (often undetected) that provoked re- hormones, insulin release is pulsatile, the hyperglycemia was ameliorated by release of counterregulatory hormones. with rapid low-amplitude pulses every ducing (rather than increasing) the insu- Recent studies, including studies of such 8–15 min (25,26), as well as slower ultra- lin dose (14). He attributed this patients with sensitive methods that have dian oscillations (27,28). Oscillatory pat-

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duced sensitivity to insulin during clamp studies (36). Surgical resection of the insulinoma completely restored glucose metabolism and insulin sensitivity after normalization of insulin secretion from ␤-cells (36,37). While insulinoma patients differ in some ways from other patients with hyperinsulinemia and insulin resistance (e.g., immunologic assays of insulin may overestimate the bioactivity of circulating insulin of insulinoma patients; the basal secretion from the tumor may suppress the normal pancreas), the primary hyperinsulinemia remains a dominant feature.

MECHANISMS OF INSULIN- INDUCED RESISTANCE TO INSULIN — Like other hormone- sensitive pathways, the intracellular pathway of insulin action is continuously being regulated by a multiplicity of influ- ences. In this section, we focus on the effects of insulin itself on the sensitivity of Figure 3— Insulin tolerance tests in transgenic hyperinsulinemic (thin) mice. Mice were injected its own pathway with particular emphasis intraperitoneally with insulin (0.5 mU/g body wt). Blood for glucose determinations was drawn on homologous desensitization, i.e., the before and at 30 and 60 min after insulin injection. Each point represents the mean Ϯ SE of 6–10 individual glucose determinations. *P Ͻ 0.02 vs. control. Adapted from Marban and Roth (9). dampening effects produced by continuous exposure of the target cells to stimulatory levels of insulin. terns are considered important in sure to insulin without pulsatility might The insulin receptor itself is a well- maintaining glucose within the normal be capable of producing insulin resistance. studied mediator of negative feedback range. that involves reduction in receptor affin- Enhanced action of insulin in the set- BASAL HYPERINSULINEMIA ity, reduction in the number of receptors ting of pulsatile release has been sup- WITH INSULINOMAS — Patients exposed on the surface of the target cell, ported by in vitro studies, in which with insulinoma provide an alternative and diminution of the effectiveness of the hepatocytes were perfused with either a setting to study the effects of persistent receptor as a transmitter of stimulatory constant or pulsatile delivery of insulin. basal hyperinsulinemia on insulin sensi- signals. Each insulin receptor has two Insulin receptor expression was signifi- tivity. Like patients with insulin resis- binding sites for insulin. One insulin mol- cantly higher in hepatocytes exposed to tance due to other conditions, insulinoma ecule binds with high affinity, whereas oscillatory concentrations of insulin com- patients have the following: 1) elevated binding of a second insulin molecule oc- pared with continuous insulin exposure levels of circulating insulin, 2) insulin re- curs with lower affinity (38). At increas- (29). Furthermore, isolated rat adipocytes sistance, 3) impaired insulin secretion in ing concentrations of insulin, occupancy exposed to continuous hyperinsulinemia response to glucose (31,32), 4)anin- of receptor sites increases, but average af- led to a dose-dependant loss of insulin crease in the long isoform (lower insulin finity diminishes (“negative cooperativ- receptors, as well as a marked postrecep- binding affinity) of the insulin receptor ity”) (39). tor defect in glucose transport (30). In (33), 5) reduced insulin effects at receptor Another mechanism for insulin- insulin-resistant states, continuous expo- and postreceptor sites (34,35), and 6) re- induced regulation of receptor affinity is

Table 1—Insulin secretory defects in knockout models

Pancreatic Insulin secretion insulin content (ng(ng DNA)Ϫ1 (␮g/mg pancreas) ␤-Cell mass (mg) Fasting insulin Fed insulin (60 min)Ϫ1) Fasting blood (2-week-old mice) (2-week-old mice) level (ng/ml) level (ng/ml) (4-week-old mice) glucose (mg/dl) Control 0.32 Ϯ 0.06 1.2 Ϯ 0.1 0.4 Ϯ 0.1 1.9 Ϯ 0.4 1.4 Ϯ 0.3 72 Ϯ 13 ␤IRKO 0.27 Ϯ 0.05 1.0 Ϯ 0.2 0.9 Ϯ 0.08* 2.6 Ϯ 1.1 1.3 Ϯ 0.2 58 Ϯ 9 ␤IGF1RKO 0.35 Ϯ 0.06 0.9 Ϯ 0.4 0.9 Ϯ 0.2* 2.4 Ϯ 0.9 1.3 Ϯ 0.2 82 Ϯ 9 ␤DKO 0.11 Ϯ 0.05* 0.5 Ϯ 0.1* Not available 0.6 Ϯ 0.6* 0.2 Ϯ 0.5* 396 Ϯ 102* Data are compiled from References 10–13. *P Ͻ 0.05 vs. control mice. ␤IRKO, ␤-cell–specific insulin receptor knockout; ␤IGF1RKO, ␤-cell–specific IGF-1 receptor knockout; ␤DKO, ␤-cell–specific insulin and IGF-1 receptor knockout.

DIABETES CARE, VOLUME 31, SUPPLEMENT 2, FEBRUARY 2008 S265 Insulin resistance and hyperinsulinemia exercised via regulation of the relative The mechanisms occur in a concentra- insulin receptor (and later of postreceptor proportion of the two molecular isoforms tion- and time-dependent way. They are pathways) made those insights possible. (40) of the insulin receptor. Continuous complex and as yet incompletely de- Whereas insulin resistance in general exposure to insulin results in a reduction fined. The pathways vary between target was linked to metabolism of glucose and in the proportion of short (higher affinity) cells, between pathways within an indi- later to other substrates in patients with isoforms to long (lower affinity) isoforms. vidual target cell, and among pathological obesity and type 2 diabetes, the link be- The relative contribution from changes in states and individual patients. While the tween hyperinsulinemia and other con- production versus degradation rates has complexity is daunting, it provides ditions arrived later. In 1981, hyperinsu- not been fully established. opportunities for specific therapeutic linemia had been ascribed a pathogenetic Continuous exposure to insulin interventions. role in obese hypertension via increased causes a reduction in the number of re- renal sodium retention (58). In 1985, Mo- ceptors exposed on the cell surface by HISTORICAL NOTES — Insulin re- dan et al. (59) proposed that hyperinsu- promoting internalization as well as deg- sistance was initially recognized in insulinemia, reflecting peripheral insulin radation of hormone-occupied receptors lin-treated patients who required larger resistance, is linked to hypertension, obe- (6). The insulin receptor is a tyrosine ki- than usual doses of insulin. Infections, en- sity, and glucose intolerance in humans, nase that activates itself and then trans- docrinopathies, allergy to insulin, and and in 1988, Modan et al. (60) further mits its stimulatory message by (later) antibodies to insulin were recog- reported that hyperinsulinemia is charac- promoting the phosphorylation of se- nized as early causes (48–51). terized by jointly disturbed plasma lipids. lected tyrosines on the receptor and on The recognition of insulin resistance The same year, Reaven (1) proposed the postreceptor partner molecules such as in patients who were not receiving insulin term “Syndrome X” for the cluster of in- insulin receptor substrate family mem- awaited the introduction of 1) the insulin sulin resistance and hyperinsulinemia, bers IRS-1 and IRS-2 in the family of intolerance test, 2) measurement of the ef- impaired glucose tolerance, abnormalities sulin receptor substrates. With fects of insulin infused into arterial blood of plasma lipids, and hypertension, now continuous exposure to insulin, the re- of the forearm (52,53), 3) the immunoas- commonly called the metabolic syn- ceptor’s kinase activity is diminished, say of insulin (the first reliable quantita- drome. probably because of combined effects of tive measure of endogenous circulating phosphorylation of serine residues on the insulin) (54), and 4) clamp techniques. CONCLUSIONS/FUTURE receptor, dephosphorylation of tyrosines Our discussion here is devoted to PROSPECTS — Hyperinsulinemia in by the action of phosphatases, and the moderate insulin resistance, i.e., a few- the basal state of any origin produces binding of inhibitory molecules (41–45). fold diminution in sensitivity to insulin widespread insulin resistance. All tissues Receptor-mediated tyrosine phos- (extreme insulin resistance, e.g., a 5- to that have insulin receptor pathways will phorylation activates downstream pro- 10-fold or more reduction in sensitivity to be affected, including the pancreatic teins, especially the IRS proteins insulin was first described in patients with ␤-cell, and possibly the brain (61,62). De- (mentioned earlier) to promote the down- lipoatrophic diabetes and later in patients fective insulin signaling at the ␤-cell im- stream activation of the target cell. The with high concentrations of anti-insulin pairs glucose-stimulated insulin release. IRS proteins also become phosphorylated antibodies after treatment with insulin). At steady state, basal hyperinsulinemia on serine (and threonine) residues, prob- Later, patients with autoantibodies generates and sustains insulin resistance, ably by the action of multiple kinases. against the insulin receptor and patients irrespective of where the pathology started. Serine phosphorylated forms of the IRS with inborn defects of the insulin receptor Hyperinsulinemia, insulin resistance, and proteins have reduced ability to activate were added to the list. impairment of glucose-stimulated insulin downstream elements and also act up- In the period just before widespread release are intertwined biologically. A sin- stream to inhibit the activity of the insulin acceptance of the immunoassay, bioas- gle process (hyperinsulinemia) could receptor. says were in ascendancy, which detected generate all three simultaneously. Several other molecules downstream plasma components that diminished in- There are several factors that contrib- in the insulin pathway (e.g., m-TOR and sulin action in these assays; these sub- ute to insulin release. In the basal state, phosphatidylinositol 3-kinase) transmit stances were collectively labeled free fatty acid levels act in part to stimu- the activation process downstream and circulating insulin antagonists (55–57). late the release of insulin. Obese subjects also provide upstream negative feedback The immunoassay swept away all but the have high levels of free fatty acids, and signals. In addition, chronic exposure of circulating anti-insulin antibodies and this might be a major contributor to the the cell to insulin may result in a dimin- well-defined hormones such as cat- hyperinsulinemia present in these pa- ished concentration of downstream ele- echolamines, glucocorticoids, growth tients (63). Basal insulin levels are such an ments, including key components such as hormone, and glucagon. The immunoas- important determinant of insulin sensitiv- the IRS proteins (44,45). say also left behind a negative attitude to- ity, it is important to understand the mul- The insulin-stimulated pathway, as ward other circulating antagonists or tiple elements that are driving the noted at the beginning of this section, is inhibitors of insulin action. In our opin- hyperinsulinemia in the basal state. It may regulated by heterologous agents. Inter- ion, PC-1 and other well-defined circulat- be that the stimulus for basal hyperinsu- estingly, some of these heterologous mod- ing molecules deserve greater attention linemia varies by patient and/or disease ifiers (e.g., tumor necrosis factor and free than they have been receiving. In retro- state. fatty acids) are themselves under the in- spect, it is highly likely that the circulating One of the characteristics of hyperin- fluence of insulin (46,47). antagonist of insulin action that everyone sulinemic states, specifically the meta- This brief superficial survey shows was searching for may be insulin itself. bolic syndrome, is an elevated level of that insulin regulates its own sensitivity. The introduction of direct studies of the inflammatory markers, including cyto-

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