Reviews/Commentaries/Position Statements PERSPECTIVES ON THE NEWS

Obesity and

ZACHARY T. BLOOMGARDEN, MD deficiency may contribute to insulin resis- tance. McGarry speculated that approaches of this sort may “prevent the transition from IGT [impaired glucose tolerance] to , an exciting challenge.” his report focuses on a series of lec- fat accumulations in liver and -cells con- Rudolph Leibel, New York, NY, dis- tures that were presented in New tribute to hepatic and islet dysfunction. cussed the regulation of energy home- TYork over the past year. Many of the Muscle fat accumulation may involve ostasis at the symposium. Caloric stores lectures describe aspects of the relation- abnormal regulation of mitochondrial car- are related to a variety of factors, including ship between both fat and adipocytes and nitine palmitate transferase (CPT)-1, which food intake, energy expenditure, growth, diabetes and were presented at the Mount is inhibited by malonyl CoA. The increase puberty, fertility, and insulin sensitivity Sinai Institute. Presenters mentioned here in muscle malonyl CoA in diabetes may and secretion, and “the discovery of include, among others, Angeliki Georg- decrease -oxidation of fats, with an atten- [represents] an outgrowth of the efforts to opoulos, Willa Hsueh, Harold Lebovitz, J. dant increase in triglyceride synthesis. This find one of the signals.” In all of the mam- Dennis McGarrry, Gerald Shulman, can be replicated with administration of mals studied, the energy required to main- Michael Schwartz, Joshua Tannenbaum, etomoxir, which leads to etomoxir CoA tain body weight is 70 kcal/[body wt]0.75; and Helen Vlassara. synthesis, thereby decreasing CPT-1 activ- individuals of all species show compen- At the Gerald J. Friedman Symposium, ity and causing insulin resistance that is satory increases or decreases in energy New York, NY, on 7 November 1999, J. then exacerbated by triglyceride loading. expenditure with corresponding changes in Dennis McGarry, Dallas, TX, discussed the McGarry pointed out that, under some cir- caloric intake. The total energy expenditure role of fatty acids (FAs) in glucose home- cumstances, fats lower glucose levels. The in is 36.4 fat free mass plus 9.4 ostasis. He reflected on the difficulty in increase in circulating free fatty acid (FFA) fat mass. Subsequently, as fat mass understanding the interaction among basal levels with heparin plus triglyceride emul- increases for a given body mass, caloric hyperinsulinemia, the early increase in sion infusion acutely increases insulin requirements decrease. When weight is insulin response to glucose, the increase in responses, whereas nicotinic acid, which maintained at 10% below basal, the resting hepatic glucose production, and insulin decreases FFA levels, is associated with energy expenditure decreases 8%, but non- resistance. A speculation is that the lipid decreased insulin secretion. In the transition resting energy expenditure decreases 36% abnormality of high triglyceride and FA lev- from the fed to fasted states, the -cell with an overall 15% fall in energy expen- els may underlie the glycemic abnormality becomes dependent on FFAs to respond to diture. The fall in nonresting energy expen- (with, perhaps, defects in leptin signaling) a glucose load. Saturated fats have the diture has been directly demonstrated with in the capacity of muscle to oxidize FAs or greatest effect in potentiating the insulin NMR studies of exercising skeletal muscle, in hepatic, -cell, and adipocyte fat metab- response. Chronically, however, increases showing a decline in high-energy phos- olism, which leads to the accumulation of in islet fat cause -cell dysfunction. Thus, phate consumption after weight reduction. fat in these tissues. There is evidence that lipotoxicity contributes to the insulin defi- Potential causes include decreased leptin muscle fat accumulation is related to insulin ciency of type 2 diabetes. A potential mech- levels and decreased sympathetic tone. resistance (1). By using nuclear magnetic anism of action of thiazolidinediones occurs Other factors include the thermic effect of resonance (NMR) proton spectroscopy to by decreasing muscle fat accumulation and feeding and the effect of uncoupling pro- measure muscle fat, McGarry observed that improving insulin sensitivity, which possi- teins (UCPs) on adipocyte energy release. there are two types of muscle fat: that which bly has an additional effect on -cell fat to Thus, after weight loss, energy expendi- is found within myocytes and that which is improve insulin secretion. Leptin may affect ture is depressed, and “if you integrate that found in the surrounding ; the sympathetic outflow and lead to dispersion over 6 months to a year, it dooms most of former is “massively increased” in type 2 of fat from muscle, liver, and pancreas to those [who have lost weight] to re-gain.” diabetes. McGarry speculated that similar similarly improve glycemia, whereas leptin Taking a long-term perspective, humans ingest 900,000 kcal yearly; a mere 0.15% excess of calories from age 25–55 years Dr. Zachary T. Bloomgarden is a practicing endocrinologist in New York, New York, and is affiliated with the will lead to a 20-lb weight gain. Division of Endocrinology, Mount Sinai School of Medicine, New York, New York. Hypothalamic efferent signals influ- Abbreviations: AGE, advanced glycation end product; AgRP, Agouti-related protein; apo, apolipoprotein; ence both energy intake and expenditure; BAT, brown adipose tissue; CHD, coronary heart disease; CNS, central nervous system; CPT, carnitine palmi- fat stores provide the primary signals con- tate transferase; CT, computed tomography; CVD, cardiovascular disease; FA, fatty acid; FFA, free FA; G6P, glucose-6-phosphate; IRS, insulin receptor substrate; MAPK, mitogen-activated protein kinase; MRI, magnetic cerning energy stores to the brain. Animals resonance imaging; MS, metabolic syndrome; NMR, nuclear magnetic resonance; NOS, nitric oxide syn- with mutations in the leptin/leptin recep- thetase; NPY, neuropeptide Y; PAI-1, plasminogen activator inhibitor 1; PI3-K, phosphatidylinositol 3-kinase; tor axis eat more, expend less energy, and POMC, proopiomelanocortin; PPAR, peroxisome proliferator–activated receptor; PVN, paraventricular store more calories as fat, suggesting that nucleus; RXR, retinoid X receptor; TZD, thiazolidinedione; UCP, uncoupling protein; WAT, white adipose tis- sue; WHR, waist-to-hip ratio. leptin influences all of these systems. Lep- A table elsewhere in this issue shows conventional and Système International (SI) units and conversion tin is produced in adipocytes, is increased factors for many substances. by insulin and glucocorticoids, and is

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decreased by catecholamines. It enters the NPY and POMC in a variety of experimen- During his lecture at the Mount Sinai brain by facilitated transport and stimulates tal states, with fasting, uncontrolled dia- Diabetes Conference on 18 May 2000, hypothalamic signals to suppress food betes, and leptin or Joshua Tannenbaum discussed UCPs, which intake and increase sympathetic nervous deficiency increasing hypothalamic NPY appear to play a major role in regulating system activity. Leibel pointed out that lep- and decreasing POMC, whereas leptin energy expenditure. The mitochondrial tin provides “a signal of the sufficiency of administration and overfeeding cause the transport superfamily includes anion carri- energy storage.” It is therefore less likely to opposite effects. POMC has an endogenous ers, such as those for ATP/ADP, magne- help the individual avoid excess fat than to antagonist, the Agouti-related protein sium, and dicarboxylic acid; cation carriers, prevent deficiency, with low levels of lep- (AgRP), which is expressed in the arcuate including the transporters for ornithine and tin leading to hypometabolism, infertility, nucleus, with experimental overexpression carnitine; and the UCPs themselves, which hunger, and relative growth hormone defi- or local administration of AgRP causing lead to heat generation by uncoupling the ciency. Such decreases in leptin levels are hyperphagia and . AgRP is coex- re-entry of protons from the new formation seen within 24 h of initiation of an extreme pressed in NPY neurons, whereas POMC of ATP. Up until a few years ago, these pro- hypocaloric diet, but they are also seen in neurons, which are separate, coexpress teins were thought to act by promoting FA weight-reduced individuals with decreased cocaine-amphetamine–regulated tran- oxidation. There is a transmembrane elec- adipocyte stores. Individuals may differ in script, the precise role of which is less clear. trical charge gradient across the mitochon- their thresholds for changes in leptin secre- The current concept is that these arcuate drion with H at greater levels outside. In tion because of either genetic or acquired nucleus neuropeptides are the main CNS effect, the mitochondria act as batteries, and differences in insulin or neuropeptide effectors of signals related to energy bal- UCPs short-circuit the transmembrane elec- response. It should be noted that a consid- ance; other peptides that change with lep- trical charge gradient. UCPs account for erable increase in leptin is required to cause tin excess and deficiency are secondary 20% of energy metabolism. UCP-1 was hypophagia and hypermetabolism. Thus, signals. Signals in the lateral hypothalamus discovered in brown adipose tissue (BAT), leptin treatment may play a role in main- stimulate and those in the paraventricular which is present only to a minimal extent taining reduced weight rather than produc- nucleus (PVN) inhibit food intake. Schwartz beyond the neonatal period in humans. In ing weight loss, because leptin could “trick pointed out that insulin “was actually the 1997, UCP-2 was found, showing 50% the brain into thinking there’s more fat.” first proposed signal that provides negative homology with UCP-1 and coded on a locus Michael Schwartz, Seattle, WA, sug- feedback to the brain” by entering the brain linked to obesity and hyperinsulinemia. In gested at the Friedman symposium that via receptor-mediated transport with arcu- rodents, UCP-2 is expressed in BAT, kidney, “obesity and diabetes are diseases of the ate nucleus receptors leading to NPY sup- heart, and white adipose tissue (WAT), and brain” and claimed that the “virtual explo- pression, PVN activation, and weight loss. it shows regulation by diet; cold exposure sion of CNS [central nervous system] sig- Potential therapeutic approaches may and 3 agonists do not affect UCP-2 but naling molecules” leads to completely new include leptin itself, POMC agonists, and increase UCP-1. A/J mice, which are resis- potential approaches to treating diabetes. NPY antagonists. tant to diet-induced obesity and diabetes, The model is characterized by a negative Luciano Rossetti, New York, NY, dis- have twice the UCP-2 expression with high- feedback loop; higher fat stores generate cussed the relationship between nutrient fat diet compared with the susceptible white humoral signals that change levels of CNS sensing and insulin action at the sympo- B6 mice, which do not show induction of effectors and thereby cause negative energy sium. Insulin resistance in type 2 diabetes is UCP-2 with overeating. UCP-3 shows 73% balance. In the brain, leptin has two com- associated with genetic, obesity-related, and homology with UCP-2; both are coded on plementary actions: it stimulates weight environmental factors, and almost every chromosome 11q13, whereas UCP-1 is loss and inhibits weight gain. The mela- experimental model of leptin resistance or coded on chromosome 4q31. UCP-3 is tonins are major mediators of leptin’s deficiency is associated with insulin resis- mainly expressed in muscle. Half of the anorectic effects, which are expressed in the tance or actual diabetes. Leptin levels peak increase in energy expenditure with hyper- arcuate nucleus of the hypothalamus and at 40% over baseline at 2:00 A.M. and thyroidism is related to proton leak, with project to proopiomelanocortin (POMC) also have meal-related changes, which are thyroid hormones appearing to regulate receptors in the lateral hypothalamus. potential mechanisms of feedback to insulin UCP-3. 3 agonists increase UCP-3 in WAT. POMC agonists cause anorexia, and POMC target tissues. Thus, nutrients may indi- Experimental data are inconclusive as to antagonists cause hyperphagia; the latter rectly regulate gene expression in muscle, whether decreased UCP activity may con- observation suggests that there is tonic fat, and liver via an energy-sensing feedback tribute to diabetes or obesity. UCP-1, UCP-3, basal POMC input. Indeed, animals with loop involving the leptin/POMC system. and double UCP-1/UCP-3 knockout mice leptin or leptin receptor deficiency show a Rossetti proposed that the short-term action do not develop obesity, perhaps because of a decrease in hypothalamic POMC expres- of leptin may be as a “nutrient-counterreg- compensatory increase in the other UCPs, sion. Furthermore, experimental POMC ulatory” hormone. Leptin potentiates such as those reported with the increased receptor blockade prevents the anorectic insulin action, and leptin resistance, as a UCP-2 and UCP-3 expression in the UCP-1 response to leptin. Leptin’s second action, result of either a decreased ability of nutri- knockout mice. In humans, three UCP-3 that of inhibiting weight gain, appears to ents to stimulate leptin biosynthesis or polymorphisms have been described. G→A occur by decreasing the expression of neu- decreased leptin action, may be an impor- in exon 6 is associated with increased obesity ropeptide Y (NPY) and other anabolic sig- tant component of the insulin resistance prevalence but has only been found in one nals. Leptin-deficient mice have markedly syndrome. Another question concerns population. UCP-1 mutations and 3 adren- increased hypothalamic NPY levels. Thus, whether insulin resistance involves CNS ergic receptor mutations have also been Schwartz showed reciprocal regulation of resistance to leptin action. described and may be associated with lesser

DIABETES CARE, VOLUME 23, NUMBER 10, OCTOBER 2000 1585 Perspectives on the News degrees of weight loss on a calorie-restricted half as much liver glycogen as control sub- insulin sensitivity, decreased muscle glyco- diet and a greater weight gain on weight- jects with half as much glycogenolysis, gen, and decreased G6P levels are observed. maintaining diet. When obese patients are whereas gluconeogenesis is 60% greater These findings suggest that FFAs actually act maintained at 20% weight loss, UCP-2 lev- than that in nondiabetic individuals. by interfering with glucose transport and, els increase whereas UCP-3 levels decrease Shulman assessed the effect of exercise. subsequently, by decreasing intracellular glu- in muscle and WAT. It is worth noting that By examining young healthy insulin-resis- cose levels. Thus, the defect is indeed due to the UCP-3 promoter has a peroxisome pro- tant offspring to assess whether exercise decreased transport. Potential sites of action liferator–activated receptor (PPAR)- reversed the defect in glucose transport and include FFA interference with GLUT4 /retinoid X receptor (RXR) response phosphorylation, he showed that, after 6 translocation or activity or with the insulin- element as well as a thyroid hormone weeks of training, there was an 60% signaling cascade at the insulin receptor, at response element. Retinoic acid increases increase in insulin-stimulated glucose insulin receptor substrate (IRS)-1 or -2, or at UCP-1 and decreases UCP-2 and -3. Gluco- metabolism in these offspring. In control phosphatidylinositol 3-kinase (PI3-K), corticoids reduce all UCP mRNA levels. subjects, he noted that a similar increase which increases during the hyperinsuline- UCP-2 mRNA increases with increased lep- was seen and, thus, the relative difference mic clamp. This increase is abolished by tin, though to a varying extent, whereas remained. To a large degree, nevertheless, FFAs as a decrease in IRS-1 tyrosine phos- food-restricted diets do not affect UCP-2 the increased response to insulin corrected phorylation and an increase in IRS-1 serine but decrease UCP-1 and -3 levels. Effects the abnormalities of the insulin-resistant phosphorylation also occurs. Protein kinase of PPAR agonists are of interest. Adminis- state. AMP kinase acts as a sensor of muscle C-, a known serine kinase, is activated. tration of bezafibrate, like fat feeding, energy stores, and an increase in AMP Shulman noted that c-Jun kinase also acti- increases UCP-3 levels, whereas adminis- potentially explains the effect of exercise vates serine phosphorylation of IRS-1, sug- tration of rosiglitazone increases UCP-1, an training on the increase in muscle energy gesting that the mitogenic insulin pathway effect that may be blocked by bezafibrate. stores. Other factors include mitochondrial decreases activity of the metabolic pathway. Gerald Shulman, New Haven, CT, metabolism. In studies on the mechanism of In mice that do not express adipose tissue, spoke at the Mount Sinai Institute on 13 action of troglitazone, Shulman noted that there is insulin resistance in muscle and liver April 2000. By using NMR spectroscopy there was a dose-related increase—though with decreased PI3K signaling but with with 31P to measure ATP and glycolytic not to normal levels—in glucose uptake in markedly increased muscle and liver triglyc- intermediates and 13C to allow assessment type 2 diabetic patients who were treated eride levels. When fat is transplanted, the of glycogen and lipids, the incremental with troglitazone. Interestingly, in nondia- glucose metabolism defect is normalized, change in muscle glycogen during labeled betic animal models, there is similarly no and tissue triglycerides are reduced to nor- glucose infusion with a hyperglycemic- increase in insulin action above normal lev- mal levels. Shulman suggested that the thi- hyperinsulinemic clamp decreases by 50% els. Troglitazone increases glucose oxidation azolidinediones (TZDs) may act by in patients with type 2 diabetes. Most and glycogen synthesis in association with decreasing muscle and liver triglyceride lev- nonoxidative glucose metabolism occurs increases in G6P levels during clamp proce- els. In mice with increased levels of lipopro- during muscle glycogen synthesis. Because dures. An important question concerns tein lipase specifically expressed in liver or oxidative glucose uptake is similar in indi- whether this increase in glucose transport muscle, the respective triglyceride levels are viduals with and without diabetes, “the big and the other effects of troglitazone are direct increased with insulin resistance, further defect is getting glucose into muscle glyco- or indirect (due to effects on fat cells). Shul- suggesting increased intracellular triglyc- gen.” Muscle glucose-6-phosphate (G6P) man noted that metformin acts principally eride to contribute to the abnormal glucose levels increase from 0.1 to 0.2 mmol/l in on hepatic glucose production, whereas homeostasis of type 2 diabetes. nondiabetic individuals during clamp stud- troglitazone acts on increasing peripheral Harold Lebovitz, New York, NY, dis- ies but show little change in patients with glucose uptake. The effect of metformin on cussed the interactions between abdominal type 2 diabetes. In insulin-resistant off- the periphery may be due to a decrease in obesity and -cell defects in a lecture at the spring of two parents with type 2 diabetes, glucose toxicity. Mount Sinai Medical Center on 9 March G6P levels similarly do not increase. The Assessing the mechanisms of insulin 2000. Insulin resistance is seen in 50–90% essential defect is in the GLUT4 glucose resistance in muscle and liver, Shulman of type 2 diabetic patients. Lebovitz sug- transporter. In liver, direct NMR measure- noted the inverse relationship between gested that the variation reflects different ment of changes in hepatic glycogen shows plasma FFA levels and insulin sensitivity. degrees of visceral obesity, which leads to an that approximately half of basal glucose Proton NMR allows measurement of increased risk of cardiovascular disease production derives from gluconeogenesis. intramyocellular triglyceride levels, which (CVD), whereas hyperglycemia is related to After a 24-h fast, basal glucose production show an even stronger inverse relationship the -cell defect. In thin (BMI 24 kg/m2) increases to 80%, and, after 48 h of fasting, with insulin sensitivity. It is worth noting patients with type 2 diabetes, insulin resis- it increases to 95% while glycogenolysis that the Randle hypothesis suggests that tance is infrequent; those patients with a decreases and the gluconeogenic rate is rel- with increasing FFA levels, there will be BMI 28 kg/m2 typically have insulin resis- atively constant. The hepatic glucose pro- increased mitochondrial acetyl CoA levels tance. Ohlson et al. (2) matched insulin- duction rate has a strong correlation with via pyruvate dehydrogenase inhibition, resistant and insulin-sensitive patients with the fasting blood glucose level. To assess the which would inhibit hexokinase via G6P the same degree of obesity, and found that driving force for hepatic glucose produc- accumulation. Contrary to expectations, fasting insulin levels were almost twice as tion in glycogenolysis versus gluconeogen- during heparin/lipid emulsion infusion to high in the former group, who also had low esis, Shulman pointed out that patients increase FFA levels and during a hyperinsu- HDL cholesterol and high triglyceride levels with type 2 diabetes have approximately linemic-hyperglycemic clamp, decreased (2). Patients with a low waist-to-hip ratio

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(WHR) infrequently have diabetes, regard- insulin sensitivity or resistance is primary, somatostatin to normal subjects for the first less of BMI, whereas both the BMI and particularly because existing treatments are 30 min of a glucose tolerance test simulates WHR show association with CVD outcome incomplete. More important, he stated, one both the initial and the subsequent pattern (3). Patients matched for total body fat lev- should ask whether both are needed for seen in individuals with impaired glucose els show increasing insulin and triglyceride type 2 diabetes. Certainly, insulin deficiency tolerance. Furthermore, studies of first- levels and decreasing HDL cholesterol levels causes diabetes, and one could always argue degree relatives more often show insulin with higher proportion of visceral fat (4). A that if -cells could respond to any present deficiency than insulin resistance. Evalua- number of measures of regional fat have degree of insulin resistance, then diabetes tion of monozygotic twins given a lifetime been proposed, including skinfold mea- would not exist. Extensive literature shows 80% diabetes concordance shows that surement, waist circumference, WHR, and that insulin resistance is present in type 2 when only one of the twins has diabetes, the computed tomography (CT) and magnetic diabetes and is only partially responsive to difference lies not in insulin sensitivity but resonance imaging (MRI) scanning. MRI glucose-lowering treatment. Both relatives in the diabetic twin having a decrease in measures of intramuscular and intrahepatic of patients with type 2 diabetes and indi- first-phase insulin release. To address the fat have the potential to be extremely use- viduals with impaired glucose tolerance questions of reversibility and determination ful, and measuring waist circumference have evidence of insulin resistance. Those of therapeutic response, Gerich suggested appears to be more useful than measuring studies following offspring of two parents that, with diet and weight loss, insulin sen- WHR (5,6). Lebovitz showed CT fat mea- with diabetes are among the most impor- sitivity can be improved, but that insulin surement studies in which intra-abdominal tant studies presently being conducted. In response shows little change. fat strongly correlated with insulin resis- one such study, Warram et al. (11) showed Scott Grundy, Dallas, TX, discussed the tance and triglyceride levels in a curvilinear that 25 of 155 such individuals developed insulin resistance syndrome on 1 June 2000 relationship in which the degree of insulin diabetes over a 13-year follow-up period. at the Mount Sinai Diabetes Conference. He resistance plateaued above a certain level. The baseline fasting insulin was two times suggested that high FFA levels may cause the Interestingly, leptin correlates more closely higher among those who did versus those syndrome; secondary increases in tissue with subcutaneous fat than with visceral who did not develop diabetes. Levels of triglyceride then affect hepatic and muscle fat. Waist circumferences 94 cm (38 first-phase insulin release were similar in the insulin sensitivity and -cell insulin pro- inches) and 80 cm (34 inches) in men and two groups, which suggests insulin resis- duction. Grundy deemed this condition the women, respectively, appear to convey the tance rather than deficiency to be the earli- “metabolic syndrome” (MS). He pointed out lowest degree of risk (7). Visceral fat consti- est abnormality. Neither fasting glucose nor that, “when it comes down to managing tutes 2.5% of body weight in insulin-sen- weight contributed significantly to the patients, [...] there is less consensus” con- sitive individuals and 4.5% of body fat in development of diabetes in multivariate cerning the components and the pathogen- insulin-resistant individuals (8,9). In analyses, suggesting that insulin deficiency esis of the syndrome, which consists of women, total body fat is 80% greater than may be the result of the underlying insulin- atherogenic dyslipidemia with high triglyc- that in men, but visceral fat mass is similar. resistant state. Other studies have shown eride, low HDL cholesterol, and small LDL Southeast Asian populations show relatively great heterogeneity between populations. particles; hypertension and insulin resis- low BMI but increased visceral fat, which Offspring of diabetic patients with high and tance with or without glucose intolerance; explains their increased risk of diabetes and low fasting insulin have higher and lower and prothrombotic and proinflammatory CVD. Thus, at a BMI of 24 kg/m2, 75% of insulin levels, suggesting the heritability of states. Grundy deemed LDL cholesterol “the individuals from such ethnic groups display insulin resistance. Gerich, however, argued primary driving force” for atherosclerosis, insulin resistance. TZDs, however, appear to that much of the insulin resistance in the but acknowledged that “once a population decrease abdominal fat by 20%, even population is due to obesity—the genetic has a certain level of LDL, other factors come though they increase total body fat by predisposition to insulin resistance actually into prominence.” In particular, an impor- 4.5% (10). Subsequently, some of the represents the genetic predisposition to obe- tant cause of artherosclerosis is abdominal benefits of TZD administration may be sim- sity. He pointed out that -cell dysfunction obesity, which leads to high plasma FFA ilar to those of metformin, which decreases is always required for the development of levels (12). The reproduction of the MS by total body and visceral fat. Lebovitz specu- diabetes; insulin resistance is not. Patients lipodystrophy further suggests abnormali- lated that visceral fat has particular adverse with type 2 diabetes have a marked ties of tissue triglyceride stores to underlie effects because of an increased release of decrease in insulin response. Gerich sug- these insulin-resistant states. Grundy FFAs, which may interfere with insulin gested that those individuals without obe- pointed out that clinical manifestations of action in both muscle and liver. sity, particularly without an excess of the MS vary in different populations. Cau- Jack Gerich, Rochester, NY, and Henry abdominal fat, have insulin sensitivity sim- casians mainly show dyslipidemia, African Ginsberg, New York, NY, debated at the ilar to that seen in control subjects, particu- populations show hypertension, Native Metropolitan Diabetes Society on 29 Feb- larly when controlling for insulin levels Americans show hyperglycemia, and South ruary 2000. Their debate focused on during “clamp” studies. He argued against Asians show both hyperglycemia and accel- whether insulin deficiency or insulin resis- the view that insulin resistance is the major erated coronary heart disease (CHD), tance is of primary importance in the genetic factor in subjects with subsequent whereas East Asian populations appear par- development of type 2 diabetes (Gerich -cell exhaustion. Gerich’s studies have tially protected. With decreased physical expressed similar ideas to those suggested shown a strong negative correlation activity resulting in increased prevalence of by Lebovitz). Ginsberg, who argued for a between the initial insulin response to glu- the syndrome, the MS is “increasingly a pre- primary role of insulin resistance, stressed cose and the degree of increase in glucose 2 h cursor of CHD and stroke.” Weight reduc- the difficulty in determining whether after an oral load. Thus, administration of tion and physical activity are primary com-

DIABETES CARE, VOLUME 23, NUMBER 10, OCTOBER 2000 1587 Perspectives on the News ponents of treatment, with the former result- agonists and metformin “must be one of the leads to increased FA uptake by intestinal ing in increased insulin sensitivity (13). most promising” approaches, with the for- epithelial cells and a two- to fourfold Moreover, surgical treatment of extreme mer agents in particular appearing to act by increase in intestinal triglyceride secretion. obesity is associated with falls in blood pres- lowering FFA levels and having triglyceride Georgopoulos showed data from a study of sure of 10 mmHg and increases in HDL and HDL effects similar to those of fibrates. 287 type 2 diabetic patients, of whom 108 cholesterol of 33% (14). Grundy showed On 20 April 2000, Angeliki Geor- and 31 were heterozygous and homozy- data that LDL cholesterol is lowered simi- gopoulos, Minneapolis, MN, spoke at the gous, respectively. Interestingly, the mutation larly with low-fat and high–monounsatu- Mount Sinai Diabetes Conference on post- in this group was associated with increased rated fat diets, but that HDL cholesterol prandial lipidemia in diabetes. Atheroscle- triglyceride and non-HDL cholesterol levels decreases and triglycerides increase with the rosis accounts for 60–75% of mortality in in a dose-related fashion. These patients low-fat but not with the high–monounsatu- patients with type 1 diabetes aged 20 showed increased postprandial triglyceride rated fat diets when both are kept at weight- years, with mortality rates 2–4 times those of as well as increased fasting levels, with the maintaining levels. Of course, the benefits of nondiabetic individuals, even when exclud- elevation mostly in chylomicron versus a high–monosaturated fat diet must be bal- ing patients with nephropathy. Despite their VLDL particles. In contrast, in nondiabetic anced with the need for weight reduction, normal fasting lipid values, they exhibit an populations and in patients with type 1 dia- which is more readily achieved with atherogenic state. “Maybe,” she suggested, betes, fasting lipid levels are not increased, hypocaloric diets not containing monoun- “there are hidden factors,” recalling the sug- although postprandial lipids have not been saturated fats. While discussing proinflam- gestion of Zilversmit in the 1970s that thoroughly studied. matory factors, which Grundy considered to atherogenesis is a postprandial phenomenon Mitchell Roslin, New York, NY, dis- be “intriguing and not fully understood,” he (17), because patients with diabetes spend cussed surgical treatment of obesity at mentioned that obesity itself may be proin- most of the day in the postprandial state. Mount Sinai on 17 February 2000. Obesity flammatory and that markers of inflamma- Epidemiological data support the association surgery has become a successful approach tion are associated with CHD (15). C-reac- with atherosclerosis of triglyceride-rich to treatment, with two approaches having tive protein levels have an additive risk to lipoproteins derived from chylomicrons. been used. The induction of malabsorption that of increasing the cholesterol-to-HDL Chyomicron remnants produce greater with jejeunoileal bypass was initially rec- ratio (16). Grundy suggested that vitamin E macrophage uptake in the sterol-loaded ommended, but caused hepatic dysfunc- may be useful for treatment of both the pro- state via specific receptors, the LDL-related tion. Currently, obesity is treated with thrombotic and the proinflammatory state. protein receptors, which account for gastric restriction surgery, which Roslin There may be a role of antibiotic treatment approximately half of chylomicron uptake. described as “taking a 20-gallon tank and for the latter, based on the concept of infec- Plasmapheresis of patients with type 1 dia- making a 2-gallon tank.” Gastric surgery tion in the arterial wall. Statins are important betes after fat loading shows that they pro- approaches include vertical-banded gastro- in patients with the MS and high LDL levels, duce particles with decreased uptake of plasty, which is associated with a 25–30% and recent studies suggest that pravastatin both chylomicrons and remnants due to failure rate and causes fixed obstruction lowers C-reactive protein levels as well. decreased tissue uptake rather than with the potential for esophageal dysmotil- Fibrates act on PPAR-, regulate hepatic decreased lipolysis. The remnant particles ity syndromes, and gastric bypass, which he nuclear factor-4, and decrease apolipopro- have increased cholesterol and decreased recommended as being the best method tein (apo) C3 synthesis, which leads to phospholipids. Furthermore, incubation of currently used. Both open and laparoscopic increased VLDL catabolism. The Helsinki macrophages with the particles isolated approaches are used, and somewhat higher Heart Study showed that gemfibrozil from patients with type 1 diabetes shows complication approaches have been reduced CHD end points in patients with increased cholesterol ester accumulation; the described with the latter. Gastric restriction hypertriglyceridemia. Furthermore, the VA- process of lipid uptake lasts 7 h rather results in a form of “forced behavior modi- HIT (Veterans Affairs Cooperative Studies than peaking at 4 h in nondiabetic control fication”—the ingestion of anything more Program–High-Density Lipoprotein Choles- subjects. Low-fat diets and statins are help- than a small meal causes nausea and vom- terol Intervention Trial) studied “perfect ful in treating type 1 diabetes, although the iting. Maximal weight loss is observed at examples of the MS” and was able to question of whether postprandial lipids 6–9 months, with half-maximal weight loss increase HDL cholesterol levels by 7.5% and should specifically be measured and treated maintained at a 10-year follow-up. Fur- lower triglyceride levels by 24.5% with a has not been addressed. In type 2 diabetes, thermore, comparison of operated versus 21–27% decrease in CHD and stroke over dyslipidemia, obesity, and abnormal post- nonoperated patients indicated marked the 7-year study period. Grundy suggested prandial lipids are present with increased reduction in mortality and improvement in that in patients with type IIb dyslipidemia, VLDL production, perhaps because of emotional as well as medical status with administration of fenofibrates may be more increased FFA and glucose levels. Geor- treatment. Roslin noted the importance of effective than statins and that statin-gemfi- gopoulos addressed the question of whether vagal afferent impulses in satiety, recalling brozil combination treatment “could prove there is increased intestinal triglyceride-rich the observation that vagotomy prevents the [to be] a rational approach.” Given the 1% lipid production by studying the common decrease in food intake caused by cholecys- risk of myositis, however, caution is needed. genetic abnormality of fatty acid binding tokinin in animal models. Vagal nerve stim- He also stated that “the results look very protein 2. This 15-kDa protein binds long- ulation is currently used clinically for the good” for low-dose niacin in combination chain fatty acids and is only found in the treatment of seizure disorders. Roslin with statins, although there is potential for intestine. The Ala54→Thr mutation is pres- showed the results of studies of chronic hyperglycemia in diabetic patients. Finally, ent in one-third of the normal population, bilateral vagal nerve stimulation in dogs, treatment of insulin resistance with PPAR- having 10% homozygosity. This mutation which showed a decrease in food intake and

1588 DIABETES CARE, VOLUME 23, NUMBER 10, OCTOBER 2000 Bloomgarden

thereby suggested a potential use for treat- both vascular smooth muscle cells and cause release of free radicals. Plasma AGE- ing obesity. macrophages and is upregulated in vascular apoB correlates with arterial tissue AGE in Willa Hsueh, Los Angeles, CA, spoke on cells of injured tissue. PPAR- ligands nondiabetic individuals with atherosclerosis. insulin resistance and vascular disease at inhibit platelet-derived growth factor– In diabetic patients, skin biopsy shows Mount Sinai on 27 January 2000. Increased induced migration in coronary increased collagen AGE-links to correlate plasminogen activator inhibitor-1 (PAI-1) is artery smooth muscle cells and TZD con- with retinopathy and nephropathy. Thus, seen with increasing degrees of insulin resis- centrations similar to those achieved by oral diabetes increases a process already patho- tance, and both insulin and angiotensin lev- treatment. MAPK phosphorylation of tran- genic in individuals without diabetes. AGEs els are associated with levels of PAI-1, which scription factors are inhibited by TZD, lead- can cause irreversible cross-linking, oxida- is produced locally in sites of atherosclerotic ing to decreased growth and migration, tive changes, changes in enzyme activities, vascular disease. Thus, the question con- whereas TZD does not inhibit MAPK path- production of reactive oxygen species, cerning the role of hyperinsulinemia in the way activation per se. Furthermore, TZD impairment of antioxidant systems, inacti- atherosclerotic process arises. Hsueh recalled does not affect phosphorylation of myosin vation of nitric oxide, DNA modification, the two major cellular pathways of insulin light chains. Pretreatment of animals with and cellular inflammatory effects by means action. The first pathway involves IRS 1–4 troglitazone 4 days before balloon injury of of cytokine induction. Two metabolic dis- and leads to PI3K activation, in turn result- the aorta results in a decrease in intimal posal mechanisms are available for AGEs ing in glucose metabolism, particularly with hyperplasia. A study with intravascular (either cycling to “glycotoxins” or the pro- increased glucose transport. Endothelial ultrasound showed that 14 patients under- duction of nonreactive AGEs), which are nitric oxide synthetase (NOS) activation also going angioplasty who were treated with excreted in the kidneys, with renal impair- involves this pathway, which is potentially troglitazone had 28% intimal hyperplasia at ment leading to accumulation of these prod- an antiatherosclerotic process. The other 6 months, whereas 12 patients who were ucts and AGE peptides that displayed pathway leads to activation of mitogen-acti- not treated with troglitazone had 49% toxicity to collagen and LDL. AGE adminis- vated protein kinase (MAPK), which leads to hyperplasia. Hsueh noted that the initiation tration in animal models has effects similar a variety of anabolic effects. These effects of atherosclerosis involves both LDL entry to cholesterol feeding (increased aortic inti- include vascular smooth muscle growth and and oxidation and an inflammatory com- mal width and fat content); lipids and AGEs production of PAI-1, the vasoconstrictor ponent of monocyte adherence, which leads together cause additional effects. Thus, a endothelin, and a number of chemoattrac- to uptake into the vessel wall. A study in her number of disease states, including diabetes, tants that potentially act in a proatheroscle- laboratory showed that a PPAR- ligand dyslipidemia, and renal insufficiency, inter- rotic fashion. Insulin resistance is defined by inhibited migration of monocytes, another act with the effects of AGEs. Another impor- the defect in the glucose metabolism arm of MAPK-modulated process. With high-fat tant factor is cigarette smoking, which the first pathway, but this association does and high-fructose diet models of athero- increases serum and tissue AGE levels. Cur- not imply resistance in the proatherosclerotic sclerosis, troglitazone attenuated lesion ing of tobacco involves drying under heat in pathway. Insulin sensitizers, such as the formation and decreased macrocyte infil- the presence of sugar, which results in a TZDs, turn on glucose metabolism, and a tration. Troglitazone also inhibited the very high AGE content when ingested. AGE- number of studies suggest increased NOS MAPK-directed process of vascular prolifer- modified LDL levels double with tobacco activity with this treatment. Individuals ation under stimulation by vascular use. AGE content of food similarly increases with insulin resistance show a defect in endothelial growth factor and is being stud- with broiling and, to a lesser extent, baking endothelial NOS, which further supports ied in models of proliferative retinopathy. or frying, though not as markedly with boil- this concept. Helen Vlassara discussed the develop- ing or steaming. Cooked meats show the Steps involved in macrophage migra- ment of glycation, an aspect of the bio- highest AGE content. Approximately 10% of tion into the arterial wall include attach- chemistry of glucose toxicity, at Mount Sinai dietary AGEs are absorbed, of which 65% is ment, which doesn’t involve MAPK; on 14 October 1999 and 16 March 2000, retained in individuals without diabetes and locomotion, which involves MAPK phos- stressing that the Diabetes Control and 97% is retained in individuals with both dia- phorylation of myosin light-chain kinase in Complications Trial showed that “glucose betes and renal insufficiency. Low dietary the cytosol; and invasion, which appears to itself always plays a major role” in organ AGEs prevent the development of renal dis- be a MAPK-related pathway involving met- damage in diabetes. Though it was not ease in animal models of diabetes and lower alloproteinase activation. Antisense directly related to obesity and adiposity, this serum AGE levels in humans; they may nucleotides for several MAPKs inhibit their line of inquiry has fascinating implications prove to offer important therapeutic benefits. expression and the migration of vascular for a new approach to dietary treatment of smooth muscle cells. Similarly, the agent diabetes. Glycation and glycoxidation are PD98059 inhibits MAPK pathway activa- continuous processes based on the reversible References tion and vascular cell migration. Hsueh binding of glucose to amino groups, thereby 1. Pan DA, Lillioja S, Kriketos AD, Milner showed that both of these approaches block leading to the reversible formation of Schiff MR, Baur LA, Bogardus C, Jenkins AB, the growth-promoting action of insulin on bases, the more slowly reversible formation Storlien LH: Skeletal muscle triglyceride the vasculature. The TZDs activate the of Amadori products, and the irreversible levels are inversely related to insulin action. Diabetes 46:983–988, 1997 nuclear PPAR-–RXR heterodimer. Both formation of advanced glycation end prod- 2. Ohlson LO, Larsson B, Svardsudd K, Welin PPAR- and RXR- mRNA are present in ucts (AGEs). AGEs “contain a myriad of L, Eriksson H, Wilhelmsen L, Bjorntorp P, macrophages and vascular endothelial and chemical structures.” These involve amino Tibblin G: The influence of body fat distri- smooth muscle cells. PPAR- is also groups of proteins, as well as phospholipid bution on the incidence of diabetes mellitus: expressed in human coronary lesions in AGEs, which initiate lipid oxidation and 13.5 years of follow-up of the participants in

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