Barbara C. Hansen

A selective peroxisome proliferator-activated receptor δ agonist promotes reverse cholesterol transport

The peroxisome proliferator-activated receptors (PPARs) are dietary lipid sensors that regulate fatty acid and carbohydrate metabolism. The hypolipidemic effects of the fibrate drugs and the antidiabetic effects of the glitazone drugs in humans are due to activation of the α (NR1C1) and γ (NR1C3) subtypes, respectively. By contrast, the therapeutic potential of the δ (NR1C2) subtype is unknown, due in part to the lack of selective ligands. We have used combinatorial chemistry and structure-based drug design to develop a potent and subtype-selective PPARδ agonist, GW501516. In macrophages, fibroblasts, and intestinal cells, GW501516 increases expression of the reverse cholesterol transporter ATP-binding cassette A1 and induces apolipoprotein A1-specific cholesterol efflux. When dosed to insulin-resistant middle-aged obese rhesus monkeys, GW501516 causes a dramatic dose-dependent rise in serum high density lipoprotein cholesterol while lowering the levels of small-dense low density lipoprotein, fasting triglycerides, and fasting insulin. Our results suggest that PPARδ agonists may be effective drugs to increase reverse cholesterol transport and decrease cardiovascular disease associated with the metabolic syndrome X.

A 50,000-Year Record of Climate Oscillations from Florida and Its Temporal Correlation with the Heinrich Events

Oscillations of Pinus (pine) pollen in a 50,000-year sequence from Lake Tulane, Florida, indicate that there were major vegetation shifts during the last glacial cycle. Episodes of abundant Pinus populations indicate a climate that was more wet than intervening phases dominated by Quercus (oak) and Ambrosia-type (ragweed and marsh-elder). The Pinus episodes seem to be temporally correlated with the North Atlantic Heinrich events, which were massive, periodic advances of ice streams from the eastern margin of the Laurentide Ice Sheet. Possible links between the Tulane Pinus and Heinrich events include hemispheric cooling, the influences of Mississippi meltwater on sea-surface temperatures in the Gulf of Mexico, and the effects of North Atlantic thermohaline circulation on currents in the Gulf.

Vegetation and environment in Eastern North America during the Last Glacial Maximum

Abstract Knowledge of the vegetation and environment of eastern North America during the Last Glacial Maximum (LGM) is important to understanding postglacial vegetational and biogeographic dynamics, assessing climate sensitivity, and constraining and evaluating earth-system models. Our understanding of LGM conditions in the region has been hampered by low site density, problems of data quality (particularly dating), and the possibility that LGM vegetation and climate lacked modern analogs. In order to generate improved reconstructions of LGM vegetation and environment, we assembled pollen and plant macrofossil data from 21 and 17 well-dated LGM sites, respectively. All sites have assemblages within the LGM timespan of 21,000±1500 calendar yr BP. Based on these data, we prepared maps of isopolls, macrofossil presence/absence, pollen-analogs, biomes, inferred mean January and July temperatures and mean annual precipitation for the LGM. Tundra and open Picea -dominated forest grew along the Laurentide ice sheet, with tundra predominantly in the west. In the east, Pinus -dominated vegetation (mainly P. banksiana with local P. resinosa and P. strobus ) occurred extensively to 34°N and possibly as far south as 30°N. Picea glauca and a now-extinct species, P. critchfieldii , occurred locally. Picea -dominated forest grew in the continental interior, with temperate hardwoods ( Quercus , Carya , Juglans , Liriodendron , Fagus , Ulmus ) growing locally near the Lower Mississippi Valley at least as far north as 35°N. Picea critchfieldii was the dominant species in this region. The Florida peninsula was occupied by open vegetation with warm-temperate species of Pinus . Eastern Texas was occupied by open vegetation with at least local Quercus and Picea . Extensive areas of peninsular Florida and the continental interior had vegetation unmatched by any modern pollen samples. The paleovegetational data indicate more extensive cooling in eastern North America at the LGM than simulated by either the NCAR CCM0 or CCM1 climate models. The occurrence of cool-temperate conifers and hardwoods as far north as 34-35°N, however, indicates less severe cooling than some previous reconstructions. Paleoclimate inferences for the LGM are complicated by lowered atmospheric CO 2 concentrations, which may be responsible for the open nature and dominance of conifers in LGM vegetation.

Prevention Conference VII Obesity, a Worldwide Epidemic Related to Heart Disease and Stroke: Group III: Worldwide Comorbidities of Obesity

Current concerns about the increased risk of cardiovascular and other diseases induced by excessive weight gain in children and adults have been highlighted by the Surgeon General’s report on the problem of obesity in the United States.1 This call to action followed a global analysis of the problem of excess weight and how to define and combat it that was undertaken by the World Health Organization (WHO) in 19972 and an analogous National Institutes of Health (NIH) assessment and reclassification of US rates of overweight and obesity in 1998.3 It is generally accepted that body mass index (BMI), or weight in kilograms per square meter of height, is a convenient measure of an approximate height-independent index of both children and adults’ weight for height and provides a crude indication of the body’s fat content. It is becoming clear that different ethnic groups have different proportions of fat-to-lean tissues at equivalent BMIs4,5 and that the magnitude of the multiple comorbidities associated with higher BMIs also may differ among different ethnic groups for reasons that may reflect the impact of environmental–genetic interactions. Nevertheless, current international comparisons use a standard format and classification system. In all societies a spectrum of BMIs exists for children and adults of all ages. Individual positions within the percentile range tend to remain the same as children grow and adults steadily gain weight. As the average weight of children and adults increases, so does the spread of BMIs, with a marked progressive increase in the numbers with very high BMIs (see Figure 1). Thus, the escalation in obesity rates reflects the upward shift in body weights of the whole population in response to environmental changes. Adults with a BMI of 18.5 to 24.9 are categorized as being of normal weight, on the basis of …

Low Urinary chiro-Inositol Excretion in Non-Insulin-Dependent Diabetes Mellitus

BACKGROUND AND METHODS Inositol is a major component of the intracellular mediators of insulin action. To investigate the possible role of altered inositol metabolism in non-insulin-dependent diabetes mellitus (NIDDM), we used gas chromatography and mass spectrometry to measure the myo-inositol and chiro-inositol content of urine specimens from normal subjects and patients with NIDDM: The study subjects were whites, blacks, and Pima Indians. The type of inositol and its concentration in insulin-mediator preparations from muscle-biopsy specimens from normal subjects and diabetic patients were also determined. RESULTS The urinary excretion of chiro-inositol was much lower in the patients with NIDDM (mean [+/- SE], 1.8 +/- 0.8 mumol per day) than in the normal subjects (mean, 84.9 +/- 26.9 mumol per day; P less than 0.01). In contrast, the mean urinary myo-inositol excretion was higher in the diabetic patients than in the normal subjects (444 +/- 135 vs. 176 +/- 46 mumol per day; P less than 0.05). There was no correlation between chiro-inositol excretion and the age, sex, or weight of the diabetic patients, nor was there any correlation between urinary chiro-inositol and myo-inositol excretion in either group. The results were similar in a primate model of NIDDM, and chiro-inositol excretion was decreased to a lesser extent in animals with prediabetic insulin resistance. chiro-Inositol was undetectable in insulin-mediator preparations from muscle-biopsy samples obtained from patients with NIDDM: Similar preparations from normal subjects contained substantial amounts of chiro-inositol. Furthermore, the chiro-inositol content of such preparations increased after the administration of insulin during euglycemic-hyperinsulinemic-clamp studies in normal subjects but not in patients with NIDDM: CONCLUSIONS NIDDM is associated with decreased chiro-inositol excretion and decreased chiro-inositol content in muscle. These abnormalities seem to reflect the presence of insulin resistance in NIDDM:

The metabolic syndrome X.

The Metabolic Syndrome X is a “work-in-progress,” with its chosen designation, features, causes, and treatments all in a dynamic period of expanded thinking and investigation. In the late 1940s and early 1950s, Jean Vague presented a series of reports on the sexual differentiation of obesity and its consequences. He identified the masculine form of abdominal obesity as carrying a particular predisposition to diabetes, atherosclerosis, gout, and uric calculous disease, and when he addressed the Fifth International Congress on Obesity in 1987, he reviewed the progress of what he then termed “diabetogenic obesity.”1–5 As early as the 1960s, the link with cardiovascular disease was made by Welborn and others.6,7 Camus was another early observer of these associations, and in 1966 he identified the “trisyndrome métabolique” to include goutte, diabéte, and hyperlipémie.8 In reporting on two population studies in Finland in 1979, Pyörälä also showed strong links between glucose intolerance, hyperinsulinemia, and coronary heart disease.9 In the 1980s, Modan and associates extended the link between symptoms of obesity, hypertension, and cardiovascular disease,10,11 and included elevated serum uric acid as a facet of insulin resistance. A strong association between the Metabolic Syndrome X and coronary heart disease continues to be observed, even in the absence of diabetes,12 and the link of elevated serum uric acid as a component of the Syndrome contributing to increased cardiovascular disease mortality has also recently been confirmed.13,14 Reaven brought special attention to this group of frequently associated disorders when, in his Banting Lecture to the American Diabetes Association, he labeled it “Syndrome X.”15 He included as major characteristics hypertension, impaired glucose metabolism, impaired lipid metabolism, and insulin resistance. Insulin resistance was also cited as the central feature of this syndrome by others, including Foster,16 and DeFronzo and Ferrannini.17 Further, hyperinsulinemia and impaired insulin action, obesity, and dyslipidemia were found to be both familial and predictive of Type 2 diabetes onset.18 “Diabesity” was the term preferred by Shafrir in discussing the consequences of insulin resistance as gleaned from animal models,19 and as described by Ethan Sims. Others have referred to it as the metabolic syndrome (e.g., refs. 20 and 21), noting the relationship of metabolism to many of the features. Other names have also been coined for this cluster of symptoms carrying increased risk of morbidity and premature mortality, as shown in TABLE 1.

Heterogeneity of insulin responses: phases leading to Type 2 (non-insulin-dependent) diabetes mellitus in the rhesus monkey

SummaryTo determine the natural history of the development of Type 2 (non-insulin-dependent) diabetes mellitus, basal plasma insulin and glucose levels and responses to intravenous glucose tolerance tests were determined over a period of 6 years in 42 adult male rhesus monkeys (Macaca mulatta). Among the 28 obese monkeys (percent body fat > 22%) over the age of 10 years, 9 developed overt Type 2 diabetes (fasting plasma glucose, > 7.8 mmol/l; and reduced glucose disappearance rates, KG < 1.5), and 14 monkeys have shown progressive changes which suggest that they may also become diabetic. Application of a highly constant antecedent diet and a consistent 16-h fast minimized experimental variability, and permitted the identification of 8 phases in the progression from normal lean young adult to overt Type 2 diabetes. The earliest changes which could be detected were a slight increase followed by a progressive rise in fasting plasma insulin levels and an increased insulin secretion in response to a glucose stimulus. These events preceded by several years the onset of a gradual deterioration of glucose tolerance. We found that hyper-, normo-, or hypoinsulinaemia could be associated with normoglycaemia or varying degrees of hyperglycaemia; however, the prospective longitudinal study of individual monkeys clearly identified this apparent heterogeneity of plasma insulin and glucose levels as reflecting sequential changes in a continuum of events preceding or accompanying the development of impaired glucose tolerance and Type 2 diabetes mellitus.

Clinical Management of Metabolic Syndrome Report of the American Heart Association/National Heart, Lung, and Blood Institute/American Diabetes Association Conference on Scientific Issues Related to Management

The National Cholesterol Education Program’s Adult Treatment Panel III report (ATP III)1 identified the metabolic syndrome as a multiplex risk factor for cardiovascular disease (CVD) that is deserving of more clinical attention. Subsequently, the National Heart, Lung, and Blood Institute (NHLBI), in collaboration with the American Heart Association (AHA), convened a conference to examine scientific issues related to definition of the metabolic syndrome.2 The present report summarizes a second conference devoted to clinical management of the metabolic syndrome, which was sponsored by the AHA in partnership with the NHLBI and cosponsored by the American Diabetes Association (ADA). This latter conference considered the following issues: (1) pathogenesis and presentation of the metabolic syndrome, (2) management of underlying risk factors, (3) management of metabolic risk factors, and (4) unresolved issues and research challenges. The conference on definition2 confirmed CVD as a major clinical outcome of metabolic syndrome and identified 6 major components of the syndrome: abdominal obesity, atherogenic dyslipidemia, elevated blood pressure, insulin resistance ± glucose intolerance, a proinflammatory state, and a prothrombotic state. The follow-up conference on management was structured around therapies for these components. Clinical recognition of the metabolic syndrome is generally based on finding several well-recognized signs in clinical practice: abdominal obesity, elevated triglycerides, reduced HDL cholesterol, raised blood pressure, and elevated plasma glucose. In addition, research shows that other components not routinely measured commonly aggregate with the major components: elevated apolipoprotein B, small LDL particles, insulin resistance and hyperinsulinemia, impaired glucose tolerance (IGT), elevated C-reactive protein (CRP), and variation in coagulation factors (eg, plasminogen activator inhibitor [PAI]-1 and fibrinogen). The conference on definition2 also emphasized that risk for type 2 diabetes is higher in persons with metabolic syndrome and that diabetes is a major risk factor for CVD. It also examined various criteria for …

Diabetes mellitus in Macaca mulatta monkeys is characterised by islet amyloidosis and reduction in beta-cell population

SummaryDiabetes mellitus in Macaca mulatta rhesus monkeys is preceded by phases of obesity and hyperinsulinaemia and is similar to Type 2 (non-insulin-dependent) diabetes mellitus in man. To relate the progression of the disease to quantitative changes in islet morphology, post-mortem pancreatic tissue from 26 monkeys was examined. Four groups of animals were studied: group I — young, lean and normal (n=3); group II — older (>10 years), lean and obese, normoglycaemic (n=9); group III — normoglycaemic and hyperinsulinaemic (n=6); group IV — diabetic (n=8). Areas of islet amyloid, beta cells and islets were measured on stained histological sections. Islet size was larger in animals from groups III (p<0.01) and IV (p<0.0001) compared to groups I and II. The mean beta-cell area per islet in Μm2 was increased in group III (p<0.05) and reduced in group IV (p<0.001) compared to groups I and II. Mean beta-cell area per islet correlated with fasting plasma insulin (r=0.76, p<0.001) suggesting that hyper- and hypoinsulinaemia are related to the beta-cell population. Amyloid was absent in group I but small deposits were present in three of nine (group II) and in four of six (group III) animals, occupying between 0.03–45% of the islet space. Amyloid was present in eight of eight diabetic animals (group IV) occupying between 37–81% of the islet area. Every islet was affected in seven of eight diabetic monkeys. There was no correlation of degree of amyloidosis with age, body weight, body fat proportion or fasting insulin. Islet amyloid appears to precede the development of overt diabetes in Macaca mulatta and is likely to be a factor in the destruction of islet cells and onset of hyperglycaemia.

Primary Prevention of Diabetes Mellitus by Prevention of Obesity in Monkeys

Many, but not all, adult rhesus monkeys spontaneously develop significant increases in body fat mass, and many, but not all, progress to develop overt adult-onset type II diabetes. The purpose of this study was to determine whether both an increase in body fat and onset of diabetes could be simultaneously prevented through long-term maintenance of stable normal adult body weight by caloric titration. Eight adult male monkeys were provided a complete normal chow diet, but with daily amounts restricted and titrated on a weekly basis to maintain a constant body weight (weight-stabilized group). This regimen has been continued for 5–9 yr (mean ± SD of 7 ± 0.5 yr) with monkeys attaining the age of 17.9 ± 0.6 yr and with maintenance of normal body fat (17.7 ± 1.8%). The age-matched ad libitum fed group (18.1 ± 0.2 yr of age) consisted of 19 monkeys maintained under identical laboratory conditions and diet, but with food available ad libitum. Results showed weight-stabilized monkeys weighed significantly < ad libitum fed monkeys (10.4 ± 0.2 vs. 16.1 ± 0.7 kg, respectively, P < 0.05) and had significantly better glucose tolerance as measured by Kglucose (glucose disappearance rate) (3.9 ± 0.3 vs. 2.4 ± 0.2, P ± 0.05). Of the 19 ad libitum fed age-matched monkeys, 4 were overtly diabetic, and 6 others had significantly reduced glucose tolerance. Hyperinsulinemia did not develop in the weight-stabilized group, and β-cell response to glucose remained normal; both were significantly different from the exaggerated levels of the ad libitum fed group (P < 0.05). This form of obesity-associated type II diabetes and impaired glucose tolerance, thus, appears to be completely prevented or onset indefinitely delayed by sustained caloric restriction and maintenance of normal body composition.