Total and high-molecular-weight adiponectin and risk of incident diabetes in older people

OBJECTIVE

To delineate the associations of total adiponectin, high-molecular-weight (HMW) adiponectin, and the HMW-to-total adiponectin ratio with diabetes in older adults.

RESEARCH DESIGN AND METHODS

Total and HMW adiponectin were measured in a population-based study of older adults. The relations of total adiponectin, HMW adiponectin, and their ratio with incident diabetes (n = 309) were assessed in 3,802 individuals.

RESULTS

Total and HMW adiponectin were highly correlated (r = 0.94). Analysis using cubic splines revealed that the associations between total and HMW adiponectin and new-onset diabetes were not linear. Specifically, after adjustment for confounders, there were similar inverse relationships for total (hazard ratio per SD 0.49 [95% CI 0.39–0.63]) and HMW adiponectin (0.42 [0.32–0.56]) with diabetes up to values of 20 and 10 mg/L, respectively, above which the associations plateaued. These associations persisted after adjustment for potential mediators (blood pressure, lipids, C-reactive protein, and homeostasis model assessment of insulin resistance [HOMA-IR]). There was, however, evidence of interaction by HOMA-IR in the lower range of adiponectin, with stronger inverse associations among insulin-sensitive than insulin-resistant participants. HMW-to-total adiponectin ratio showed a linear adjusted association with outcome, but this was abolished by inclusion of mediating variables.

CONCLUSIONS

In this older cohort, increasing concentrations of total and HMW adiponectin were associated with comparably lower risks of diabetes, but these associations leveled off with further increases above concentrations of 20 and 10 mg/L, respectively. The more pronounced risk decreases at the lower range among participants without insulin resistance support a role for adiponectin that is independent of baseline hyperinsulinemia, but this will require further investigation.The widening epidemic of type 2 diabetes poses a major challenge to the public health (1). Although the increasing burden of diabetes in the U.S. has been borne by adults in all age categories, the greatest share has fallen upon the older segment, with nearly one-third of adults aged ≥65 years affected (1,2). As in younger age groups, the prevalence of dysglycemia in elders has risen in tandem with excess adiposity, yet the proportion of older adults with diabetes who are overweight or obese is more modest (3). This has led to the concept that diabetes in older adults may have different pathophysiologic features, with a greater role for impaired pancreatic insulin secretion relative to the obesity-associated insulin resistance that predominates in diabetes occurring earlier in life (3).Still, the prevailing link between adiposity and diabetes across the age spectrum has focused attention on the role of various bioactive peptides secreted by adipocytes as potential mediators of obesity-associated dysglycemia (4). Of these adipokines, adiponectin circulates in concentrations three orders of magnitude greater than any other, although plasma levels of adiponectin exhibit a paradoxic decline with increasing adiposity (5). In animal models, elimination of adiponectin production leads to insulin resistance, whereas repletion of adiponectin restores insulin sensitivity (6). Acting through cognate receptors, adiponectin stimulates AMP-activated protein kinase and peroxisome-proliferator activated receptor-α (PPAR-α) to promote fatty acid catabolism and enhance insulin sensitivity in the liver and skeletal muscle (6). The strongest insulin-sensitizing actions appear to reside with the high-molecular-weight (HMW) fraction of adiponectin, which increases preferentially in response to PPAR-γ agonists and may mediate the insulin-sensitizing effects of these agents (7). Yet adiponectin also influences the function of pancreatic β-cells, and its antiapoptotic actions on such cells could contribute to its favorable glycometabolic properties (8).Consistent with preclinical investigations, a meta-analysis of prospective epidemiologic studies demonstrated an inverse association between total circulating adiponectin levels and incident diabetes (9). This systematic review reported that the association tended to be stronger for younger than older adults, based principally on two published studies (10,11) focusing on older people, although effect-measure modification by age was not significant. Fewer prospective studies (12–14) have evaluated the association for HMW adiponectin, documenting similar protective associations as for total adiponectin, but no study to date has addressed this question longitudinally in an older population. We sought to examine in detail the relative associations of HMW and total adiponectin, as well as their ratio (7), with diabetes incidence in a prospective cohort of older adults, in order to determine the extent to which findings from middle-aged cohorts apply to older individuals.     

Lipoprotein-associated phospholipase A(2) mass and activity and risk of cardiovascular disease in a population with high prevalences of obesity and diabetes: the Strong Heart Study

OBJECTIVE

To investigate the association of lipoprotein-associated phospholipase A₂ (LpPLA₂) mass and activity with incident cardiovascular disease (CVD) in a population with high prevalences of insulin resistance and diabetes, conditions for which epidemiological data remain sparse.

RESEARCH DESIGN AND METHODS

We conducted a nested, case-control study (n = 1,008) within a population-based cohort of American Indians. Case subjects were defined by incidence of first-ever CVD up to 10 years later. Control subjects comprised participants free of CVD events during the follow-up period who were frequency matched to case subjects by age, sex, and diabetes status. LpPLA₂ mass and activity were measured using commercially available assays.

RESULTS

LpPLA₂ mass and activity were moderately correlated with each other (r = 0.30), but only LpPLA₂ activity exhibited moderate correlations with lipid fractions. After extensive adjustment for covariates, both LpPLA₂ measures were significantly associated with incident CVD, but the relationship was inverse for LpPLA₂ mass (highest versus lowest tertile, relative risk [RR] 0.55 [95% CI 0.39–0.79]) and positive for LpPLA₂ activity (highest versus lowest tertile, 1.65 [1.12–2.42]). These associations were similar when participants with and without diabetes were examined separately.

CONCLUSIONS

In this population-based cohort enriched with dysmetabolic phenotypes, LpPLA₂ mass and activity showed divergent associations with CVD. The inverse relationship for LpPLA₂ mass is contrary to observations from predominantly nondiabetic populations and will require independent replication. Whether this finding relates to redistribution of LpPLA₂ to lipoprotein classes where it is less atherogenic or reflects incomplete measurement of LpPLA₂ mass associated with altered lipoprotein composition in insulin resistance warrants further investigation.Recognition of the seminal role of inflammation in atherogenesis (1) has led to a search for key molecular drivers of the vascular inflammatory response as potential therapeutic targets or markers of prognosis in at-risk individuals. One such candidate is the enzyme lipoprotein-associated phospholipase A₂ (LpPLA₂), a secretory product of inflammatory cells that binds primarily to apolipoprotein B–containing lipoproteins such as LDL (2). Because excess LDL accumulates within the subendothelial space during atherogenesis, LpPLA₂ function may have particular specificity for inflammation within the vascular compartment (3).LpPLA₂ catalyzes the hydrolysis of oxidized phospholipids to lysophosphatidyl choline and oxidized, nonesterified fatty acids, mediators that can trigger inflammatory cell activation and retard clearance of apoptotic cells within the atheroma’s necrotic core (4). Such proinflammatory actions would act to foster progression of atherosclerosis and plaque instability (4). The pathophysiologic role of LpPLA₂ in atherosclerosis remains controversial, however, because the enzyme’s removal of proatherogenic oxidized phospholipids can itself have an atheroprotective effect (3). Moreover, in vitro LpPLA₂ can also hydrolyze platelet-activating factor (PAF), which is a potent mediator of thrombotic, allergic, and inflammatory responses (3). Although degradation of PAF would serve an anti-inflammatory function, the extent to which LpPLA₂ can effect PAF breakdown in vivo remains uncertain (3,4).Against such experimental observations is a large body of epidemiological studies that have predominantly found a positive association between LpPLA₂ mass and activity and cardiovascular outcomes (5). Few studies to date, however, have addressed the link between LpPLA₂ and clinical events in populations with high prevalences of insulin resistance and diabetes, disorders where vascular inflammation and oxidative stress are particularly pronounced (6). We examined the relations between LpPLA₂ mass and activity and incident cardiovascular disease (CVD) in a population-based cohort of American Indians enriched with dysmetabolic phenotypes.     

GTP-binding proteins inhibit cAMP activation of chloride channels in cystic fibrosis airway epithelial cells.

Cystic fibrosis (CF) is a genetic disease characterized, in part, by defective regulation of Cl- secretion by airway epithelial cells. In CF, cAMP does not activate Cl- channels in the apical membrane of airway epithelial cells. We report here whole-cell patch-clamp studies demonstrating that pertussis toxin, which uncouples heterotrimeric GTP-binding proteins (G proteins) from their receptors, and guanosine 5'-[beta-thio]diphosphate, which prevents G proteins from interacting with their effectors, increase Cl- currents and restore cAMP-activated Cl- currents in airway epithelial cells isolated from CF patients. In contrast, the G protein activators guanosine 5'-[gamma-thio]triphosphate and AlF4- reduce Cl- currents and inhibit cAMP from activating Cl- currents in normal airway epithelial cells. In CF cells treated with pertussis toxin or guanosine 5'-[beta-thio]diphosphate and in normal cells, cAMP activates a Cl- conductance that has properties similar to CF transmembrane-conductance regulator Cl- channels. We conclude that heterotrimeric G proteins inhibit cAMP-activated Cl- currents in airway epithelial cells and that modulation of the inhibitory G protein signaling pathway may have the therapeutic potential for improving cAMP-activated Cl- secretion in CF.     

Pesticide food poisoning from contaminated watermelons in California, 1985

Aldicarb, a carbamate pesticide, is the most potent pesticide in the market and has a LD50 of 1 mg/kg. In the United States it is illegal to use aldicarb on certain crops, e.g., watermelons, because it is incorporated into the flesh of the fruit. Once an accidental or illegal use of such a potent pesticide occurs, there is no easy way for the agricultural or public health system to protect the populace. This paper describes the impact of one such event upon the health of individuals and the institutions of California. On July 4, 1985, California and other western states experienced the largest known outbreak of food-borne pesticide illness ever to occur in North America. This was attributed to watermelons contaminated through the illegal or accidental use of aldicarb by a few farmers in one part of the state. Within California, a total of 1,376 illnesses resulting from consumption of watermelons was reported to the California Department of Health Services (CDHS). Of the 1,376 illnesses, 77% were classified as being probable or possible carbamate illnesses. Many of the case reports involved multiple illnesses associated with the same melon among unrelated individuals. Seventeen individuals required hospitalization. There were 47 reports of illness involving pregnant women, two of whom reported having subsequent stillbirths. Thirty-five of the remaining pregnant women were followed-up 9 mo after the epidemic; no additional stillbirths were found.(ABSTRACT TRUNCATED AT 250 WORDS)     

Problems associated with the use of immediately dangerous to life and health (IDLH) values for estimating the hazard of accidental chemical releases

The possibility of accidental industrial chemical releases has generated considerable recent attention. One area requiring research for emergency planning is the development of safe exposure concentrations for the public in the event of an inadvertent release. The United States Environmental Protection Agency (EPA) has established a list of extremely hazardous substances and suggested that the toxicity ranking for 92 hazardous materials could be based on the "immediately dangerous to life or health" (IDLH) values developed by the National Institute for Occupational Safety and Health (NIOSH) and the Occupational Safety and Health Administration (OSHA). Eighty-four compounds with IDLH values for which published toxicologic data were available were reviewed to assess the appropriateness of applying such values to accidental release situations. When compared with 30-min animal median lethal concentrations (LC50s), 18 of the IDLHs reviewed were in the same range as lethal levels for animals. For 45 compounds the IDLH values were comparable to concentrations producing severe toxic effects (specifically, unconsciousness, incapacitation, or intolerable irritation). Where available, emergency planning guidelines for the military were compared to IDLHs, and in all 31 cases, the IDLHs exceeded the military exposure guidelines. Twenty compounds also were found to pose a potential cancer risk according to common regulatory guidelines, even under the assumption of a single, 30-min exposure at the IDLH concentration. In addition, the high degree of variability (four orders of magnitude) in the relationship of IDLH values to outcomes of lethality or severe toxicity suggests that the use of IDLH values as emergency planning guidelines for accidental releases is questionable.(ABSTRACT TRUNCATED AT 250 WORDS)