Lisa S. Chow

Nondiagnostic Thyroid Fine-Needle Aspiration Cytology: Management Dilemmas

Approximately 10% to 20% of thyroid biopsies by fine-needle aspiration (FNA) are nondiagnostic. The management of thyroid nodules in which FNA is nondiagnostic remains controversial because few studies have addressed this issue. We retrospectively reviewed the medical records of 153 patients with nondiagnostic FNAs of the thyroid performed in 1994. Sixty patients had reaspiration biopsies performed. Thirty-seven specimens (62%) were diagnostic and 23 (38%) remained nondiagnostic. Of the 27 patients who had a thyroid operation, 10 (37%) had a malignancy. Preoperative information about physical examination, ultrasound imaging, or nondiagnostic FNA did not predict outcome. Nondiagnostic FNAs of the thyroid may be associated with a high probability of thyroid malignancy. Nondiagnostic FNAs should not be considered benign. Reaspiration followed by selective surgical treatment is recommended.

Asian Indians Have Enhanced Skeletal Muscle Mitochondrial Capacity to Produce ATP in Association with Severe Insulin-Resistance

OBJECTIVE— Type 2 diabetes has become a global epidemic, and Asian Indians have a higher susceptibility to diabetes than Europeans. We investigated whether Indians had any metabolic differences compared with Northern European Americans that may render them more susceptible to diabetes. RESEARCH DESIGN AND METHODS— We studied 13 diabetic Indians, 13 nondiabetic Indians, and 13 nondiabetic Northern European Americans who were matched for age, BMI, and sex. The primary comparisons were insulin sensitivity by hyperinsulinemic-euglycemic clamp and skeletal muscle mitochondrial capacity for oxidative phosphorylation (OXPHOS) by measuring mitochondrial DNA copy number (mtDNA), OXPHOS gene transcripts, citrate synthase activity, and maximal mitochondrial ATP production rate (MAPR). Other factors that may cause insulin resistance were also measured. RESULTS— The glucose infusion rates required to maintain identical glucose levels during the similar insulin infusion rates were substantially lower in diabetic Indians than in the nondiabetic participants (P < 0.001), and they were lower in nondiabetic Indians than in nondiabetic Northern European Americans (P < 0.002). mtDNA (P < 0.02), OXPHOS gene transcripts (P < 0.01), citrate synthase, and MAPR (P < 0.03) were higher in Indians irrespective of their diabetic status. Intramuscular triglyceride, C-reactive protein, interleukin-6, and tumor necrosis factor-α concentrations were higher, whereas adiponectin concentrations were lower in diabetic Indians. CONCLUSIONS— Despite being more insulin resistant, diabetic Indians had similar muscle OXPHOS capacity as nondiabetic Indians, demonstrating that diabetes per se does not cause mitochondrial dysfunction. Indians irrespective of their diabetic status had higher OXPHOS capacity than Northern European Americans, although Indians were substantially more insulin resistant, indicating a dissociation between mitochondrial dysfunction and insulin resistance.

Human Brain Glycogen Metabolism During and After Hypoglycemia

OBJECTIVE We tested the hypotheses that human brain glycogen is mobilized during hypoglycemia and its content increases above normal levels (“supercompensates”) after hypoglycemia. RESEARCH DESIGN AND METHODS We utilized in vivo 13C nuclear magnetic resonance spectroscopy in conjunction with intravenous infusions of [13C]glucose in healthy volunteers to measure brain glycogen metabolism during and after euglycemic and hypoglycemic clamps. RESULTS After an overnight intravenous infusion of 99% enriched [1-13C]glucose to prelabel glycogen, the rate of label wash-out from [1-13C]glycogen was higher (0.12 ± 0.05 vs. 0.03 ± 0.06 μmol · g−1 · h−1, means ± SD, P < 0.02, n = 5) during a 2-h hyperinsulinemic-hypoglycemic clamp (glucose concentration 57.2 ± 9.7 mg/dl) than during a hyperinsulinemic-euglycemic clamp (95.3 ± 3.3 mg/dl), indicating mobilization of glucose units from glycogen during moderate hypoglycemia. Five additional healthy volunteers received intravenous 25–50% enriched [1-13C]glucose over 22–54 h after undergoing hyperinsulinemic-euglycemic (glucose concentration 92.4 ± 2.3 mg/dl) and hyperinsulinemic-hypoglycemic (52.9 ± 4.8 mg/dl) clamps separated by at least 1 month. Levels of newly synthesized glycogen measured from 4 to 80 h were higher after hypoglycemia than after euglycemia (P ≤ 0.01 for each subject), indicating increased brain glycogen synthesis after moderate hypoglycemia. CONCLUSIONS These data indicate that brain glycogen supports energy metabolism when glucose supply from the blood is inadequate and that its levels rebound to levels higher than normal after a single episode of moderate hypoglycemia in humans.

Skeletal muscle insulin resistance: the interplay of local lipid excess and mitochondrial dysfunction.

This review explores the complex relationship between excess lipid exposure, mitochondrial dysfunction, and insulin resistance at the level of human skeletal muscle. Lipotoxicity — i.e., the elevation of lipids and/or associated lipid metabolites within blood and tissues with subsequent metabolic derangement — has been proposed as a possible mechanism of skeletal muscle insulin resistance. Intravenous lipid infusion is a well-documented method of inducing insulin resistance. Although IMCL content has been correlated with insulin resistance, there is increasing evidence that lipid metabolites such as 4-HNE, DAG, ceramide, and LC-CoA may play a more significant role than triglycerides in producing skeletal muscle insulin resistance. The association between mitochondrial dysfunction and insulin resistance is unclear, particularly due to the varied options for measuring mitochondrial function. The effect of acute lipid exposure producing skeletal muscle insulin resistance in humans is well documented. The effects of chronic lipid exposure from dietary ingestion on skeletal muscle insulin resistance and skeletal muscle mitochondrial function remain disputed. The effects of skeletal muscle mitochondrial dysfunction on accumulation of lipotoxic species and skeletal muscle insulin resistance also remain uncertain. Certainly, pursuit of the role of lipid metabolites and their roles in the generation of skeletal muscle insulin resistance remain an exciting area for future research. Moreover, alteration in skeletal muscle insulin resistance does not occur in isolation as functional perturbations of any component of the glucose homeostatic system may initiate development of insulin resistance in skeletal muscle through “cross talk” between tissues. Nevertheless, understanding pathophysiology of skeletal muscle insulin resistance remains critically important due to its role in preceding and facilitating the development of Type 2 diabetes.

Organizational Transition to Object Technology: Theory and Practice

The use of object technology (OT) has been highly successful for many software development companies, yet there are still a large number of organizations who have not yet adopted OT. For those companies currently adopting object technology, the transition from traditional procedurally-oriented technologies remains a challenge. Indeed, there is sparse empirical evidence to suggest the best ways to undertake this culture change. Here, we reports on action research results of two case studies within the software development arm of a large multinational professional information solutions provider. The company used the Trans-OPEN process for their transition process. This transition process has seven major activities: initiation, planning, technology insertion, deployment, the use of a retrospective for evaluation, improvement planning and further improvement - the process is incremental and iterative. Furthermore, the case studies underline the need for a more formal approach to culture change in the context of the adoption of object technology.

Physical activity and cardiovascular risk factors in childhood cancer survivors

Childhood cancer survivors (CCS) are at high risk of developing treatment‐related late effects, including cardiovascular disease and diabetes. Late effects can be exacerbated by low physical activity (PA) levels. Relationships between PA and cardiovascular risk factors during childhood have not been well described in CCS.

Training status diverges muscle diacylglycerol accumulation during free fatty acid elevation

How endurance training alters muscle lipid metabolism while preserving insulin sensitivity remains unclear. Because acute free fatty acid (FFA) elevation by lipid infusion reduces insulin sensitivity, we hypothesized that training status would alter accumulation of muscle triacylglycerol (TAG), diacylglycerol (DAG), ceramide, and acylcarnitine during acute FFA elevation. Trained (n = 15) and sedentary (n = 13) participants matched for age, sex, and BMI received either a 6-h infusion of lipid (20% Intralipid at 90 ml/h) or glycerol (2.25 g/100 ml at 90 ml/h) during a hyperinsulinemic euglycemic clamp. Muscle biopsies were taken at 0, 120, and 360 min after infusion initiation to measure intramyocellular concentrations of TAG, DAG, ceramides, and acylcarnitines by liquid chromatography-tandem mass spectrometry. Trained participants had a higher Vo2 max and insulin sensitivity than sedentary participants. The lipid infusion produced a comparable elevation of FFA (594 ± 90 μmol/l in trained, 721 ± 30 μmol/l in sedentary, P = 0.4) and a decline in insulin sensitivity (-44.7% trained vs. -47.2% sedentary, P = 0.89). In both groups, lipid infusion increased the linoleic and linolenic acid content of TAG without changing total TAG. In the sedentary group, lipid infusion increased total, oleic, and linoleic acid and linolenic acid content of DAG. Regardless of training status, lipid infusion did not alter total ceramide, saturated ceramide, palmitoyl-carnitine, or oleoyl-carnitine. We conclude that during acute FFA elevation, trained adults have a similar decline in insulin sensitivity with less accumulation of muscle DAG than sedentary adults, suggesting that lipid-induced insulin resistance can occur without elevation of total muscle DAG.

Blunted response to a growth hormone stimulation test is associated with unfavorable cardiovascular risk factor profile in childhood cancer survivors

Childhood cancer survivors (CCS) are at risk for growth hormone (GH) deficiency. CCS are also at increased risk for early mortality from cardiovascular (CV) disease, but the association between GH levels and CV risk remains poorly understood. The goal of this study was to examine the cross‐sectional association between stimulated GH levels and CV risk factors in CCS younger than 18 years.

The relative contributions of the abdominal visceral and subcutaneous fat depots to cardiometabolic risk in youth

The aim of this study was to evaluate the association of abdominal visceral and subcutaneous fat, independent of total body fat, with cardiometabolic risk factors and insulin resistance among youth. Visceral and subcutaneous fat, percentage total body fat, insulin resistance (adjusted for lean body mass: Mlbm), blood pressure, glucose, insulin and lipids were obtained in 472 youth ages 6–18 years. Linear regression, adjusted for age, sex, race, Tanner stage and percentage total body fat, was used to evaluate associations of visceral and subcutaneous fat with cardiometabolic risk factors. Visceral fat was associated inversely with Mlbm (P = 0.003) and positively with fasting insulin (P = 0.002) and triglycerides (P = 0.002). Visceral fat levels above the mean were associated inversely with high‐density lipoprotein (HDL) cholesterol (P = 0.002), and positively with systolic blood pressure (P < 0.0001) and non‐HDL cholesterol (P < 0.0001). Subcutaneous fat was associated inversely with Mlbm (P = 0.003) and HDL cholesterol (P < 0.05), and positively with fasting glucose (P < 0.05), fasting insulin (P = 0.0003), systolic blood pressure (P = 0.005) and triglycerides (P = 0.003). Subcutaneous fat levels above the mean were associated with non‐HDL cholesterol (P = 0.0002). These findings suggest that there may be a threshold level of visceral and subcutaneous fat (regardless of total body fat), that when exceeded in childhood, is more likely to be associated with many cardiometabolic risk factors. Triglycerides and insulin resistance appear to be associated with these fat depots at even lower thresholds of abdominal adiposity.

Estimated plasma stearoyl co-A desaturase-1 activity and risk of incident diabetes: The Atherosclerosis Risk in Communities (ARIC) study

OBJECTIVE Evidence from pre-clinical studies suggests inhibition of stearoyl co-A desaturase-1 (SCD-1) activity improves insulin sensitivity. Translation of these findings to humans remains less defined. The purpose of this research was to evaluate the association between different measures of SCD-1 activity and incident diabetes in a large, prospective human study. METHODS In 2738 white participants (aged 45-64 yrs, 47% men) who were free of diabetes at baseline, SCD-1 activity was estimated at baseline by plasma fatty acid ratios in cholesterol esters (SCD16c=16:1n-7/16:0, SCD18c =18:1n-9/18:0) and in phospholipids (SCD16p=16:1n-7/16:0, SCD18p=18:1n-9/18:0). Incident diabetes was ascertained during 3 follow-up visits. Cox proportional hazards regression was used to determine the association between estimated SCD-1 activity and incident diabetes. RESULTS During follow-up (mean 8.0±SE 2.1 years), 207 (7.6%) participants developed diabetes. After adjusting for age and sex, higher SCD16c, higher SCD16p, and lower SCD18p were significantly associated with incident diabetes. After additional adjustment for education, parental history of diabetes, smoking, dietary intake (carbohydrate, fiber, saturated/monounsaturated/polyunsaturated fat), alcohol use, physical activity, body mass index (BMI), waist-hip ratio, blood pressure, and lipid composition - only SCD16c remained significantly associated with incident diabetes (Hazard Ratio=1.1 linearly across decreasing quintiles, 95% CI 1.01-1.30; p =0.03) which remained nominally associated after adjusting for insulin resistance (p=0.05). CONCLUSIONS In a large community-based prospective cohort study, the estimate of SCD-1 activity by SCD16c had the strongest association with incident diabetes. Refinement of SCD-1 measurement and replication of its association with incident diabetes in an independent cohort is recommended.