Prevalence of cardiovascular and metabolic events in patients prescribed clozapine: a retrospective observational, clinical cohort study

BACKGROUND: The efficacy of clozapine for the treatment of schizophrenia has been demonstrated. However, a range of adverse events have been associated with its use. To date, there remains a paucity of data regarding the prevalence of clozapine-induced cardiovascular (CV) and parameters associated with the development of metabolic syndrome, alongside associated risk factors for their development. METHODS: An observational, clinical cohort study design of 355 clozapine patients who were enrolled in the Barwon Health Clozapine Program at Geelong Hospital, Victoria, Australia, between 2008-12. Medical records were accessed retrospectively. Multivariate logistic regression was used to determine associations with adverse event(s). RESULTS: Older age of commencement with clozapine was consistently associated with increased risk of CV abnormalities, with the exception of tachycardia where older age was protective (Odds Ratio [OR]: 0.97; 95% Confidence Intervals [CI]: 0.95, 0.99). Males had significantly greater odds of most metabolic disturbances with the exception of being obese (BMI: ≥30 OR: 0.45; 95% CIs: 0.24, 0.85). Older age of commencement was a significantly associated variable with High- Density Lipoprotein-cholesterol (OR: 1.03; 95% CIs: 1.01, 1.07) and fasting glucose (OR:1.04; 95% CIs: 1.02, 1.07). An increase in BMI was consistently and significantly associated with all metabolic events. CONCLUSION: Male patients who are obese at any point during treatment and older at treatment commencement may be the most vulnerable to adverse CV and metabolic events. While future studies using a matched case-control design may be required to verify these findings, we recommend that treating clinicians consider these risks when assessing patient suitability to clozapine therapy.

Hypothalamo-pituitary adrenal axis and sympatho-adrenal medullary system responses to psychological stress were not attenuated in women with elevated physical fitness levels

It is not clear if higher levels of cardiorespiratory fitness are associated with lower hypothalamo-pituitary adrenal (HPA) axis and sympatho-adrenal medullary (SAM) system reactivity to psychological stress in women. The association between cardio-metabolic risk markers and acute physiological responses to psychological stress in women who differ in their cardiorespiratory fitness status has also not been investigated. Women with high (n = 22) and low (n = 22) levels of fitness aged 30-50 years (in the mid-follicular phase of the menstrual cycle) were subjected to a Trier Social Stress Test (TSST) at 1500 h. Plasma concentrations of cortisol, adrenaline (Adr), noradrenaline (NA), and dopamine (DA) were measured in samples collected every 7-15 min from 1400 to 1700 h. Heart rate and blood pressure were measured at the same time points. Low-fit women had elevated serum triglyceride, cholesterol/HDL ratio, fasting glucose, and HOMA-IR levels compared with high-fit women. While cortisol, Adr, NA, HR, and blood pressure all demonstrated a significant response to the TSST, the responses of these variables did not differ significantly between high- and low-fit women in response to the TSST. Dopamine reactivity was significantly higher in the low-fit women compared with high-fit women. There was also a significant negative correlation between VO2 max and DA reactivity. These findings suggest that, for low-fit women aged 30-50 years, the response of HPA axis and SAM system to a potent acute psychological stressor is not compromised compared to that in high-fit women.

Evaluation of AUSDRISK as a screening tool for lifestyle modification programs: international implications for policy and cost-effectiveness

OBJECTIVE: To evaluate the current use of Australian Type 2 Diabetes Risk Assessment Tool (AUSDRISK) as a screening tool to identify individuals at high risk of developing type 2 diabetes for entry into lifestyle modification programs.

RESEARCH DESIGN AND METHODS: AUSDRISK scores were calculated from participants aged 40-74 years in the Greater Green Triangle Risk Factor Study, a cross-sectional population survey in 3 regions of Southwest Victoria, Australia, 2004-2006. Biomedical profiles of AUSDRISK risk categories were determined along with estimates of the Victorian population included at various cut-off scores. Sensitivity, specificity, positive predictive value (PPV), negative predictive value, and receiver operating characteristics were calculated for AUSDRISK in determining fasting plasma glucose (FPG) ≥6.1 mmol/L.

RESULTS: Increasing AUSDRISK scores were associated with an increase in weight, body mass index, FPG, and metabolic syndrome. Increasing the minimum cut-off score also increased the proportion of individuals who were obese and centrally obese, had impaired fasting glucose (IFG) and metabolic syndrome. An AUSDRISK score of ≥12 was estimated to include 39.5% of the Victorian population aged 40-74 (916 000), while a score of ≥20 would include only 5.2% of the same population (120 000). At AUSDRISK≥20, the PPV for detecting FPG≥6.1 mmol/L was 28.4%.

CONCLUSIONS: AUSDRISK is powered to predict those with IFG and undiagnosed type 2 diabetes, but its effectiveness as the sole determinant for entry into a lifestyle modification program is questionable given the large proportion of the population screened-in using the current minimum cut-off of ≥12. AUSDRISK should be used in conjunction with oral glucose tolerance testing, fasting glucose, or glycated hemoglobin to identify those individuals at highest risk of progression to type 2 diabetes, who should be the primary targets for lifestyle modification.

Intensifying insulin regimen after basal insulin optimization in adults with type 2 diabetes: a 24-week, randomized, open-label trial comparing insulin glargine plus insulin glulisine with biphasic insulin aspart (LanScape)

AIM: To test the hypothesis that a 'basal plus' regimenadding once-daily main-meal fast-acting insulin to basal insulin once dailywould be non-inferior to biphasic insulin twice daily as assessed by glycated haemoglobin (HbA1c) concentration (predefined as ≤0.4%), but would provide superior treatment satisfaction. METHODS: This open-label trial enrolled adults to an 8- or 12-week run-in period, during which oral therapies except metformin were stopped and insulin glargine dose was titrated. Those with fasting glucose <7 mmol/l but HbA1c >7% (53 mmol/mol) were randomized to insulin glargine/glulisine once daily (n = 170) or insulin aspart/aspart protamine 30/70 twice daily (n = 165) for 24 weeks, with dose titration to glucose targets using standardized algorithms. RESULTS: For HbA1c, the basal plus regimen was non-inferior to biphasic insulin (least squares mean difference, 0.21%, upper 97.5% confidence limit 0.38%) meeting the predefined non-inferiority margin of 0.4%. Treatment satisfaction (Diabetes Treatment Satisfaction Questionnaire change version and Insulin Treatment Satisfaction Questionnaire total scores) significantly favoured basal plus. No difference was observed between the basal plus and the biphasic insulin groups in responders (HbA1c <7%, 20.6 vs 27.9%; p = 0.12), weight gain (2.06 vs 2.50 kg; p = 0.2), diabetes-specific quality of life (Audit of Diabetes-Dependent Quality of Life average weighted impact (AWI) score) and generic health status (five-dimension European Quality of Life questionnaire). Overall hypoglycaemia rates were similar between groups (15.3 vs 18.2 events/patient-year; p = 0.22); nocturnal hypoglycaemia was higher with the basal plus regimen (5.7 vs 3.6 events/patient-year; p = 0.02). CONCLUSION: In long-standing type 2 diabetes with suboptimal glycaemia despite oral therapies and basal insulin, the basal plus regimen was non-inferior to biphasic insulin for biomedical outcomes, with a similar overall hypoglycaemia rate but more nocturnal events.

Mothers after gestational diabetes in Australia (MAGDA) : a randomised controlled trial of a postnatal diabetes prevention program

BACKGROUND: Gestational diabetes mellitus (GDM) is an increasingly prevalent risk factor for type 2 diabetes. We evaluated the effectiveness of a group-based lifestyle modification program in mothers with prior GDM within their first postnatal year. METHODS AND FINDINGS: In this study, 573 women were randomised to either the intervention (n = 284) or usual care (n = 289). At baseline, 10% had impaired glucose tolerance and 2% impaired fasting glucose. The diabetes prevention intervention comprised one individual session, five group sessions, and two telephone sessions. Primary outcomes were changes in diabetes risk factors (weight, waist circumference, and fasting blood glucose), and secondary outcomes included achievement of lifestyle modification goals and changes in depression score and cardiovascular disease risk factors. The mean changes (intention-to-treat [ITT] analysis) over 12 mo were as follows: -0.23 kg body weight in intervention group (95% CI -0.89, 0.43) compared with +0.72 kg in usual care group (95% CI 0.09, 1.35) (change difference -0.95 kg, 95% CI -1.87, -0.04; group by treatment interaction p = 0.04); -2.24 cm waist measurement in intervention group (95% CI -3.01, -1.42) compared with -1.74 cm in usual care group (95% CI -2.52, -0.96) (change difference -0.50 cm, 95% CI -1.63, 0.63; group by treatment interaction p = 0.389); and +0.18 mmol/l fasting blood glucose in intervention group (95% CI 0.11, 0.24) compared with +0.22 mmol/l in usual care group (95% CI 0.16, 0.29) (change difference -0.05 mmol/l, 95% CI -0.14, 0.05; group by treatment interaction p = 0.331). Only 10% of women attended all sessions, 53% attended one individual and at least one group session, and 34% attended no sessions. Loss to follow-up was 27% and 21% for the intervention and control groups, respectively, primarily due to subsequent pregnancies. Study limitations include low exposure to the full intervention and glucose metabolism profiles being near normal at baseline. CONCLUSIONS: Although a 1-kg weight difference has the potential to be significant for reducing diabetes risk, the level of engagement during the first postnatal year was low. Further research is needed to improve engagement, including participant involvement in study design; it is potentially more effective to implement annual diabetes screening until women develop prediabetes before offering an intervention. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry ACTRN12610000338066.

Trial for reducing weight retention in new mums: a randomised controlled trial evaluating a low intensity, postpartum weight management programme

BACKGROUND: Failure to return to pregnancy weight by 6 months postpartum is associated with long-term obesity, as well as adverse health outcomes. This research evaluated a postpartum weight management programme for women with a body mass index (BMI) > 25 kg m(-2) that combined behaviour change principles and a low-intensity delivery format with postpartum nutrition information. METHODS: Women were randomised at 24-28 weeks to control (supported care; SC) or intervention (enhanced care; EC) groups, stratified by BMI cohort. At 36 weeks of gestation, SC women received a 'nutrition for breastfeeding' resource and EC women received a nutrition assessment and goal-setting session about post-natal nutrition, plus a 6-month correspondence intervention requiring return of self-monitoring sheets. Weight change, anthropometry, diet, physical activity, breastfeeding, fasting glucose and insulin measures were assessed at 6 weeks and 6 months postpartum. RESULTS: Seventy-seven percent (40 EC and 41 SC) of the 105 women approached were recruited; 36 EC and 35 SC women received a programme and 66.7% and 48.6% completed the study, respectively. No significant differences were observed between any outcomes. Median [interquartile range (IQR)] weight change was EC: -1.1 (9.5) kg versus SC: -1.1 (7.5) kg (6 weeks to 6 months) and EC: +1.0 (8.7) kg versus SC: +2.3 (9) kg (prepregnancy to 6 months). Intervention women breastfed for half a month longer than control women (180 versus 164 days; P = 0.10). An average of 2.3 out of six activity sheets per participant was returned. CONCLUSIONS: Despite low intervention engagement, the high retention rate suggests this remains an area of interest to women. Future strategies must facilitate women's engagement, be individually tailored, and include features that support behaviour change to decrease women's risk of chronic health issues.

Beneficial associations of physical activity with 2-h, but not fasting, blood glucose in Australian adults

OBJECTIVE--We examined the associations of physical activity with fasting plasma glucose (FPG) and with 2-h postload plasma glucose (2-h PG) in men and women with low, moderate, and high waist circumference.

RESEARCH DESIGN AND METHODS--The Australian Diabetes, Obesity and Lifestyle (AusDiab) study provided data on a population-based cross-sectional sample of 4,108 men and 5,106 women aged [greater than or equal to] 25 years without known diabetes or health conditions that could affect physical activity. FPG and 2-h PG were obtained from an oral glucose tolerance test. Self-reported physical activity level was defined according to the current public health guidelines as active ([greater than or equal to] 150 min/week across five or more sessions) or inactive (<150 min/week and/or less than five sessions). Sex-specific quintiles of physical activity time were used to ascertain dose response.

RESULTS--Being physically active and total physical activity time were independently and negatively associated with 2-h PG. When physical activity level was considered within each waist circumference category, 2-h PG was significantly lower in active high-waist circumference women ([beta] -0.30 [95% CI -0.59 to -0.01], P = 0.044) and active low-waist circumference men ([beta] -0.25 [-0.49 to -0.02], P = 0.036) compared with their inactive counterparts. Considered across physical activity and waist circumference categories, 2-h PG levels were not significantly different between active moderate-waist circumference participants and active low-waist circumference participants. Associations between physical activity and FPG were nonsignificant.

CONCLUSIONS--There are important differences between 2-h PG and FPG related to physical activity. It appears that 2-h PG is more sensitive to the beneficial effects of physical activity, and these benefits occur across the waist circumference spectrum.

Elevation in tanis expression alters glucose metabolism and insulin sensitivity in H4IIE cells

Increased hepatic glucose output and decreased glucose utilization are implicated in the development of type 2 diabetes. We previously reported that the expression of a novel gene, Tanis, was upregulated in the liver during fasting in the obese/diabetic animal model Psammomys obesus. Here, we have further studied the protein and its function. Cell fractionation indicated that Tanis was localized in the plasma membrane and microsomes but not in the nucleus, mitochondria, or soluble protein fraction. Consistent with previous gene expression data, hepatic Tanis protein levels increased more significantly in diabetic P. obesus than in nondiabetic controls after fasting. We used a recombinant adenovirus to increase Tanis expression in hepatoma H4IIE cells and investigated its role in metabolism. Tanis overexpression reduced glucose uptake, basal and insulin-stimulated glycogen synthesis, and glycogen content and attenuated the suppression of PEPCK gene expression by insulin, but it did not affect insulin-stimulated insulin receptor phosphorylation or triglyceride synthesis. These results suggest that Tanis may be involved in the regulation of glucose metabolism, and increased expression of Tanis could contribute to insulin resistance in the liver.

Regulation of selenoprotein SelS by glucose deprivation and endoplasmic reticulum stress - SelS is a novel glucose-regulated protein

SelS is a newly identified selenoprotein and its gene expression is up-regulated in the liver of Psammomys obesus after fasting. We have examined whether SelS is regulated by glucose deprivation and endoplasmic reticulum (ER) stress in HepG2 cells. Glucose deprivation and the ER stress inducers tunicamycin and thapsigargin increased SelS gene expression and protein content several-fold in parallel with glucose-regulated protein 78. The overexpression of SelS increased Min6 cell resistance to oxidative stress-induced toxicity. These results indicate that SelS is a novel member of the glucose-regulated protein family and its function is related to the regulation of cellular redox balance.

Palatability and glucose, insulin and satiety responses of chickpea flour and extruded chickpea flour bread eaten as part of a breakfast

Objective: To determine the effect of adding chickpea flour or extruded chickpea flour to white bread on palatability and postprandial glycaemia, insulinaemia and satiety.

Design: A randomised, single-blind, cross-over study of four 50 g available carbohydrate breakfasts.

Setting: School of Exercise and Nutrition Sciences, Deakin University.

Subjects: In all, 12 healthy subjects were recruited through posted notices. Totally, 11 (nine male, two female) completed the study (meanplusminuss.e.m.; age 32±2 y; body mass index, 24.7±0.8 kg/m²).

Intervention: After overnight fasting, subjects consumed a control (white) bread (WB) breakfast twice, a chickpea bread (CHB) breakfast once and an extruded chickpea bread (EXB) breakfast once. Palatability and postprandial blood glucose, insulin and satiety responses were determined. Following this, food intakes from an ad libitum buffet and for the remainder of the day were assessed.

Results: A trend towards a lower incremental area under the curve (IAUC) of glucose for the CHB breakfast compared to the WB breakfast was observed (P=0.087). The IAUC of insulin and insulinaemic index (II) of the CHB breakfast were higher (P<0.05) than for the WB breakfast. No differences in glycaemic index (GI), satiety response, food intake or palatability were observed.

Conclusions: CHB and EXB demonstrated acceptable palatability. CHB demonstrated some hypoglycaemic effect compared to WB, but neither CHB nor EXB demonstrated effects on satiety or food intake. The hyperinsulinaemic effect of CHB observed in this study requires further investigation.

Randomised controlled trial evaluating the effectiveness of behavioural interventions to modify cardiovascular risk factors in men and women with imparied glucose tolerance: outcomes at 6 months

Aims: To evaluate the efficacy of interventions to promote a healthy diet and physical activity in people with impaired glucose tolerance (IGT). Methods: A randomised controlled trial in Newcastle upon Tyne, UK, 1995–98. Participants included 67 adults (38 men; 29 women) aged 24–75 years with IGT. The intervention consisted of regular diet and physical activity counselling based on the stages of change model. Main outcome measures were changes between baseline and 6 months in nutrient intake; physical activity; anthropometric and physiological measurements including serum lipids; glucose tolerance; insulin sensitivity. Results: The difference in change in total fat consumption was significant between intervention and control groups (difference −21.8 (95% confidence interval (CI) −37.8 to −5.8) g/day, P=0.008). A significantly larger proportion of intervention participants reported taking up vigorous activity than controls (difference 30.1, (95% CI 4.3–52.7)%, P=0.021). The change in body mass index was significantly different between groups (difference −0.95 (95% CI −1.5 to −0.4) kg/m2, P=0.001). There was no significant difference in change in mean 2-h plasma glucose between groups (difference −0.19 (95% CI −1.1 to 0.71) mmol/l, NS) or in serum cholesterol (difference 0.02 (95% CI −0.26 to 0.31) mmol/l, NS). The difference in change in fasting serum insulin between groups was significant (difference −3.4 (95% CI −5.8 to −1.1) mU/l, P=0.005). Conclusions: After 6 months of intensive lifestyle intervention in participants with IGT, there were changes in diet and physical activity, some cardiovascular risk factors and insulin sensitivity, but not glucose tolerance. Further follow-up is in progress to investigate whether these changes are sustained or augmented over 2 years.

Long-term 5-year effects of a reduced-fat diet intervention in individuals with glucose intolerance

OBJECTIVE: To determine whether reducing dietary fat would reduce body weight and improve long-term glycemia in people with glucose intolerance. RESEARCH DESIGN AND METHODS: A 5-year Follow-up of a 1-year randomized controlled trial of a reduced-fat ad libitum diet versus a usual diet. Participants with glucose intolerance (2-h blood glucose 7.0-11.0 mmol/l) were recruited from a Workforce Diabetes Survey. The group that was randomized to a reduced-fat diet participated in monthly small-group education sessions on reduced-fat eating for 1 year. Body weight and glucose tolerance were measured in 136 participants at baseline 6 months, and 1 year (end of intervention), with follow-up at 2 years (n = l04), 3 years (n = 99), and 5 years (n = 103). RESULTS: Compared with the control group, weight decreased in the reduced-fat-diet group (P < 0.0001); the greatest difference was noted at 1 year (-3.3 kg), diminished at subsequent follow-up (-3.2 kg at 2 years and -1.6 kg at 3 years), and was no longer present by 5 years (1.1 kg). Glucose tolerance also improved in patients on the reduced-fat diet; a lower proportion had type 2 diabetes or impaired glucose tolerance at 1 year (47 vs. 67%, P < 0.05), but in subsequent years, there were no differences between groups. However, the more compliant 50% of the intervention group maintained lower fasting and 2-h glucose at 5 years (P = 0.041 and P = 0.026 respectively) compared with control subjects. CONCLUSIONS: The natural history for people at high risk of developing type 2 diabetes is weight gain and deterioration in glucose tolerance. This process may be ameliorated through adherence to a reduced fat intake

Physical activity and television viewing in relation to risk and undiagnosed abnormal glucose metabolism in adults

OBJECTIVE--The goal of this study was to assess the associations of physical activity time and television (TV) time with risk of "undiagnosed" abnormal glucose metabolism in Australian adults.

RESEARCH DESIGN AND METHODS--This population-based cross-sectional study using a stratified cluster design involving 42 randomly selected Census Collector Districts across Australia included 8,299 adults aged 25 years or older who were free from new type 2 diabetes and self-reported ischemic disease and did not take lipid lowering or antihypertensive drugs. Abnormal glucose metabolism (impaired fasting glycetnia [IFG], impaired glucose tolerance [IGT], or new type 2 diabetes) was based on an oral glucose tolerance test Self reported physical activity time and TV time (previous week) were assessed using interviewer administered questionnaires.

RESULTS--Alter adjustment for known confounders and TV time, the odds ratio (OR) of having abnormal glucose metabolism was 0.62 (95% CI 0.41-0.96) in men and 0.71 (0.501.00) in women for those engaged in physical activity [greater than or equal to] 2.5 h/week compared with those who were sedentary (0 h/week). The ORs of having abnormal glucose metabolism were 1.16 (0.791.70) in men and 1.49 (1.12-1.99) in women who watched TV > 14 h/week compared with those who watched [less than or equal to] 7.0 h/week. Higher TV viewing (> 14 h/week) was also associated with an increased risk of new type 2 diabetes in men and women and IGT in women compared with those watching < 14 h/week. Total physical activity of [greater than or equal to] 2.5 h/week was associated with a reduced risk of IFG, IGT, and new type 2 diabetes in both sexes: however, only the association with IGT in women was statistically significant.

CONCLUSIONS--These findings suggest a protective effect of physical activity and a deleterious effect of TV time on the risk of abnormal glucose metabolism in adults. Population strategies to reduce risk of abnormal glucose metabolism should focus on reducing sedentary behaviors such as TV time, as well as increasing physical activity.

Objectively measured light-intensity physical activity is independently associated with 2-H plasma glucose

Objective: We examined the associations of objectively measured sedentary time, light-intensity physical activity, and moderate- to vigorous-intensity activity with fasting and 2-h postchallenge plasma glucose in Australian adults.

Research Design and Methods: A total of 67 men and 106 women (mean age ± SD 53.3 ± 11.9 years) without diagnosed diabetes were recruited from the 2004–2005 Australian Diabetes, Obesity, and Lifestyle (AusDiab) study. Physical activity was measured by Actigraph  accelerometers worn during waking hours for 7 consecutive days and summarized as sedentary time (accelerometer counts/min <100; average hours/day), light-intensity (counts/min 100-1951), and moderate- to vigorous-intensity (counts/min ≥1,952). An oral glucose tolerance test was used to ascertain 2-h plasma glucose and fasting plasma glucose.

Results: After adjustment for confounders (including waist circumference), sedentary time was positively associated with 2-h plasma glucose (b = 0.29, 95% CI 0.11–0.48, P = 0.002); light-intensity activity time (b = –0.25, –0.45 to –0.06, P = 0.012) and moderate- to vigorous-intensity activity time (b = –1.07, –1.77 to –0.37, P = 0.003) were negatively associated. Light-intensity activity remained significantly associated with 2-h plasma glucose following further adjustment for moderate- to vigorous-intensity activity (b = –0.22, –0.42 to –0.03, P = 0.023). Associations of all activity measures with fasting plasma glucose were nonsignificant (P > 0.05).

Conclusions: These data provide the first objective evidence that light-intensity physical activity is beneficially associated with blood glucose and that sedentary time is unfavorably associated with blood glucose. These objective data support previous findings from studies using self-report measures, and suggest that substituting light-intensity activity for television viewing or other sedentary time may be a practical and achievable preventive strategy to reduce the risk of type 2 diabetes and cardiovascular disease.

Pyruvate dehydrogenase activation and kinase expression in human skeletal muscle during fasting

Fasting forces adaptive changes in whole body and skeletal muscle metabolism that increase fat oxidation and decrease the oxidation of carbohydrate. We tested the hypothesis that 40 h of fasting would decrease pyruvate dehydrogenase (PDH) activity and increase PDH kinase (PDK) isoform mRNA expression in human skeletal muscle. The putative transcriptional activators of PDK isozymes, peroxisome proliferator-activated receptor-α (PPAR-α) protein, and forkhead homolog in rhabdomyosarcoma (FKHR) mRNA were also measured. Eleven healthy adults fasted after a standard meal (25% fat, 60% carbohydrate, 15% protein) with blood and skeletal muscle samples taken at 3, 15, and 40 h postprandial. Fasting increased plasma free fatty acid, glycerol, and β-hydroxybutyrate concentrations and decreased glucose and insulin concentrations. PDH activity decreased from 0.88 ± 0.11 mmol acetyl-CoA · min^-1 · kg wet muscle wt^-1 at 3 h to 0.62 ± 0.10 (P = not significant) and 0.39 ± 0.06 (P < 0.05) mmol · min^-1 · kg wet mass^-1 after 15 and 40 h of fasting. Although all four PDK isoforms were expressed in human skeletal muscle, PDK^-2 and -4 mRNA were the most abundant. PDK^-1 and ^-3 mRNA abundance was ~1 and 15% of the PDK^-2 and 4^- levels, respectively. The 40-h fast had no effect on PDK^-1, ^-2, and ^-3 mRNA expression. PDK-4 mRNA was significantly increased ~3-fold after 15 h and ~14-fold after 40 h of fasting. Skeletal muscle PPAR-α protein and FKHR mRNA abundance were unaffected by the fast. The results suggest that decreased PDH activation after 40 h of fasting may have been a function of the large increase in PDK-4 mRNA expression and possible subsequent increase in PDK protein and activity. The changes in PDK-4 expression and PDH activity did not coincide with increases in the transcriptional activators PPAR-α and FKHR.