The Nurses' Role in the Cardiac Rehabilitation Team: Data From the Perfect-CR Study.

BACKGROUND: Nurses constitute a central profession in the cardiac rehabilitation (CR) team delivering comprehensive CR to individuals with cardiovascular disease. We aimed to identify specific components reflecting the nurses' role in the CR team associated with attainment of risk factor targets post myocardial infarction. METHODS: Center-level data (n = 78) was used from the Perfect-CR study, in which structure and processes applied at CR centers in Sweden (including details on the nurses' role) were surveyed. Patient-level data (n = 6755) was retrieved from the SWEDEHEART registry. Associations between structure/processes and target achievement for systolic blood pressure (BP) (<140 mm Hg) and low-density lipoprotein cholesterol (LDL-C, <1.8 mmol/L) at 1 year post myocardial infarction were assessed using logistic regression. RESULTS: Structure and processes reflecting nurses' autonomy and role in the CR team associated with patients achieving systolic BP and/or LDL-C targets included the following: nurses having treatment algorithms to adjust BP medication (odds ratio [95% confidence interval]: systolic BP, 1.22 [1.05-1.42]; LDL-C, 1.17 [1.03-1.34]) and lipid-lowering medication (systolic BP, 1.14 [1.00-1.29]; LDL-C, 1.17 [1.05-1.30]), patients having the same nurse throughout follow-up (systolic BP, 1.07 [1.03-1.11]; LDL-C, 1.10 [1.06-1.14]), number of follow-up hours with a nurse (systolic BP, 1.13 [1.07-1.19]), having regular case rounds to discuss patient cases during follow-up (LDL-C, 1.22 [1.09-1.35]), and nurses having training in counseling methods (systolic BP, 1.06 [1.03-1.10]). CONCLUSION: Components reflecting CR nurses' autonomy and role in the team are of importance for patients attaining risk factor targets post myocardial infarction. The results could provide guidance for optimizing nurses' competence and responsibilities within the CR team to improve patient care.

Overcoming the struggle of living with type 2 diabetes - diabetes specialist nurses' and patients' perspectives on digital interventions.

BACKGROUND: Diabetes self-management education and support (DSMES) is a cornerstone in the treatment of type 2 diabetes mellitus (T2DM). It is unclear whether delivering DSMES as a digital health intervention (DHI) might meet the needs experienced by patients with T2DM and diabetes specialist nurses (DSN) of the primary health care system in Sweden. METHODS: Fourteen patients with T2DM and four DSN participated in three separate focus groups: two groups comprised patients and one group comprised DSN. The patients discussed the questions: "What needs did you experience after your T2DM diagnosis?" and "How might these needs be met with a DHI?" The DSN discussed the questions: "What needs do you experience when treating a patient with newly diagnosed T2DM?" and "How might these needs be met with a DHI?". Furthermore, data were collected in the form of field notes from group discussions at a meeting including 18 DSNs working with T2DM in PHCCs. The discussions from focus groups were transcribed verbatim and analyzed together with the field notes from the meeting using inductive content analysis. RESULTS: The analysis yielded the overall theme: "Overcoming the struggle of living with T2DM", which was summarized in two categories: "learning and being prepared" and "giving and receiving support". Important findings were that, for success, a DHI for DSMES must be integrated into routine care, provide structured, high-quality information, suggest tasks to stimulate behavioral changes, and provide feedback from the DSN to the patient. CONCLUSION: This study highlighted several important aspects, from the perspectives of both the patient with T2DM and the DSN, which should be taken into consideration for the successful development and use of a DHI for DSMES.

Paradoxes of breast cancer incidence and mortality in two corners of Europe.

BACKGROUND: Breast cancer incidence is rising globally, while mortality rates show a geographical heterogenous pattern. Early detection and treatment have been proven to have a profound impact on breast cancer prognosis. The aim of his study was to compare breast cancer incidence, mortality, and survival rates in two contrasting corners of Europe, Sweden and Crete, to better understand cancer determinants with focus on disease burden and sociocultural factors. METHODS: Breast cancer data from Sweden and Crete was derived from registries. Incidence and mortality were expressed as Age-Standardized Incidence Rates (ASIR), Age-Standardized Mortality Rates (ASMR). FINDINGS: Breast cancer incidence has for decades risen in Sweden and on Crete. In 2019, ASIR was 217.5 in Sweden and 58.9 on Crete, (p < 0.001). Mortality rates showed opposite trends. ASMR in Sweden was reduced from 25.5 to 16.8 (2005-2019) while on Crete, ASMR increased from 22.1 to 25.3. A successive rise in survival rate in Sweden with a 5-year survival rate of 92% since 2015, but a converse development on Crete with 85% 5-year survival rate the same year. INTERPRETATION: The incidence of breast cancer is slowly rising in both studied regions, but mortality increases on Crete in contrast to Sweden with sinking mortality rates. The interpretation of these findings is that differences in health care systems and health policies including differences in early detection like screening programs and early treatment, as well as sociocultural factors in the two countries might play an important role on the differences found in breast cancer burden.

Oral glucose tolerance testing as a complement to fasting plasma glucose in screening for type 2 diabetes: population-based cross-sectional analyses of 146 000 health examinations in Västerbotten, Sweden.

OBJECTIVE: To assess the effect of adding an oral glucose tolerance test (OGTT) to fasting plasma glucose (FPG) in terms of detection of type 2 diabetes (T2D) and impaired glucose tolerance (IGT). DESIGN: Retrospective analysis of serial cross-sectional screening study. SETTING: Population-based health examinations within primary care in Västerbotten County, Sweden. PARTICIPANTS: Individuals aged 40- 50 and 60 years with participation from 1985 to 2017. Those with previously diagnosed diabetes and FPG≥7 mmol/L were excluded. PRIMARY AND SECONDARY OUTCOME MEASURES: Prevalence of hyperglycaemia on the OGTT (IGT and T2D defined as 2-hour postload capillary plasma glucose of 8.9-12.1 mmol/L and ≥12.2 mmol/L, respectively). Analyses were further stratified by age, sex and risk factor burden to identify groups at high or low risk of IGT and T2D on testing. The numbers needed to screen (NNS) to prevent one case of T2D through detection and treatment of IGT was estimated, combining prevalence numbers with average progression rates and intervention effects from previous meta-analyses. RESULTS: The prevalence of IGT ranged from 0.9% (95% CI 0.7% to 1.1%) to 29.6% (95% CI 27.4% to 31.7%), and the prevalence of T2D ranged from 0.06% (95% CI 0.02% to 0.11%) to 7.0% (95% CI 5.9% to 8.3%), depending strongly on age, sex and risk factor burden. The estimated NNS to prevent one case of T2D through detection and lifestyle treatment of IGT ranged from 1332 among 40-year-old men without risk factors, to 39 among 60-year-old women with all risk factors combined. CONCLUSIONS: The prevalence of hyperglycaemia on OGTT is highly dependent on age, sex and risk factor burden; OGTT should be applied selectively to high-risk groups to avoid unnecessary testing in the general population.

Improved Peripheral and Hepatic Insulin Sensitivity after Lifestyle Interventions in Type 2 Diabetes Is Associated with Specific Metabolomic and Lipidomic Signatures in Skeletal Muscle and Plasma.

Lifestyle interventions with weight loss can improve insulin sensitivity in type 2 diabetes (T2D), but mechanisms are unclear. We explored circulating and skeletal muscle metabolite signatures of altered peripheral (pIS) and hepatic insulin sensitivity (hIS) in overweight and obese T2D individuals that were randomly assigned a 12-week Paleolithic-type diet with (diet-ex, n = 13) or without (diet, n = 13) supervised exercise. Baseline and post-intervention measures included: mass spectrometry-based metabolomics and lipidomics of skeletal muscle and plasma; pIS and hIS; ectopic lipid deposits in the liver and skeletal muscle; and skeletal muscle fat oxidation rate. Both groups lowered BMI and total % fat mass and increased their pIS. Only the diet-group improved hIS and reduced ectopic lipids in the liver and muscle. The combined improvement in pIS and hIS in the diet-group were associated with decreases in muscle and circulating branched-chain amino acid (BCAA) metabolites, specifically valine. Improved pIS with diet-ex was instead linked to increased diacylglycerol (34:2) and triacylglycerol (56:0) and decreased phosphatidylcholine (34:3) in muscle coupled with improved muscle fat oxidation rate. This suggests a tissue crosstalk involving BCAA-metabolites after diet intervention with improved pIS and hIS, reflecting reduced lipid influx. Increased skeletal muscle lipid utilization with exercise may prevent specific lipid accumulation at sites that perturb insulin signaling.

The liver-alpha-cell axis after a mixed meal and during weight loss in type 2 diabetes.

OBJECTIVE: Glucagon and amino acids may be regulated in a feedback loop called the liver-alpha-cell axis with alanine or glutamine as suggested signal molecules. We assessed this concept in individuals with type 2 diabetes in the fasting state, after ingestion of a protein-rich meal, and during weight loss. Moreover, we investigated if postprandial glucagon secretion and hepatic insulin sensitivity were related. METHODS: This is a secondary analysis of a 12-week weight-loss trial (Paleolithic diet ± exercise) in 29 individuals with type 2 diabetes. Before and after the intervention, plasma glucagon and amino acids were measured in the fasting state and during 180 min after a protein-rich mixed meal. Hepatic insulin sensitivity was measured using the hyperinsulinemic-euglycemic clamp with [6,6-2H2]glucose as a tracer. RESULTS: The postprandial increase of plasma glucagon was associated with the postprandial increase of alanine and several other amino acids but not glutamine. In the fasted state and after the meal, glucagon levels were negatively correlated with hepatic insulin sensitivity (rS = -0.51/r = -0.58, respectively; both P < 0.05). Improved hepatic insulin sensitivity with weight loss was correlated with decreased postprandial glucagon response (r = -0.78; P < 0.001). CONCLUSIONS: Several amino acids, notably alanine, but not glutamine could be key signals to the alpha cell to increase glucagon secretion. Amino acids may be part of a feedback mechanism as glucagon increases endogenous glucose production and ureagenesis in the liver. Moreover, postprandial glucagon secretion seems to be tightly related to hepatic insulin sensitivity.

Using a Paleo Ratio to Assess Adherence to Paleolithic Dietary Recommendations in a Randomized Controlled Trial of Individuals with Type 2 Diabetes.

This study is a secondary analysis of a randomized controlled trial using Paleolithic diet and exercise in individuals with type 2 diabetes. We hypothesized that increased adherence to the Paleolithic diet was associated with greater effects on blood pressure, blood lipids and HbA1c independent of weight loss. Participants were asked to follow a Paleolithic diet for 12 weeks and were randomized to supervised exercise or general exercise recommendations. Four-day food records were analyzed, and food items characterized as "Paleolithic" or "not Paleolithic". Foods considered Paleolithic were lean meat, poultry, fish, seafood, fruits, nuts, berries, seeds, vegetables, and water to drink; "not Paleolithic" were legumes, cereals, sugar, salt, processed foods, and dairy products. A Paleo ratio was calculated by dividing the Paleolithic calorie intake by total calorie intake. A multiple regression model predicted the outcome at 12 weeks using the Paleo ratio, group affiliation, and outcome at baseline as predictors. The Paleo ratio increased from 28% at baseline to 94% after the intervention. A higher Paleo ratio was associated with lower fat mass, BMI, waist circumference, systolic blood pressure, and serum triglycerides at 12 weeks, but not with lower HbA1c levels. The Paleo ratio predicted triglyceride levels independent of weight loss (p = 0.046). Moreover, an increased monounsaturated/saturated fatty acids ratio and an increased polyunsaturated/saturated fatty acids ratio was associated with lower triglyceride levels independent of weight loss. (p = 0.017 and p = 0.019 respectively). We conclude that a higher degree of adherence to the Paleolithic diet recommendations improved fat quality and was associated with improved triglyceride levels independent of weight loss among individuals with type 2 diabetes.

Sex and age differences in the incidence of acute myocardial infarction during the COVID-19 pandemic in a Swedish health-care region without lockdown: a retrospective cohort study.

BACKGROUND: The incidence of acute myocardial infarction has decreased during the COVID-19 pandemic, but sex and age differences in this change in incidence have not been tested. Thus, we aimed to compare the incidence of acute myocardial infarction in a health-care region in Sweden during the COVID-19 pandemic with previous years and to evaluate sex and age differences. METHODS: We did a retrospective, observational cohort study using data from a national registry of patients admitted to coronary care units in Sweden. All patients admitted to one of three hospitals in Region Jönköping County with a diagnosis of acute myocardial infarction during the COVID-19 pandemic (March 1 to July 31, 2020) or reference period (March 1 to July 31, 2017-19) were included. The incidence of acute myocardial infarction (ST-elevation and non-ST-elevation) was calculated for both study periods. Participants were grouped according to sex and age (<70 years vs ≥70 years). The incidence and the incidence rate ratio (IRR) between the two study periods was calculated for each group and compared between groups using the Breslow-Day test. FINDINGS: The study included 1088 participants, 846 who were admitted for acute myocardial infarction during the reference period and 242 who were admitted during the COVID-19 pandemic period. The IRR of acute myocardial infarction for the COVID-19 period compared with the reference period was 0·85 (95% CI 0·73-0·98). The IRR for acute myocardial infarction was significantly lower among women aged 70 years or older (0·56 [0·40-0·78]) than among men aged 70 years or older (0·97 [0·77-1·23]; p=0·0074). INTERPRETATION: The incidence of acute myocardial infarction decreased predominantly among women aged 70 years or older during the COVID-19 pandemic. This highlights potential sex differences in health effects of the COVID-19 pandemic, which should be further elucidated. FUNDING: None.

Standard Modifiable Cardiovascular Risk Factors Mediate the Association Between Elevated Hair Cortisol Concentrations and Coronary Artery Disease.

BACKGROUND: Increased cortisol exposure is a risk factor for coronary artery disease (CAD). It is not clear to what degree this risk is independent from the standard modifiable risk factors (SMuRFs) dyslipidemia, hypertension, and diabetes. AIM: To use path analysis to test the direct and indirect association, mediated by SMuRFs, between long-term cortisol levels measured in hair cortisol concentration (HCC) and CAD. METHODS: Hair was sampled from patients admitted with acute myocardial infarction (n = 203) and a population-based sample without a diagnosis or symptoms of CAD (n = 3,134). The HCC was analyzed using radioimmunoassay and all the participants reported whether they were diagnosed with or treated for diabetes, hypertension, and hyperlipidemia. Path analysis was used to test to what degree the association between logarithmized (ln) HCC and CAD was direct or indirect, mediated by SMuRFs. RESULTS: Participants with CAD had elevated HCC compared to those without elevated HCC [median interquartile range (IQR): 75.2 (167.1) vs. 23.6 (35.0) pg/mg, p < 0.0001]. Higher HCC was associated with diabetes, hypertension, and hyperlipidemia, which, in turn, were associated with CAD. In path models, 80% of the association between ln(HCC) and CAD were mediated by SMuRFs, while the direct path between ln(HCC) and CAD was not statistically significant. CONCLUSION: The SMuRFs diabetes, hyperlipidemia, and hypertension mediate the association between ln(HCC) and CAD. Some association between ln(HCC) and CAD did not operate via the SMuRFs considered and might have a pathway through atherosclerosis or inflammation.

Diet-induced weight loss alters hepatic glucocorticoid metabolism in type 2 diabetes mellitus.

CONTEXT: Altered tissue-specific glucocorticoid metabolism has been described in uncomplicated obesity and type 2 diabetes. We hypothesized that weight loss induced by diet and exercise, which has previously been shown to reverse abnormal cortisol metabolism in uncomplicated obesity, also normalizes cortisol metabolism in patients with type 2 diabetes. OBJECTIVE: Test the effects of a diet intervention with added exercise on glucocorticoid metabolism. DESIGN: Two groups followed a Paleolithic diet (PD) for 12 weeks with added 180 min of structured aerobic and resistance exercise per week in one randomized group (PDEX). SETTING: Umeå University Hospital. PARTICIPANTS: Men and women with type 2 diabetes treated with lifestyle modification ± metformin were included. Twenty-eight participants (PD, n = 15; PDEX, n = 13) completed measurements of glucocorticoid metabolism. MAIN OUTCOME MEASURES: Changes in glucocorticoid metabolite levels in 24-h urine samples, expression of HSD11B1 mRNA in s.c. adipose tissue and conversion of orally administered cortisone to cortisol measured in plasma. Body composition and insulin sensitivity were measured using a hyperinsulinemic-euglycemic clamp, and liver fat was measured by magnetic resonance spectroscopy. RESULTS: Both groups lost weight and improved insulin sensitivity. Conversion of orally taken cortisone to plasma cortisol and the ratio of 5α-THF + 5ß-THF/THE in urine increased in both groups. CONCLUSIONS: These interventions caused weight loss and improved insulin sensitivity with concomitant increases in the conversion of cortisone to cortisol, which is an estimate of hepatic HSD11B1 activity. This suggests that dysregulation of liver glucocorticoid metabolism in these patients is a consequence rather than a cause of metabolic dysfunction.

Elevated levels of cortisol in hair precede acute myocardial infarction.

Long term stress exposure is typical for modern societies and might trigger different diseases. This case-control study reveals that persons who had suffered an acute myocardial infarction (AMI) had elevated cortisol concentrations in the month before the acute event. Middle-aged patients admitted to cardiology clinics with acute myocardial infarction (AMI) (n = 174) were compared to 3156 controls from a population-based cohort in southeast Sweden. The median Hair Cortisol Concentrations (HCC) for those who had suffered an AMI was 53.2 pg/mg compared to 22.2 pg/mg for the control group (p < 0.001). In bivariate analysis, higher levels of HCC were strongly (OR = 5.69) and statistically significantly associated with current AMI status. The discrimination of cases with AMI from controls remained statistically significant (OR = 5.04) even after controlling for established cardiovascular risk factors in a multivariate analysis. Middle-aged persons with acute myocardial infarction had significantly elevated cortisol levels during the month before the cardiac event. This was evident for both men and women. The biomarker cortisol concentration was independently and statistically significantly related to AMI. Chronic stress seems to be a new promising risk factor for AMI.

Elevated resting-state connectivity in the medial temporal lobe and the prefrontal cortex among patients with Cushing's syndrome in remission.

Objective Cushing's syndrome is associated with long-term cognitive deficits and affective symptoms such as depression and anxiety. The alterations in brain function underlying these deficits after Cushing's syndrome are unclear and therefore we aimed to explore alterations in resting-state functional connectivity in patients with Cushing's syndrome in remission. Design Cross-sectional case-control study. Methods Nineteen women with Cushing's syndrome in remission for a median time of 7 years (IQR: 6-10) and a mean age of 45 years were included at three university clinics. These patients and 38 age-matched female controls underwent brain imaging at a single center. The main outcome measure was functional connectivity at rest, measured with functional magnetic resonance imaging. Results The medial temporal lobe (MTL) and prefrontal cortex networks, exhibited elevated functional connectivity among patients compared to controls. The degree of elevated functional connectivity in the MTL was negatively associated with time in remission. Conclusions Resting-state functional connectivity within glucocorticoid receptor-rich regions, particularly the MTL and medial prefrontal cortex, was increased in patients. These differences in connectivity may provide a neural basis for the cognitive deficits and affective symptoms commonly experienced by patients with Cushing's syndrome in remission.

Exercise Training Adds Cardiometabolic Benefits of a Paleolithic Diet in Type 2 Diabetes Mellitus.

Background The accumulation of myocardial triglycerides and remodeling of the left ventricle are common features in type 2 diabetes mellitus and represent potential risk factors for the development of diastolic and systolic dysfunction. A few studies have investigated the separate effects of diet and exercise training on cardiac function, but none have investigated myocardial changes in response to a combined diet and exercise intervention. This 12-week randomized study assessed the effects of a Paleolithic diet, with and without additional supervised exercise training, on cardiac fat, structure, and function. Methods and Results Twenty-two overweight and obese subjects with type 2 diabetes mellitus were randomized to either a Paleolithic diet and standard-care exercise recommendations ( PD ) or to a Paleolithic diet plus supervised exercise training 3 hours per week ( PD - EX ). This study includes secondary end points related to cardiac structure and function, ie, myocardial triglycerides levels, cardiac morphology, and strain were measured using cardiovascular magnetic resonance, including proton spectroscopy, at baseline and after 12 weeks. Both groups showed major favorable metabolic changes. The PD - EX group showed significant decreases in myocardial triglycerides levels (-45%, P=0.038) and left ventricle mass to end-diastolic volume ratio (-13%, P=0.008) while the left ventricle end-diastolic volume and stroke volume increased significantly (+14%, P=0.004 and +17%, P=0.008, respectively). These variables were unchanged in the PD group. Conclusions Exercise training plus a Paleolithic diet reduced myocardial triglycerides levels and improved left ventricle remodeling in overweight/obese subjects with type 2 diabetes mellitus. Clinical Trial Registration URL : http://www.clinicaltrials.gov . Unique identifier: NCT 01513798.

Treadmill workstations in office workers who are overweight or obese: a randomised controlled trial.

BACKGROUND: Treadmill workstations that enable office workers to walk on a treadmill while working at their computers might increase physical activity in offices, but long-term effects are unknown. We therefore investigated whether treadmill workstations in offices increased daily walking time. METHODS: We did a randomised controlled trial of healthy office workers who were either overweight or obese. We recruited participants from 13 different companies, which comprised 17 offices, in Umeå, Sweden. We included people who were aged 40-67 years, had sedentary work tasks, and had a body-mass index (BMI) between 25 kg/m2 and 40 kg/m2. After the baseline measurement, we stratified participants by their BMI (25-30 kg/m2 and >30 to 40 kg/m2); subsequently, an external statistician randomly assigned these participants (1:1) to either the intervention group (who received treadmill workstations for optional use) or the control group (who continued to work at their sit-stand desks as usual). Participants in the intervention group received reminders in boosting emails sent out to them at four occasions during the study period. Researchers were masked to group assignment until after analysis of the primary outcome. After the baseline measurement, participants were not masked to group belongings. The primary outcome was total daily walking time at weekdays and weekends, measured at baseline, 2 months, 6 months, 10 months, and 13 months with the accelerometer activPAL (PAL Technologies, Glasgow, UK), which was worn on the thigh of participants for 24 h a day for 7 consecutive days. We used an intention-to-treat approach for our analyses. This trial is registered with ClinicalTrials.gov, number NCT01997970, and is closed to new participants. FINDINGS: Between Nov 1, 2013, and June 30, 2014, a total of 80 participants were recruited and enrolled (n=40 in both the intervention and control groups). Daily walking time during total time awake at weekdays increased between baseline and 13 months by 18 min (95% CI 9 to 26) in the intervention group and 1 min (-7 to 9) in the control group (difference 22 min [95% CI 7 to 37], pinteraction=0·00045); for weekend walking, the change from baseline to 13 months was 5 min (-8 to 18) in the intervention group and 8 min (-5 to 21) in the control group (difference -1 min [-19 to 17]; pinteraction=0·00045). Neither measure met our predetermined primary outcome of 30 min difference in total walking time between the intervention and control group, so the primary outcome of the trial was not met. One adverse event was reported in a participant who accidently stepped on their Achilles tendon. INTERPRETATION: In a sedentary work environment, treadmill workstations result in a statistically significant but smaller-than-expected increase in daily walking time. Future studies need to investigate how increasing physical activity at work might have potentially compensatory effects on non-work activity. FUNDING: Umeå University, the Västerbotten County Council, and the Mayo Clinic Foundation for Research.

A heterogeneous response of liver and skeletal muscle fat to the combination of a Paleolithic diet and exercise in obese individuals with type 2 diabetes: a randomised controlled trial.

AIMS/HYPOTHESIS: The aim of the study was to investigate ectopic fat deposition and insulin sensitivity, in a parallel single-blinded randomised controlled trial, comparing Paleolithic diet alone with the combination of Paleolithic diet and exercise in individuals with type 2 diabetes. METHODS: Thirty-two individuals with type 2 diabetes with BMI 25-40 kg/m2 and 30-70 years of age followed a Paleolithic diet ad libitum for 12 weeks. In addition, study participants were randomised by computer program to either supervised combined exercise training (PD-EX group) or standard care exercise recommendations (PD group). Staff performing examinations and assessing outcomes were blinded to group assignment. Thirteen participants were analysed in each group: hepatic and peripheral insulin sensitivity were measured using the hyperinsulinaemic-euglycaemic clamp technique combined with [6,6-2H2]glucose infusion, and liver fat was assessed by proton magnetic resonance spectroscopy; both analyses were secondary endpoints. Intramyocellular lipid (IMCL) content was measured by magnetic resonance spectroscopy as a secondary analysis. All examinations were performed at Umeå University Hospital, Umeå, Sweden. RESULTS: Both study groups showed a median body weight loss of 7 kg. Fat mass decreased by 5.7 kg in the PD group and by 6.5 kg in the PD-EX group. Maximum oxygen uptake increased in the PD-EX group only. Liver fat showed a consistent reduction (74% decrease) in the PD group, while the response in the PD-EX group was heterogeneous (p < 0.05 for the difference between groups). IMCL content of the soleus muscle decreased by 40% in the PD group and by 22% in the PD-EX group (p < 0.05 for the difference between groups). Both groups improved their peripheral and adipose tissue insulin sensitivity, but not their hepatic insulin sensitivity. Plasma fetuin-A decreased by 11% in the PD group (p < 0.05) and remained unchanged in the PD-EX group. Liver fat changes during the intervention were correlated with changes in fetuin-A (rS = 0.63, p < 0.01). Participants did not report any important adverse events caused by the intervention. CONCLUSIONS/INTERPRETATION: A Paleolithic diet reduced liver fat and IMCL content, while there was a tissue-specific heterogeneous response to added exercise training. TRIAL REGISTRATION: ClinicalTrials.gov NCT01513798 FUNDING: Swedish Diabetes Research Foundation, County Council of Västerbotten, Swedish Heart and Lung Foundation, King Gustav V and Queen Victoria's Foundation.

A Paleolithic Diet with and without Combined Aerobic and Resistance Exercise Increases Functional Brain Responses and Hippocampal Volume in Subjects with Type 2 Diabetes.

Type 2 diabetes is associated with impaired episodic memory functions and increased risk of different dementing disorders. Diet and exercise may potentially reverse these impairments. In this study, sedentary individuals with type 2 diabetes treated by lifestyle ± metformin were randomized to a Paleolithic diet (PD, n = 12) with and without high intensity exercise (PDEX, n = 12) for 12 weeks. Episodic memory function, associated functional brain responses and hippocampal gray matter volume was measured by magnetic resonance imaging. A matched, but not randomized, non-interventional group was included as a reference (n = 6). The PD included a high intake of unsaturated fatty acids and protein, and excluded the intake of dairy products, grains, refined sugar and salt. The exercise intervention consisted of 180 min of supervised aerobic and resistance exercise per week. Both interventions induced a significant weight loss, improved insulin sensitivity and increased peak oxygen uptake without any significant group differences. Furthermore, both interventions were associated with increased functional brain responses within the right anterior hippocampus, right inferior occipital gyrus and increased volume of the right posterior hippocampus. There were no changes in memory performance. We conclude that life-style modification may improve neuronal plasticity in brain areas linked to cognitive function in type 2 diabetes. Putative long-term effects on cognitive functions including decreased risk of dementing disorders await further studies. Clinical trials registration number: Clinicaltrials. gov NCT01513798.

Carbonyl reductase 1 catalyzes 20ß-reduction of glucocorticoids, modulating receptor activation and metabolic complications of obesity.

Carbonyl Reductase 1 (CBR1) is a ubiquitously expressed cytosolic enzyme important in exogenous drug metabolism but the physiological function of which is unknown. Here, we describe a role for CBR1 in metabolism of glucocorticoids. CBR1 catalyzes the NADPH- dependent production of 20ß-dihydrocortisol (20ß-DHF) from cortisol. CBR1 provides the major route of cortisol metabolism in horses and is up-regulated in adipose tissue in obesity in horses, humans and mice. We demonstrate that 20ß-DHF is a weak endogenous agonist of the human glucocorticoid receptor (GR). Pharmacological inhibition of CBR1 in diet-induced obesity in mice results in more marked glucose intolerance with evidence for enhanced hepatic GR signaling. These findings suggest that CBR1 generating 20ß-dihydrocortisol is a novel pathway modulating GR activation and providing enzymatic protection against excessive GR activation in obesity.

Decreased prefrontal functional brain response during memory testing in women with Cushing's syndrome in remission.

Neurocognitive dysfunction is an important feature of Cushing's syndrome (CS). Our hypothesis was that patients with CS in remission have decreased functional brain responses in the prefrontal cortex and hippocampus during memory testing. In this cross-sectional study we included 19 women previously treated for CS and 19 controls matched for age, gender, and education. The median remission time was 7 (IQR 6-10) years. Brain activity was studied with functional magnetic resonance imaging during episodic- and working-memory tasks. The primary regions of interest were the prefrontal cortex and the hippocampus. A voxel-wise comparison of functional brain responses in patients and controls was performed. During episodic-memory encoding, patients displayed lower functional brain responses in the left and right prefrontal gyrus (p<0.001) and in the right inferior occipital gyrus (p<0.001) compared with controls. There was a trend towards lower functional brain responses in the left posterior hippocampus in patients (p=0.05). During episodic-memory retrieval, the patients displayed lower functional brain responses in several brain areas with the most predominant difference in the right prefrontal cortex (p<0.001). During the working memory task, patients had lower response in the prefrontal cortices bilaterally (p<0.005). Patients, but not controls, had lower functional brain response during a more complex working memory task compared with a simpler one. In conclusion, women with CS in long-term remission have reduced functional brain responses during episodic and working memory testing. This observation extends previous findings showing long-term adverse effects of severe hypercortisolaemia on brain function.

Benefits of a Paleolithic diet with and without supervised exercise on fat mass, insulin sensitivity, and glycemic control: a randomized controlled trial in individuals with type 2 diabetes.

BACKGROUND: Means to reduce future risk for cardiovascular disease in subjects with type 2 diabetes are urgently needed. METHODS: Thirty-two patients with type 2 diabetes (age 59 ± 8 years) followed a Paleolithic diet for 12 weeks. Participants were randomized to either standard care exercise recommendations (PD) or 1-h supervised exercise sessions (aerobic exercise and resistance training) three times per week (PD-EX). RESULTS: For the within group analyses, fat mass decreased by 5.7 kg (IQR: -6.6, -4.1; p < 0.001) in the PD group and by 6.7 kg (-8.2, -5.3; p < 0.001) in the PD-EX group. Insulin sensitivity (HOMA-IR) improved by 45% in the PD (p < 0.001) and PD-EX (p < 0.001) groups. HbA1c decreased by 0.9% (-1.2, -0.6; p < 0.001) in the PD group and 1.1% (-1.7, -0.7; p < 0.01) in the PD-EX group. Leptin decreased by 62% (p < 0.001) in the PD group and 42% (p < 0.001) in the PD-EX group. Maximum oxygen uptake increased by 0.2 L/min (0.0, 0.3) in the PD-EX group, and remained unchanged in the PD group (p < 0.01 for the difference between intervention groups). Male participants decreased lean mass by 2.6 kg (-3.6, -1.3) in the PD group and by 1.2 kg (-1.3, 1.0) in the PD-EX group (p < 0.05 for the difference between intervention groups). CONCLUSIONS: A Paleolithic diet improves fat mass and metabolic balance including insulin sensitivity, glycemic control, and leptin in subjects with type 2 diabetes. Supervised exercise training may not enhance the effects on these outcomes, but preserves lean mass in men and increases cardiovascular fitness. Copyright © 2016 John Wiley & Sons, Ltd.

Higher diurnal salivary cortisol levels are related to smaller prefrontal cortex surface area in elderly men and women.

OBJECTIVE: Elevated cortisol levels with aging have been associated with atrophy of the hippocampus and prefrontal cortex (PFC), as well as with impaired cognitive functions in men. However, coexisting diseases have confounded many studies examining these relationships. Studies in women are lacking. Our objective was to test whether salivary cortisol levels were related to morphology of the hippocampus and the PFC, and to cognitive performance. DESIGN: A cross-sectional study including 200 elderly (55-80 years old) men and women. METHOD: We used magnetic resonance imaging, tests of episodic-, semantic-, and working memory, visuospatial ability, and cortisol levels in four saliva samples collected during 1 day. RESULTS: Area under the curve (AUC) for cortisol levels was negatively related to cortical surface area of the left anterior cingulate gyrus (caudal P<0.001; rostral P=0.006), right lateral orbitofrontal cortex (P=0.004), and right rostral middle frontal gyrus (P=0.003). In women, there was also a negative relationship with cortical surface area in the left rostral middle frontal gyrus (P=0.006). No relationship was found between cortisol levels and hippocampal volume. CONCLUSION: This study suggests that the structure of the medial PFC is related to cortisol levels in both elderly women and men.