Comparison of patient characteristics, clinical management, infectious specialist consultation, and outcome in men and women with methicillin-sensitive Staphylococcus aureus bacteremia: a propensity-score adjusted retrospective study.

BACKGROUND: Sex-related treatment inequalities are suggested to explain outcome differences between men and women in Staphylococcus aureus bacteremia (SAB). We compared patient characteristics, clinical management, infectious specialist consultation (ISC) and outcome in men and women with SAB. METHODS: Multicenter retrospective study of methicillin-sensitive (MS-) SAB patients categorized according to sex and ISC consultation provided within 7 days of diagnosis. RESULTS: Altogether 617 SAB patients were included in the analysis: 62% males and 38% females. Male sex was associated less often to nosocomial bacteremia (OR 0.69, 95% CI 0.50-0.96, p = 0.029) and more often to alcoholism (OR 2.25, 95% CI 1.31-3.87, p = 0.003). No sex-related differences were seen in basic or immunologic laboratory tests, illness severity, intensive care unit treatment or thromboembolic events. ISC was provided to most patients (94%) irrespective of sex. No differences were seen in clinical management of men or women: Transthoracic or -esophageal echocardiography (61% vs. 65%), deep infection (77% vs. 72%), infection removal (30% vs. 27%) and anti-staphylococcal antibiotics as first-line treatment (54% vs. 51%). However, male sex was connected to more frequent adjunctive rifampicin treatment (52% vs. 41%, p = 0.025). No difference in 28- or 90-day mortality (13% vs. 13% and 18% vs. 20%) or SAB relapse (0% vs. 1%) was observed between men and women. Propensity-score adjusted Cox proportional analysis gave no connection of sex to mortality within 90 days. CONCLUSION: Patient characteristics, clinical management, ISC guidance, bacteremia relapse, and outcome did not differ in men and women with MS-SAB.

Methicillin-sensitive Staphylococcus aureus bacteremia in aged patients: the importance of formal infectious specialist consultation.

BACKGROUND: Infectious specialist consultations (ISC) provide ever more evidence for improved outcome in Staphylococcus aureus bacteremia (SAB). Most ISC are formal (bedside). However, the impact of ISC on clinical management and prognosis lacks evaluation in aged patients with SAB. METHODS: Multicenter retrospective analysis of methicillin-sensitive (MS) SAB. Patients were stratified according to age ≥ 60 years (sub-analyses for ≥ 75 years and females) and formal (bedside) ISC given within 7 days of SAB diagnosis. The impact on management and outcome of formal ISC was explored. Statistics were performed with univariate analysis, Cox proportional hazards regression model analysis, including propensity-score adjustment, and graphic Kaplan-Meier interpretation. RESULTS: Altogether 617 patients were identified and 520 (84%) had formal ISC. Presence of formal ISC resulted in equivalent clinical management regardless of age over or under 60 years: localization and eradication of infection foci (80 vs. 82% and 34 vs. 36%) and use of anti-staphylococcal antibiotics (65 vs. 61%). Patients aged ≥ 60 years managed without formal ISC, compared to those with formal ISC, had less infection foci diagnosed (53 vs. 80%, p < 0.001). Lack of formal ISC in patients aged ≥ 60 years resulted in no infection eradication and absence of first-line anti-staphylococcal antibiotics. Formal ISC, compared to absence of formal ISC, lowered mortality at 90 days in patients aged ≥ 60 years (24 vs. 47%, p = 0.004). In Cox proportional regression, before and after propensity-score adjustment, formal ISC was a strong positive prognostic parameter in patients aged ≥ 60 years (HR 0.45; p = 0.004 and HR 0.44; p = 0.021), in patients aged ≥ 75 years (HR 0.18; p = 0.001 and HR 0.11; p = 0.003) and in female patients aged ≥ 75 years (HR 0.13; p = 0.005). CONCLUSION: Formal ISC ensures proper active clinical management irrespective of age and improve prognosis in aged patients with MS-SAB.

Correction to: Methicillin-sensitive Staphylococcus aureus bacteremia in aged patients: the importance of formal infectious specialist consultation.

[This corrects the article DOI: 10.1007/s41999-018-0038-2.].

Prognostic impact of hyperglycemia at onset of methicillin-sensitive Staphylococcus aureus bacteraemia.

Previous reports have associated hyperglycemia to poor outcome among aged and comorbid Staphylococcus aureus bacteraemia (SAB) patients. However, the prognostic impact of hyperglycemia in SAB irrespective of age and underlying conditions including a diagnosis of diabetes has received little attention. The objective here was to evaluate the prognostic relevance of hyperglycemia at onset of methicillin-sensitive SAB (MS-SAB). It was a retrospective study of MS-SAB patients. Blood glucose was measured within 24 h of positive blood cultures. The patient cohort was analyzed en bloc and by categorization according to age, underlying conditions and a diagnosis of diabetes. Altogether 161 patients were identified. High initial blood glucose levels were observed among diabetics (p < 0.001), patients with deep infections (p < 0.05) and poor outcome at 28- or 90-days (p < 0.05). Receiver operating characteristics presented the glucose cut-off level of 7.2 mmol/L as a significant predictor of mortality with an area under the curve of 0.63 (95% CI 0.52-0.75, p < 0.05). Blood glucose ≥7.2 mmol/L connected to higher 28- (9 vs. 20%, p < 0.05) and 90-day (14 vs. 29%, p < 0.01) mortality. In Cox proportional hazard regression the blood glucose cut-off value of 7.2 mmol/L significantly predicted 90-day mortality (HR, 2.12; 95% CI, 1.01-4.46; p < 0.05). Among young and healthy non-diabetics the negative prognostic impact of high glucose was further accentuated (HR 7.46, p < 0.05). High glucose levels had no prognostic impact among diabetics. Hyperglycemia at SAB onset may associate to poor outcome. The negative prognostic impact is accentuated among young and healthy non-diabetics.

Thrombocytopaenia during methicillin-sensitive Staphylococcus aureus bacteraemia.

The prognostic impact of thrombocytopaenia in Staphylococcus aureus bacteraemia (SAB) has previously been determined at bacteraemia onset only and relevant pre-bacteraemic thrombocytopaenia predisposing parameters have not been accounted for. We evaluated the prognostic impact of low thrombocyte count in SAB excluding pre-bacteraemic factors potentially causing thrombocytopaenia. This was a multicentre retrospective analysis of methicillin-sensitive SAB (MS-SAB) patients. Thrombocyte count was determined at blood culture collection and at days 3 and 7. Thrombocytopaenia was defined as a thrombocyte count less than 150 ×109/L. Patients with chronic alcoholism, liver diseases and haematologic malignancies were excluded. Altogether, 495 patients were identified. Thrombocytopaenia at blood culture and at day 3 associated to endocarditis (p < 0.05 and p < 0.01) and defervescence (p < 0.001 and p < 0.01). Mortality at 90 days was higher for patients with thrombocytopaenia at blood culture collection (26 vs. 16%, p < 0.05), at day 3 (32 vs. 13%, p < 0.01) and at day 7 (50 vs. 14%, p < 0.001). In receiver operating characteristic analyses, thrombocytopaenia predicted a poor outcome at blood culture collection (p < 0.05), at day 3 (p < 0.001) and at day 7 (p < 0.001). When accounting for all prognostic parameters, thrombocytopaenia at day 3 [hazard ratio (HR), 1.83; p = 0.05] demonstrated a trend towards poor outcome, whereas thrombocytopaenia at day 7 (HR, 3.64; p < 0.001) associated to poor outcome. Thrombocytopaenia at blood culture collection was not a prognostic parameter when all prognostic factors were taken into account. However, thrombocytopaenia at day 3 indicated a poor outcome and thrombocytopaenia at day 7 was a significant independent negative prognostic marker that has not been previously reported in SAB.

Should all adjunctive corticosteroid therapy be avoided in the management of hemodynamically stabile Staphylococcus aureus bacteremia?

The purpose of this study was to examine the prognostic impact of corticosteroids in hemodynamically stabile Staphylococcus aureus bacteremia (SAB). There were 361 hemodynamically stabile methicillin-sensitive SAB patients with prospective follow-up and grouping according to time-point, dose and indication for corticosteroid therapy. To enable analyses without external interfering corticosteroid therapy all patients with corticosteroid therapy equivalent to prednisone >10 mg/day for ≥1 month prior to positive blood culture results were excluded. Twenty-five percent (92) of patients received corticosteroid therapy of which 11 % (40) had therapy initiated within 1 week (early initiation) and 9 % (31) had therapy initiated 2-4 weeks after (delayed initiation) positive blood culture. Twenty-one patients (6 %) had corticosteroid initiated after 4 weeks and were not included in the analyses. A total of 55 % (51/92) received a weekly prednisone dose >100 mg. Patients with early initiated corticosteroid therapy had higher mortality compared to patients treated without corticosteroid therapy at 28 days (20 % vs. 7 %) (OR, 3.11; 95%CI, 1.27-7.65; p < 0.05) and at 90 days (30 % vs. 10 %) (OR, 4.01; 95%CI, 1.82-8.81; p < 0.001). Considering all prognostic markers, early initiated corticosteroid therapy predicted 28-day (HR, 3.75; 95%CI, 1.60-8.79; p = 0.002) and 90-day (HR, 3.10; 95%CI, 1.50-6.39; p = 0.002) mortality in Cox proportional hazards regression analysis. When including only patients receiving early initiated corticosteroid therapy with prednisone ≥100 mg/week the negative prognostic impact on 28-day mortality was accentuated (HR 4.8, p = 0.001). Corticosteroid therapy initiation after 1 week of positive blood cultures had no independent prognostic impact. Early initiation of corticosteroid therapy may be associate to increased mortality in hemodynamically stabile SAB.

Telephone consultation cannot replace bedside infectious disease consultation in the management of Staphylococcus aureus Bacteremia.

BACKGROUND: Infectious disease specialist (IDS) consultation improves the outcome of Staphylococcus aureus bacteremia (SAB). Although telephone consultations constitute a substantial part of IDS consultations, their impact on treatment outcome lacks evaluation. METHODS: We retrospectively followed 342 SAB episodes with 90-day follow-up, excluding 5 methicillin-resistant S. aureus SAB cases. Patients were grouped according to bedside, telephone, or no IDS consultation within the first week. Patients with fatal outcome within 3 days after onset of SAB were excluded to allow for the possibility of death occurring before IDS consultation. RESULTS: Seventy-two percent of patients received bedside, 18% telephone, and 10% no IDS consultation. Patients with bedside consultation were less often treated in an intensive care unit during the first 3 days compared to those with telephone consultation (odds ratio [OR], 0.53; 95% confidence interval [CI], .29-.97; P = .037; 21% vs 34%), with no other initial differences between these groups. Patients with bedside consultation more often had deep infection foci localized as compared to patients with telephone consultation (OR, 3.11; 95% CI, 1.74-5.57; P < .0001; 78% vs 53%). Patients with bedside consultation had lower mortality than patients with telephone consultation at 7 days (OR, 0.09; 95% CI, .02-.49; P = .001; 1% vs 8%), at 28 days (OR, 0.27; 95% CI, .11-.65; P = .002; 5% vs 16%) and at 90 days (OR, 0.25; 95% CI, .13-.51; P < .0001; 9% vs 29%). Considering all prognostic markers, 90-day mortality for telephone-consultation patients was higher (OR, 2.31; CI, 95% 1.22-4.38; P = .01) as compared to bedside consultation. CONCLUSIONS: Telephone IDS consultation is inferior to bedside IDS consultation.

Elevated soluble urokinase plasminogen activator receptor (suPAR) predicts mortality in Staphylococcus aureus bacteremia.

The soluble form of urokinase-type plasminogen activator receptor (suPAR) is a new inflammatory marker. High suPAR levels have been shown to associate with mortality in cancer and in chronic infections like HIV and tuberculosis, but reports on the role of suPAR in acute bacteremic infections are scarce. To elucidate the role of suPAR in a common bacteremic infection, the serum suPAR levels in 59 patients with Staphylococcus aureus bacteremia (SAB) were measured using the suPARnostic ELISA assay and associations to 1-month mortality and with deep infection focus were analyzed. On day three, after the first positive blood culture for S. aureus, suPAR levels were higher in 19 fatalities (median 12.3; range 5.7-64.6 ng/mL) than in 40 survivors (median 8.4; range 3.7-17.6 ng/mL, p = 0.002). This difference persisted for 10 days. The presence of deep infection focus was not associated with elevated suPAR levels as compared to patients with no deep infection focus. suPAR was found to be prognostic for mortality in receiver operator characteristic (ROC) curve analysis, which was not observed for serum C-reactive protein (CRP); the area under the curve (AUC) for suPAR was 0.754 (95% confidence interval [CI], 0.615-0.894, p = 0.003) and for CRP, it was 0.596 (95% CI, 0.442-0.750, p = 0.253). The optimal suPAR cut-off value in predicting 1-month mortality was 9.25 ng/mL. In conclusion, our study demonstrates that the new promising biomarker, serum suPAR concentration, was able to predict mortality in SAB.

Predisposing factors, disease progression and outcome in 430 prospectively followed patients of healthcare- and community-associated Staphylococcus aureus bacteraemia.

Staphylococcus aureus bacteraemia (SAB) episodes identified in a prospective multicentre study during 1999-2002 (not including MRSA) were followed up by an infectious disease specialist. The aim of this study was to compare predisposing factors, disease progression and outcome of healthcare (HA)- and community (CA)-associated SAB. Of 430 SAB episodes, 232 (54%) were HA. The HA-SAB patients were significantly older and more chronically ill compared to CA-SAB. Deep infection foci prevalence within three days of onset of SAB for HA versus CA were deep-seated abscesses (26% vs 37%, P < 0.05), pneumonia [25% vs 31%, non-significant (NS)], osteomyelitis (24% vs 36%, P<0.01), permanent foreign body (24% vs 9%, P<0.001), endocarditis (11% vs 15%, NS), septic arthritis (9% vs 13%, NS) and no infection focus (3% vs 6%, NS). The case fatality rates for HA-SAB versus CA-SAB at 28 days were 14% vs 11% (NS). Independent risk factors according to multivariate analysis for a fatal outcome were age, chronic alcoholism, immunosuppressive treatment, ultimately or rapidly fatal underlying diseases, severe sepsis on the onset of SAB, S. aureus pneumonia and endocarditis. As a result of a prospective study design, meticulous infection foci search and infectious disease specialist follow-up of each SAB episode, the case fatality remained low and 97% of the HA-SAB episodes presented infection foci within three days of onset of bacteraemia.

Genetic polymorphism of the C-reactive protein (CRP) gene and a deep infection focus determine maximal serum CRP level in Staphylococcus aureus bacteremia.

C-reactive protein (CRP) is widely used in early detection of sepsis or organ dysfunction. Several single nucleotide polymorphisms (SNPs) in the CRP gene are shown to be associated with variability of basal CRP. To clarify the effect of these SNPs to CRP response in systemic infections, we compared genetic and clinical data on patients with Staphylococcus aureus bacteremia (SAB). Six SNPs in the CRP gene region (rs2794521, rs30912449, rs1800947, rs1130864, rs1205 and rs3093075) were genotyped in 145 patients and analyzed for associations with CRP and various clinical outcomes. We found that the rare minor A-allele of triallelic SNP rs30912449 (C > T > A) and presence of a deep infection focus were strongly associated to the higher maximal CRP during the first week of SAB. Median of the maximal CRP in patients who had the A-minor allele was 282 mg/L (interquartile range [IQR, defined as the difference between the third quartile and the first quartile], 169 mg/L) but only 179 mg/L (IQR, 148 mg/L) in patients without this allele (P = 0.004), and CRP in patients who had deep infection focus was higher 208 mg/L (IQR, 147 mg/L) than in other patients 114 mg/L (IQR, 121 mg/l) (P < 0.0001). Mortality, degree of leucocytosis, time to defervescence or number of deep infections were not affected by CRP gene SNPs. The maximal CRP during the first week in SAB was partly determined by variation in the CRP gene and partly by presence of deep infection focus. This finding suggests cautiousness in interpreting exceptionally high CRPs from SAB patients and comparison between patients.

Cluster of imported malaria from Gambia in Finland--travellers do not listen to given advice.

Twelve Finnish tourists contracted falciparum malaria from Gambia in the period between 3 and 27 November 2008. None of them had used adequate malaria chemoprophylaxis.

Quality of care experienced by Finnish cancer patients during radiotherapy.

The purpose of this study is to describe patients' experiences of the quality of care received at a radiotherapy centre. The data were collected using the Good Nursing Care Scale For Patients (GNCS/P), which was modified for this study. Structured questionnaires were handed out in March-May 2004 to 150 adult curative cancer patients attending outpatient radiotherapy at a university hospital in Finland. A total of 135 completed questionnaires were returned. The patients were generally satisfied with the quality of care they received. Among the four quality categories, the highest ratings were given to staff characteristics, and the lowest to the environment. Younger patients, employed patients and those with a higher level of education gave the lowest quality ratings. Improvements are needed primarily in the counselling and education of patients and their relatives. The results of this study provide valuable clues for improving the quality of care in radiotherapy based on patients' expectations.

Common polymorphisms of calpain-10 are associated with abdominal obesity in subjects at high risk of type 2 diabetes.

AIMS/HYPOTHESIS: The mechanisms by which the calpain-10 gene (CAPN10) affects the risk of type 2 diabetes are unclear. Therefore, we investigated the effects of four polymorphisms in CAPN10 (single nucleotide polymorphism [SNP]-43, SNP-44, Insertion/Deletion [Indel]-19 and SNP-63) on insulin secretion, insulin action and abdominal fat distribution in offspring of patients with type 2 diabetes. SUBJECTS AND METHODS: Insulin secretion was determined by an IVGTT, insulin action by the hyperinsulinaemic-euglycaemic clamp and abdominal fat distribution by computed tomography in 158 non-diabetic offspring (age 34.9+/-6.3 years [mean+/-SD], BMI 26.2+/-4.9 kg/m(2)) of type 2 diabetic patients. RESULTS: SNP-43 (p=0.009 over the three genotypes, adjusted for age, sex, BMI and family relationship) and haplotypes carrying the A allele of SNP-43 were associated with intra-abdominal fat area. The A allele of SNP-43 was associated with intra-abdominal fat area in men (p=0.014) but not in women. SNP-44, InDel-19 and SNP-63 were not associated with intra-abdominal fat area or insulin action. Furthermore, we demonstrated in a separate sample of middle-aged men (n=234) who had a history of type 2 diabetes in first-degree relatives that the A allele of SNP-43 was associated with a large waist circumference, and high insulin levels in an OGTT. CONCLUSIONS/INTERPRETATION: SNP-43 of CAPN10 may contribute to the risk of diabetes by regulating abdominal obesity in subjects with high risk of type 2 diabetes.

Levofloxacin does not decrease mortality in Staphylococcus aureus bacteraemia when added to the standard treatment: a prospective and randomized clinical trial of 381 patients.

OBJECTIVES: To study whether levofloxacin, added to standard treatment, could reduce the high mortality and complication rates in Staphylococcus aureus bacteraemia. DESIGN: A prospective randomized multicentre trial from January 2000 to August 2002. SETTING: Thirteen tertiary care or university hospitals in Finland. SUBJECTS: Three hundred and eighty-one adult patients with S. aureus bacteraemia. Patients with meningitis, and those with fluoroquinolone- or methicillin-resistant S. aureus were excluded. INTERVENTIONS: Standard treatment (mostly semisynthetic penicillin) (n = 190) or that combined with levofloxacin (n = 191). Supplementary rifampicin was recommended if deep infection was suspected. MAIN OUTCOME MEASURES: Primary end-points were mortality at 28 days and at 3 months. Clinical and laboratory parameters were analysed as secondary end-points. RESULTS: Adding levofloxacin to the standard treatment offered no survival benefit. Case fatality rates were 14% in both groups at 28 days, and 21% in the standard treatment and 18% in the levofloxacin group at 3 months. Levofloxacin combination did not differ from the standard treatment in the number of complications, time to defervescence, decrease in serum C-reactive protein concentration or length of antibiotic treatment. Deep infection was found in 84% of patients within 1 week following randomization with no difference between the treatment groups. At 3 months, the case fatality rate for patients with deep infection was 17% amongst those who received rifampicin versus 38% for those without rifampicin (P < 0.001, odds ratio = 3.06, 95% confidence intervals = 1.69-5.54). CONCLUSIONS: Levofloxacin combined with standard treatment in S. aureus bacteraemia did not decrease mortality or the incidence of deep infections, nor did it speed up recovery. Interestingly, deep infections in S. aureus bacteraemia appeared to be more common than previously reported.

High amount of visceral fat mass is associated with multiple metabolic changes in offspring of type 2 diabetic patients.

OBJECTIVE: To investigate the relative contribution of total body fat mass (TFM) and intra-abdominal fat mass (IAFM) to metabolic consequences of obesity in offspring of type 2 diabetic parents. DESIGN: Cross-sectional study of 129 nondiabetic offspring of diabetic parents (59 men, 70 women, age 35.7 +/- 6.3 y, body mass index 26.2 +/- 4.6 kg/m2). Study subjects were grouped according to TFM (assessed with bioelectrical impedance) and IAFM (assessed with CT). Insulin sensitivity was assessed with the euglycemic hyperinsulinemic clamp, insulin secretion with the intravenous glucose tolerance test and energy expenditure with indirect calorimetry. Furthermore, C-reactive protein (CRP) and adiponectin levels were measured. RESULTS: Insulin resistance, low rates of oxidative and nonoxidative glucose disposal, high rates of lipid oxidation and reduced energy expenditure during hyperinsulinemia were associated with high IAFM, independently of TFM. Adiponectin level was reduced and CRP level increased in subjects with high IAFM. CONCLUSIONS: The metabolic changes relating to obesity are largely attributable to high IAFM, and are present even in normal weight subjects with high IAFM.

A 100-kDa urinary protein is associated with insulin resistance in offspring of type 2 diabetic patients.

AIMS/HYPOTHESIS: One-third of normoalbuminuric type 1 diabetic patients show immunoreactive nephrin in urine. Offspring of type 2 diabetic patients are insulin-resistant and susceptible to the development of diabetes. We investigated whether the offspring of type 2 diabetic patients show nephrin in urine and whether possible nephrinuria is associated with insulin resistance. METHODS: Urinary proteins from timed overnight urine collections from 128 offspring of type 2 diabetic patients and 9 control subjects were analysed by western blotting using an antibody against nephrin. Glucose metabolism was assessed by OGTT and IVGTT and the euglycaemic-hyperinsulinaemic clamp technique. RESULTS: Of the offspring, 12.5% were strongly and 14.1% weakly positive for a 100-kDa urinary protein. All controls were negative. During the first 10 min of an IVGTT, the offspring strongly positive for the urinary protein had a higher insulin response than the offspring without the protein (3,700 vs 2,306 pmol l(-1)min(-1), p=0.007). Insulin sensitivity (the rate of whole-body glucose uptake divided by the steady-state insulin level x 100) was lower among the offspring strongly positive for the urinary protein than among the offspring negative for the protein (11.3 vs 15.8 micromol kg(-1)min(-1)pmol(-1)l(-1), p=0.008). CONCLUSIONS/INTERPRETATION: A 100-kDa urinary protein detectable with a nephrin antibody is associated with insulin resistance in offspring of type 2 diabetic patients.

Trends and outcome of nosocomial and community-acquired bloodstream infections due to Staphylococcus aureus in Finland, 1995-2001.

In Finland, Staphylococcus aureus bloodstream infections are caused predominantly (>99%) by methicillin-sensitive strains. In this study, laboratory-based surveillance data on Staphylococcus aureus bloodstream infections occurring in Finland from 1995 to 2001 were analyzed. Preceding hospitalizations for all persons with Staphylococcus aureus bloodstream infections were obtained from the national hospital discharge registry, and data on outcome was obtained from the national population registry. An infection was defined as nosocomial when a positive blood culture was obtained more than 2 days after hospital admission or within 2 days of admission if there was a preceding hospital discharge within 7 days. A total of 5,045 cases were identified. The annual incidence of Staphylococcus aureus bloodstream infection rose by 55%, from 11 per 100,000 population in 1995 to 17 in 2001. The increase was detected in all adult age groups, though it was most distinct in patients >74 years of age. Nosocomial infections accounted for 51% of cases, a proportion that remained unchanged. The 28-day death-to-case ratio ranged from 1% in the age group 1-14 years to 33% in patients >74 years of age. The 28-day death-to-case ratios for nosocomial and community-acquired infections were 22% and 13%, respectively, and did not change over time. The increase in incidence among elderly persons resulted in an increase in the annual rate of mortality associated with Staphylococcus aureus bloodstream infections, from 2.6 to 4.2 deaths per 100,000 population per year. Staphylococcus aureus bloodstream infections are increasing in Finland, a country with a very low prevalence of methicillin resistance. While the increase may be due in part to increased reporting, it also reflects a growing population at risk, affected by such factors as high age and/or severe comorbidity.

Haplotypes of PPARGC1A are associated with glucose tolerance, body mass index and insulin sensitivity in offspring of patients with type 2 diabetes.

AIMS/HYPOTHESIS: Decreased expression of the peroxisomal proliferator activated receptor gamma coactivator 1 alpha gene (PPARGC1A) is found in patients with type 2 diabetes, and variants in this gene have been linked with type 2 diabetes. Therefore, we investigated the effects of single nucleotide polymorphisms in PPARGC1A on body composition and glucose tolerance and on insulin sensitivity and secretion. METHODS: Non-diabetic offspring (n=156, age 34.9+/-0.5 years [mean+/-SEM], BMI 26.2+/-0.4 kg/m2) underwent an OGTT and an IVGTT and the hyperinsulinaemic-euglycaemic clamp. The promoter and coding regions of PPARGC1A were sequenced. RESULTS: Two haplotype blocks in PPARGC1A were observed, one in the promoter region (G-1774A, A-1679G, T-1422C, A-1278G, C-543A) and one in the coding region and 3' regions (Thr394Thr, Asp475Asp, Gly482Ser, Thr528Thr, Thr612Met, G+2381A). The coding region haplotype carrying the rare allele in codons 482 and 528 was associated with elevated glucose levels in an OGTT (p=0.024, adjusted for age, sex and BMI) and a haplotype carrying the rare alleles in codons 394 and 475 was associated with low BMI (p=0.033), high rates of whole-body glucose uptake (p=0.045) and low glucose levels in the OGTT (p=0.037). CONCLUSIONS/INTERPRETATION: We conclude that PPARGC1A is likely to contribute to the risk of diabetes in offspring of patients with type 2 diabetes.