Phase I studies of the safety, tolerability, pharmacokinetics and pharmacodynamics of the dual glucagon receptor/glucagon-like peptide-1 receptor agonist BI 456906.

AIM: To report two phase I studies of the novel subcutaneous glucagon-like peptide-1 receptor/glucagon receptor (GLP-1R/GCGR) dual agonist BI 456906 versus placebo in healthy volunteers and people with overweight/obesity. MATERIALS AND METHODS: A phase Ia study (NCT03175211) investigated single rising doses (SRDs) of BI 456906 in 24 males with a body mass index (BMI) of 20-<30 kg/m2 . A phase Ib study (NCT03591718) investigated multiple rising doses (MRDs) of BI 456906 (escalated over 6 [Part A] or 16 [Part B] weeks) in 125 adults with a BMI of 27-40 kg/m2 . RESULTS: In the SRD study (N = 24), mean body weight decreased with increasing BI 456906 dose. In the MRD study, the maximum decreases in placebo-corrected mean body weight were at week 6 (-5.79%, dosage schedule [DS] 1; Part A) and week 16 (-13.8%, DS7; Part B). BI 456906 reduced plasma amino acids and glucagon, indicating target engagement at GCGRs and GLP-1Rs. Drug-related adverse events (AEs) increased with BI 456906 dose. The most frequent drug-related AE with SRDs was decreased appetite (n = 9, 50.0%), and two subjects (8.3%) did not complete the trial because of AEs (nausea and vomiting). During MRD Part A (N = 80), 10 subjects (12.5%) discontinued BI 456906, most commonly because of a cardiac or vascular AE (n = 6, 7.5%); during Part B (N = 45), eight subjects (17.8%) discontinued BI 456906, mainly because of AEs (n = 6, 13.3%), most commonly gastrointestinal disorders. CONCLUSIONS: BI 456906 produced a placebo-corrected body weight loss of 13.8% (week 16), highlighting its potential to promote clinically meaningful body weight loss in people with overweight/obesity.

The effects of transient receptor potential cation channel inhibition by BI 1358894 on cortico-limbic brain reactivity to negative emotional stimuli in major depressive disorder.

Abnormal emotional processing in major depressive disorder (MDD) has been associated with increased activation to negative stimuli in cortico-limbic brain regions. The authors investigated whether treatment with BI 1358894, a small-molecule inhibitor of the transient receptor potential cation channel subfamily C leads to attenuated activity in these areas in MDD patients. 73 MDD patients were randomized to receive a single oral dose of BI 1358894 (100 mg), citalopram (20 mg), or matching placebo. Brain responses to emotional faces and scenes were investigated using functional magnetic resonance imaging. Primary endpoints were BOLD signal changes in response to negative faces in cortico-limbic brain regions, i.e. bilateral amygdala (AMY), dorsolateral prefrontal cortex, anterior insula (AI), and anterior cingulate cortex. Secondary endpoints were BOLD signal changes in response to negative scenes. For each region, separate ANOVA models were computed for the comparison of treatments (BI 1358894 or citalopram) vs. placebo. The adjusted treatment differences in the % BOLD signal changes in the faces task showed that BI 1358894 induced signal reduction in bilateral AMY and left AI. In the scenes task, BI 1358894 demonstrated significant signal reduction in bilateral AMY, AI, anterior cingulate cortex and left dorsolateral prefrontal cortex. Citalopram failed to induce any significant reductions in BOLD signal in both tasks. BI 1358894-mediated inhibition of the transient receptor potential cation channel subfamily resulted in strong signal reduction in cortico-limbic brain regions, thereby supporting development of this mechanism of action for MDD patients.

In vitro responsiveness of human muscle cell peroxisome proliferator-activated receptor δ reflects donors' insulin sensitivity in vivo.

BACKGROUND: Peroxisome proliferator-activated receptor δ (PPARδ) activation enhances muscular fatty acid oxidation and oxidative phosphorylation, and muscle's oxidative capacity positively associates with whole-body insulin sensitivity. Therefore, we asked here whether human muscle cell PPARD expression is a determinant of donors' insulin sensitivity. MATERIALS AND METHODS: Skeletal muscle cells derived from 38 nondiabetic donors were differentiated in vitro to myotubes, and gene (mRNA) expression was quantified by real-time RT-PCR. Donors' insulin sensitivity was calculated from plasma insulin and glucose levels during oral glucose tolerance test (OGTT) and hyperinsulinemic-euglycemic clamp. RESULTS: Basal myotube PPARD expression was closely related to the expression of its target genes PDK4 and ANGPTL4 (P = 0·0312 and P = 0·0003, respectively). Basal PPARD, PDK4 and ANGPTL4 expression levels were not associated with donors' insulin sensitivity (P > 0·2, all). Treatment of myotubes with a selective high-affinity PPARδ agonist (GW501516) did not change mean PPARD, but enhanced mean PDK4 and ANGPTL4 expression 13- and 16-fold, respectively (P < 0·0001, both). The individual PDK4 and ANGPTL4 expression levels reached upon GW501516 treatment were associated with donors' insulin sensitivity neither (P > 0·2, both). However, GW501516-mediated fold increments in PDK4 and ANGPTL4 expression, reflecting PPARδ responsiveness, were positively associated with donors' insulin sensitivity derived from OGTT (P = 0·0182 and P = 0·0231, respectively) and hyperinsulinemic-euglycemic clamp (P = 0·0046 and P = 0·0258, respectively). CONCLUSIONS: Using a highly selective pharmacological tool, we show here that the individual responsiveness of human muscle cell PPARδ, rather than the absolute PPARD expression level, represents a major determinant of insulin sensitivity.

Morning to evening changes of intramyocellular lipid content in dependence on nutrition and physical activity during one single day: a volume selective 1H-MRS study.

OBJECT: Intramyocellular lipids (IMCL) were shown to be metabolically highly active. In order to get insight into short-term regulation of IMCL and to reveal related problems with standardization in metabolic studies using the common signal ratio IMCL/Cr3, relative concentration changes from morning to evening in the same day were examined under four different nutritional and exercise conditions. MATERIAL AND METHODS: Twelve healthy male volunteers participated in an interventional program, comprising single days of fasting (F), low-caloric/low-fat diet (LC), or high-caloric/high-fat diet (HC), combined with low physical activity. A forth day course consisted of unchanged nutrition and extensive exercise (EX). (1)H-MRS of tibialis anterior (TA) and soleus muscle (SOL) was performed on a 3 T whole-body imager in the early morning and 12 h later after the intervention applying a single voxel STEAM technique. RESULTS: Interventions resulted in a clear reduction of IMCL/ Cr3 after F (IMCL/Cr3(TA): -28.1 ± 4.9%, IMCL/Cr3(SOL): -21.0 ± 3.7%) and EX (IMCL/Cr3(TA): -33.9 ± 4.9%, IMCL/Cr3(SOL): -18.3 ± 3.9%). LC led to slightly decreased IMCL/Cr3 ratio in the evening (IMCL/Cr3(TA): -8.7 ± 4.4%, IMCL/Cr3(SOL): -7.3 ± 2.7%), whereas negligible changes were detectable after HC (IMCL/Cr3(TA): + 0.6 ± 2.3%, IMCL/Cr3L(SOL): -0.2 ± 1.3%). CONCLUSION: Only high-caloric/high-fat diet combined with low physical activity led to nearly unchanged IMCL/Cr3 ratios in the evening when compared to corresponding measurements in the morning. In contrast, low-caloric/low-fat diet and especially fasting led to increasingly depleted IMCL stores in the evening. This depletion seems to be further emphasized by increased physical activity. An interesting aspect is the marked reduction of IMCL/Cr3 after 12 h of fasting, since a dramatic increase in IMCL has been reported after starvation over several days. Results of this study imply that highly standardized conditions regarding diet and physical activity are necessary for a proper assessment of IMCL data in metabolic studies.

Follow-up whole-body assessment of adipose tissue compartments during a lifestyle intervention in a large cohort at increased risk for type 2 diabetes.

PURPOSE: To assess adipose body compartments with magnetic resonance (MR) imaging and MR spectroscopy during a lifestyle intervention program that included optimized nutrition and controlled physical activity in subjects at increased risk for type 2 diabetes to determine factors that may help predict an increase in insulin sensitivity following the intervention. MATERIALS AND METHODS: This prospective study was approved by the local review board. All participants gave written informed consent. MR imaging and MR spectroscopy were performed in 243 subjects (99 men and 144 women) before and 9 months after enrollment in a lifestyle intervention program. The results of whole-body MR imaging were used to calculate tissue profiles, differentiating between adipose tissue--especially visceral adipose tissue--and lean tissue. The concentration of hepatic lipids and intramyocellular lipids in the anterior tibial and soleus muscles was determined with MR spectroscopy, and insulin sensitivity was estimated by using an oral glucose tolerance test. The Student t test was used to assess differences between groups, and multivariate regression models were used to assess the value of adipose tissue compartments in the prediction of insulin sensitivity. RESULTS: Compared with women, men had almost twice the amount of visceral adipose tissue and a smaller amount of total adipose tissue (25.9% for men and 36.9% for women) at baseline. In addition, their insulin sensitivity was significantly lower than that of women. The most pronounced changes in adipose tissue were detected for visceral adipose tissue (from 4.9 L to 4.1 L [ie, -15.1%] in men and from 2.3 L to 1.9 L [ie, -15.8%] in women) and hepatic lipids (from 8.6% to 5.4% [ie, -36.8%] in men and from 5.1% to 4.3% [ie, -16.5%] in women). The mean insulin sensitivity improved significantly (from 11.3 arbitrary units [au] to 14.6 au [ie, +29.9%] in men and from 13.6 au to 14.6 au [ie, +7.5%] in women), with 70 of the 99 men (71%) and 84 of 144 women (58%) showing an increase in insulin sensitivity. In men, low concentrations of visceral adipose tissue, hepatic lipids, and abdominal subcutaneous fat at baseline were predictive of successful intervention in terms of changes in insulin sensitivity; in women, only low hepatic lipid levels were significantly predictive of successful intervention. CONCLUSION: Visceral adipose tissue and hepatic lipids, as assessed with MR imaging and MR spectroscopy, can be significantly reduced during lifestyle intervention. Their baseline values emerged as predictive factors for an improvement of insulin sensitivity.

Association of obesity risk SNPs in PCSK1 with insulin sensitivity and proinsulin conversion.

BACKGROUND: Prohormone convertase 1 is involved in maturation of peptides. Rare mutations in gene PCSK1, encoding this enzyme, cause childhood obesity and abnormal glucose homeostasis with elevated proinsulin concentrations. Common single nucleotide polymorphisms (SNPs) within this gene, rs6232 and rs6235, are associated with obesity. We studied whether these SNPs influence the prediabetic traits insulin resistance, beta-cell dysfunction, or glucose intolerance. METHODS: We genotyped 1498 German subjects for SNPs rs6232 and rs6235 within PCSK1. The subjects were metabolically characterized by oral glucose tolerance test with glucose, insulin, proinsulin, and C-peptide measurements. A subgroup of 512 subjects underwent a hyperinsulinemic-euglycemic clamp. RESULTS: The minor allele frequencies were 25.8% for SNP rs6235 and 6.0% for rs6232. After adjustment for sex and age, we found no association of SNPs rs6235 and rs6232 with BMI or other weight-related traits (all p >or= 0.07). Both minor alleles, adjusted for sex, age, BMI and insulin sensitivity were associated with elevated AUCproinsulin and AUCproinsulin/AUCinsulin (rs6235: p(additive) model or= 0.08). The minor allele of SNP rs6232 was additionally associated with 15% higher OGTT-derived and 19% higher clamp-derived insulin sensitivity (pdom

Evaluation of the efficacy, safety and tolerability of orally administered BI 409306, a novel phosphodiesterase type 9 inhibitor, in two randomised controlled phase II studies in patients with prodromal and mild Alzheimer's disease.

BACKGROUND: There are currently no approved treatments for the prodromal stage of Alzheimer's disease (AD). Approved symptomatic treatments for mild-to-moderate AD include acetylcholinesterase inhibitors and memantine, but more efficacious treatments are needed. BI 409306 is a potent and selective phosphodiesterase 9 inhibitor assessed for the symptomatic treatment of AD. Efficacy and safety of BI 409306 was analysed in two phase II proof-of-concept clinical trials in cognitive impairment associated with prodromal AD (study 1) and mild AD (study 2). METHODS: Two multicentre, double-blind, parallel-group, randomised controlled phase II studies were conducted (North America/Europe). Following study run-in, eligible subjects were randomised to one of four oral doses of BI 409306 (10-50 mg daily) or placebo (1:1:1:1:2 ratio) for 12 weeks. The primary efficacy endpoint was the change from baseline in Neuropsychological Test Battery (NTB) total z-score after 12 weeks' treatment. Secondary efficacy assessments included change from baseline in Clinical Dementia Rating scale-Sum of Boxes (CDR-SB), Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-Cog11) and Alzheimer's Disease Cooperative Study-Activities of Daily Living scale (ADCS-ADL; mild cognitive impairment [MCI] version for prodromal patients) after 12 weeks' treatment. Safety and tolerability assessments included adverse event reporting and vital sign monitoring. Change from baseline in NTB total z-score (primary endpoint) and CDR-SB were analysed using the restricted maximum likelihood-based mixed-effects model with repeated measurement. An analysis of covariance model was used to assess other secondary endpoints. RESULTS: Four hundred fifty-seven patients were randomised (study 1 for prodromal AD, N = 128; study 2 for mild AD, N = 329); 427 (93.4%) completed. A prespecified pooled analysis of the primary endpoint revealed no significant changes in NTB total composite z-score at week 12 in the BI 409306 treatment groups compared with placebo, with similar findings observed in the individual studies. The analysis of all secondary endpoints, including pooled analysis of CDR-SB and ADAS-Cog11, ADCS-MCI-ADL (study 1), ADCS-ADL (study 2), also gave no indication of a treatment benefit for BI 409306, compared with placebo. BI 409306 was well tolerated. CONCLUSIONS: Overall, the data do not demonstrate efficacy of BI 409306 in improving cognition in patients with prodromal and mild AD. BI 409306 is well tolerated. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02240693 and NCT02337907 . Registered 15 September 2014 and 09 January 2015, respectively.

Variations in PPARD determine the change in body composition during lifestyle intervention: a whole-body magnetic resonance study.

CONTEXT: We recently demonstrated that single-nucleotide polymorphisms (SNPs) in the peroxisome proliferator-activated receptor-delta gene (PPARD), i.e. rs1053049, rs6902123, and rs2267668, affect the improvement of mitochondrial function, aerobic physical fitness, and insulin sensitivity by lifestyle intervention (LI). OBJECTIVE: The objective of the study was to determine whether the aforementioned PPARD SNPs influence the change in body composition and ectopic fat storage during LI. DESIGN: A total of 156 subjects at an increased risk for type 2 diabetes were genotyped for rs1053049, rs6902123, and rs2267668 and participated in a LI program. Body fat depots, ectopic liver fat, and muscle volume of the leg were quantified using magnetic resonance spectroscopy and imaging. RESULTS: With regard to body composition, carriers of the minor SNP alleles displayed reduced responses to LI, i.e. LI-induced reduction in adipose tissue mass (nonvisceral adipose tissue: rs1053049, P = 0.02; rs2267668, P = 0.04; visceral adipose tissue: rs1053049, P = 0.01) and hepatic lipids (rs1053049, P = 0.04; rs6902123, P = 0.001; independent of changes in adiposity) as well as LI-induced increase in relative muscle volume of the leg (rs1053049, P = 0.003; rs2267668, P = 0.009) were less pronounced in homo- and heterozygous carriers of the minor alleles as compared with homozygous carriers of the major alleles. CONCLUSION: SNPs rs1053049, rs6902123, and rs2267668 in PPARD affect LI-induced changes in overall adiposity, hepatic fat storage, and relative muscle mass. Our findings provide a mechanistic explanation for the involvement of these genetic variations in the development of insulin resistance and type 2 diabetes.

Genetic variations in PPARD and PPARGC1A determine mitochondrial function and change in aerobic physical fitness and insulin sensitivity during lifestyle intervention.

CONTEXT: Mitochondrial function is associated with aerobic physical fitness and insulin sensitivity and may play an important role in the pathophysiology of type 2 diabetes. Peroxisome proliferator-activated receptor (PPAR)-delta (gene PPARD) and PPARgamma coactivator 1alpha (gene PPARGC1A) are determinants of mitochondrial function in animals and in vitro. OBJECTIVE: The objective of this study was to establish whether single-nucleotide polymorphisms (SNPs) in PPARD and PPARGC1A modulate the effect of exercise training on change in aerobic physical fitness and insulin sensitivity and whether they affect mitochondrial function in human myotubes in vitro. SETTING: The study setting was the Tuebingen Lifestyle Intervention Program in a university teaching hospital. RESULTS: After 9 months of intervention, the minor G allele of SNP rs2267668 in PPARD and the minor serine-encoding allele of the common Gly482Ser SNP in PPARGC1A were independently associated with less increase in individual anaerobic threshold (n = 136, P = 0.002 and P = 0.005), a precise measurement of aerobic physical fitness. Moreover, individual anaerobic threshold (+11%) and insulin sensitivity (+4%) increased less in subjects carrying the minor alleles at both SNPs (X/G-X/Ser), compared with homozygous carriers of the major alleles (A/A-Gly/Gly, +120% and +40%; P < 0.0001 and P = 0.015), suggesting an additive effect of the SNPs. In addition, low skeletal muscle mitochondrial function in vitro was detected in young carriers of the G allele of the SNP rs2267668 in PPARD (n = 19, P = 0.02). CONCLUSIONS: These data provide evidence that the rs2267668 A/G SNP in PPARD and the Gly482Ser SNP in PPARGC1A have both independent and additive effects on the effectiveness of aerobic exercise training to increase aerobic physical fitness and insulin sensitivity.

Hypomagnesemia and nephrocalcinosis in a patient with two heterozygous mutations in the CLDN16 gene.

We report the case of a 20-year-old male Caucasian patient with diagnosed nephrocalcinosis and a medical history of seizures and recurrent urinary tract infections. Laboratory investigations revealed clinical and biochemical abnormalities characteristic of familial hypomagnesemia with hypercalciuria and nephrocalcinosis (FHHNC). Since FHHNC is caused by mutations in the CLDN16 gene encoding a renal tight junction protein, we sequenced the complete coding region of this gene and detected two heterozygous mutations, the known Leu151Phe (+453G-->T) mutation and a novel Cys120Arg (+358T-->C) mutation. Due to their location within the primary structure of Claudin-16, both mutations are suggested to interfere with renal paracellular magnesium conductance.

Iodine-induced thyrotoxicosis after ingestion of kelp-containing tea.

Complementary medication is en vogue and an increasing number of patients consume herbal medicine without reporting their use to physicians. We report a case of iodine-induced hyperthyroidism due to the ingestion of a kelp-containing tea. A 39-year-old woman with multinodular goiter presented with typical signs of hyperthyroidism, which was confirmed by endocrine tests. She was not exposed to iodinated radiocontrast media and did not take medications containing iodine, such as amiodarone. However, a detailed medical history revealed that she had been treated for a period of 4 weeks by a Chinese alternative practitioner with a herbal tea containing kelp because of her enlarged thyroid. The consumption of the tea was discontinued and an antithyroid drug therapy was initiated. Physicians should advise patients with underlying thyroid disease to avoid all complementary or alternative medications containing iodine.

The -913 G/A glutamine:fructose-6-phosphate aminotransferase gene polymorphism is associated with measures of obesity and intramyocellular lipid content in nondiabetic subjects.

Increases in glutamine:fructose-6-phosphate aminotransferase (GFAT) protein levels directly activate flux through the hexosamine biosynthetic pathway. This pathway has been involved as a fuel sensor in energy metabolism and development of insulin resistance. We screened the 5'-flanking region of the human GFAT gene for polymorphisms and subsequently genotyped 412 nondiabetic, metabolically characterized Caucasians for the two single-nucleotide polymorphisms (SNP) at positions -913 (G/A) and -1412 (C/G) with rare allele frequencies of 42% and 16%, respectively. The -913 G SNP was associated with significantly higher body mass index and percent body fat in men (P = 0.02 and 0.004, respectively), but not in women (P = 0.47 and 0.26, respectively). In the subgroup of individuals (n = 193) who underwent hyperinsulinemic-euglycemic clamp, an association of the -913 G SNP with insulin sensitivity independent of body mass index was not detected. Moreover, the -913 G allele in a group of 71 individuals who had undergone magnetic resonance spectroscopy was associated with higher intramyocellular lipid content (IMCL) in tibialis anterior muscle (4.21 +/- 0.31 vs. 3.36 +/- 0.35; P = 0.04) independent of percent body fat and maximal aerobic power. The -1412 SNP had no effect on percent body fat, insulin sensitivity, or IMCL. In conclusion, we identified two polymorphisms in the 5'-flanking region of GFAT, of which the -913 SNP seems to alter the risk for obesity and IMCL accumulation in male subjects.

Plasma adiponectin concentrations predict insulin sensitivity of both glucose and lipid metabolism.

In animals, the adipocyte-derived hormone adiponectin has been shown to improve insulin sensitivity, a key factor in the pathogenesis of type 2 diabetes. In Pima Indians, high plasma adiponectin levels are associated with increased insulin sensitivity and reduced risk of type 2 diabetes. It is unclear whether this is also the case in white individuals and whether an additional beneficial effect on lipid metabolism exists. We therefore analyzed in nondiabetic individuals the associations between plasma adiponectin concentrations and insulin sensitivity measured by a euglycemic-hyperinsulinemic clamp (n = 262) and estimated by an oral glucose tolerance test (OGTT; n = 636) and serum lipid parameters using correlational analysis. Plasma adiponectin concentrations were positively correlated with insulin sensitivity, both measured with the clamp (r = 0.28, P = 0.0015 in women; r = 0.42, P < 0.0001 in men) and estimated from the OGTT (r = 0.37, P < 0.0001 in women; r = 0.41, P < 0.0001 in men) before and after adjusting for sex and percentage of body fat (all P < 0.001). Fasting triglycerides and the free fatty acid (FFA) concentrations during the OGTT (area under the curve) and at 120 min were negatively correlated in both women and men, whereas HDL was positively correlated with plasma adiponectin concentrations (all P < 0.004). Most notable, these relationships remained significant after adjusting for insulin sensitivity of glucose disposal in addition to sex and percentage of body fat (all P < 0.05). In conclusion, high adiponectin predicts increased insulin sensitivity. This relationship is independent of low body fat mass and affects not only insulin-stimulated glucose disposal but also lipoprotein metabolism and insulin-mediated suppression of postprandial FFA release. This suggests pleiotropic insulin sensitizing effects of adiponectin in humans.

Reduced skeletal muscle oxygen uptake and reduced beta-cell function: two early abnormalities in normal glucose-tolerant offspring of patients with type 2 diabetes.

OBJECTIVE: Studies on insulin sensitivity and insulin secretion in subjects with a familial predisposition for type 2 diabetes mellitus (T2DM) traditionally produce inconsistent results. This may be due to small sample size, subject selection, matching procedures, and perhaps lack of a measure of physical fitness. RESEARCH DESIGN AND METHODS: In the present study, we specifically tested the hypothesis that a family history of T2DM is associated with reduced VO(2max), measured by incremental bicycle ergometry, independent of insulin sensitivity estimated from an oral glucose tolerance test (OGTT; n = 424) and measured by a euglycemic-hyperinsulinemic clamp (n = 185). Subjects included in the study were young (34 +/- 10 years), healthy, and normal glucose tolerant with either a first-degree relative (FDR) with T2DM (n = 183), a second-degree relative with T2DM (n = 94), or no family history of T2DM (control subjects, n = 147). BMI, percent body fat, waist-to-hip ratio (WHR), and habitual physical activity (HPA; standard questionnaire) were comparable among groups. FDRs had significantly lower VO(2max) than control subjects: 40.5 +/- 0.6 vs. 45.2 +/- 0.9 ml O(2)/kg lean body mass, P = 0.01 after adjusting for sex, age, BMI, HPA, and insulin sensitivity (euglycemic-hyperinsulinemic clamp). RESULTS: BMI, percent body fat, waist-to-hip ratio (WHR), and habitual physical activity (HPA; standard questionnaire) were comparable among groups. FDRs had significantly lower VO(2max) than control subjects: 40.5 +/- 0.6 vs. 45.2 +/- 0.9 ml O(2)/kg lean body mass, P = 0.01 after adjusting for sex, age, BMI, HPA, and insulin sensitivity (euglycemic-hyperinsulinemic clamp). Insulin sensitivity per se was not affected by family history of T2DM after adjusting for age, sex, BMI, and percent body fat (P = 0.76). The appropriateness of beta-cell function for the individual insulin sensitivity (disposition index: product of a validated secretion parameter [OGTT] and sensitivity [clamp]) was significantly lower in FDRs (87 +/- 4 units) versus control subjects (104 +/- 6 units, P = 0.02 after adjusting for sex, age, and BMI). Analyses of the larger OGTT group produced essentially the same results. CONCLUSIONS: In conclusion, these data are compatible with the hypothesis that familial predisposition for T2DM impairs maximal oxygen consumption in skeletal muscle. Because habitual physical activity was not different, genetic factors may be involved. Conceivably, reduced VO(2max) precedes skeletal muscle insulin resistance, providing a partial explanation for discrepancies in the literature.

Metabolic characterization of a woman homozygous for the Ser113Leu missense mutation in carnitine palmitoyl transferase II.

Carnitine palmitoyl transferase (CPT) II is a key enzyme in transporting FFA into the mitochondrial matrix for beta oxidation. The clinical manifestation of CPT II deficiency is characterized mainly by myopathic symptoms. Conceivably, the inability of skeletal muscle to oxidize (long-chain) FFAs could also have far-reaching metabolic consequences, such as insulin resistance secondary to increased muscle lipids, about which relatively little is known. We therefore performed a series of metabolic studies in a 43-yr-old woman homozygous for the Ser113Leu mutation in the CPT II gene, the single most common genetic cause of CPT II deficiency, and compared the results with data from a male and female control group taken from the Tübingen family study database. The metabolic studies included oral glucose tolerance test (OGTT), euglycemic hyperinsulinemic clamp to measure insulin sensitivity, indirect calorimetry to measure substrate oxidation, stable isotopes for determination of glycerol turnover, and magnetic resonance spectroscopy for measurement of intramyocellular lipids. Compared with the female control group, the patient was normal glucose tolerant but severely insulin resistant, basal lipolysis was markedly reduced, and carbohydrate oxidation was maximally increased in the basal state and did not increase further during insulin stimulation. Conversely, lipid oxidation was virtually absent and did not decrease during insulin stimulation. Surprisingly, intramyocellular lipids were well within the range of the control group. In conclusion, genetic CPT II deficiency is characterized by insulin resistance, which is not explained by increased intramyomellular lipids. However, it may be partially explained by glucose oxidation already maximally increased in the basal state, which cannot be increased any further by insulin. Reduced basal lipolysis may represent a compensatory mechanism for the reduced oxidative FFA disposal characteristic for this disease.

Intramyocellular lipids: anthropometric determinants and relationships with maximal aerobic capacity and insulin sensitivity.

The existence of metabolically relevant intramyocellular lipids (IMCL) as assessed by the noninvasive (1)H-magnetic resonance spectroscopy (MRS) has been established. In the present studies, we analyzed the relationships between IMCL in two muscle types [the predominantly nonoxidative tibialis muscle (tib) and the predominantly oxidative soleus muscle (sol)] and anthropometric data, aerobic capacity (VO(2)max, bicycle ergometry, n = 77) and insulin sensitivity (hyperinsulinemic euglycemic clamp, n = 105) using regression analysis. In univariate regression, IMCL (tib) was weakly but significantly correlated with percentage of body fat (r = 0.28, P = 0.01), whereas IMCL (sol) was better correlated with waist-to-hip ratio (r = 0.41, P < 0.0001). No significant univariate correlation with age or maximal aerobic power was observed. After adjusting for adiposity, IMCL (tib) was positively correlated with measures of aerobic fitness. A significant interaction term between VO(2)max and percentage of body fat on IMCL (tib) (P = 0.04) existed (whole model r(2) = 0.26, P = 0.001). In contrast, aerobic fitness did not influence IMCL (sol). No correlation between insulin sensitivity as such and IMCL (tib) (r = -0.13, P = 0.2) or IMCL (sol) (r = 0.03, P = 0.72) was observed. Nethertheless, a significant interaction term between VO(2)max and IMCL on insulin sensitivity existed [P = 0.04 (tib) and P = 0.02 (sol)]; [whole model (sol) r(2) = 0.61, P < 0.0001, (tib) r(2) = 0.60, P < 0.0001]. In conclusion, obesity and aerobic fitness are important determinants of IMCL. IMCL and insulin sensitivity are negatively correlated in untrained subjects. The correlation between the two parameters is modified by the extent of aerobic fitness and cannot be found in endurance trained subjects. Thus, measurements of aerobic fitness and body fat are indispensable for the interpretation of IMCL and its relationship with insulin sensitivity.

Increased insulin clearance in peroxisome proliferator-activated receptor gamma2 Pro12Ala.

The Pro12Ala polymorphism of the peroxisome proliferator-activated receptor (PPARgamma(2)) is associated with reduced risk for type 2 diabetes. Although increased insulin sensitivity of glucose disposal and lipolysis has been reported, the exact mechanism by which the risk reduction is conferred is not clear. Because the conclusion of greater insulin sensitivity hinged upon lower insulin levels in some studies, it is possible that more efficient insulin clearance is involved. We therefore estimated insulin clearance during a euglycemic hyperinsulinemic clamp (insulin infusion rate divided by steady-state insulin concentration, 229 normal glucose tolerant [NGT] subjects), an oral glucose tolerance test (OGTT) (mean C-peptide divided by mean insulin concentrations, 406 NGT, 54 impaired glucose tolerant or mildly diabetic subjects), and a hyperglycemic clamp (120 minutes, 10 mmol/L, C-peptide divided by insulin in the steady-state, 56 NGT subjects). In the carriers of the Ala allele (prevalence approximately 24%), insulin clearance in all 3 protocols was significantly greater ( approximately 10%), than in controls. While the results from the euglycemic clamp reflect both hepatic and peripheral insulin clearance, those from the OGTT and the hyperglycemic clamp reflect mainly hepatic insulin extraction. Free fatty acids (FFA) during the steady state of the euglycemic hyperinsulinemic clamp were significantly lower in carriers of the Ala allele (26 +/- 5 micromol/L) than in controls (46 +/- 3 micromol/L, P =.02). In conclusion, the Pro12Ala polymorphism is associated with increased insulin clearance. This could be the result of reduced FFA delivery, which has been shown to improve hepatic insulin removal and sensitivity. Because PPARgamma(2) is mainly expressed in adipose tissue, one of the main regulatory effects of the polymorphism may well be the more efficient suppression of (possibly intra-abdominal) lipolysis.

Sensitive troponins--which suits better for hemodialysis patients? Associated factors and prediction of mortality.

BACKGROUND: In hemodialysis patients, elevated plasma troponin concentrations are a common finding that has even increased with the advent of newly developed sensitive assays. However, the interpretation and relevance of this is still under debate. METHODS: In this cross-sectional study, we analyzed plasma concentrations of sensitive troponin I (TnI) and troponin T (TnT) in stable ambulatory hemodialysis patients (n = 239) and investigated their associations with clinical factors and mortality. RESULTS: In all of the enrolled patients, plasma TnI or TnT was detectable at a median concentration of 14 pg/ml (interquartile range: 7-29) using the Siemens TnI ultra assay and 49 pg/ml (31-74) using the Roche Elecsys high sensitive TnT assay. Markedly more patients exceeded the 99th percentile for TnT than for TnI (95% vs. 14%, p<0.0001). In a multivariate linear regression model, TnT was independently associated with age, gender, systolic dysfunction, time on dialysis, residual diuresis and systolic blood pressure, whereas TnI was independently associated with age, systolic dysfunction, pulse pressure, time on dialysis and duration of a HD session. During a follow-up period of nearly two years, TnT concentration above 38 pg/mL was associated with a 5-fold risk of death, whereas elevation of TnI had a gradual association to mortality. CONCLUSION: In hemodialysis patients, elevations of plasma troponin concentrations are explained by cardiac function and dialysis-related parameters, which contribute to cardiac strain. Both are highly predictive of increased risk of death.

Active depression is associated with regional adiposity in the upper abdomen and the neck.

OBJECTIVE: In major depression, the incidence of overweight, the risk of type 2 diabetes, as well as cardiovascular disease is increased. Aim was to determine body fat distribution in depressive and healthy females using whole body Magnetic Resonance Imaging (MRI). Measurements of total adipose tissue (TAT), visceral (VAT), and subcutaneous adipose tissue (SCAT) at the trunk and the whole body fat distribution along the body axis were performed and compared. Differences in body fat distribution between depressive and healthy females and their location were evaluated. METHODS: In total, 11 women with a depressive syndrome (major depression, MD) and 45 healthy female volunteers (HC) matched for age and body mass index were compared. Total tissue (TT), TAT, VAT, and SCAT were quantified using T1-weighted whole body MRI. Adipose tissue distribution was compared along the body axis. RESULTS: MD patients showed higher adipose tissue volumes than the HC group. Especially in the upper abdomen, at the upper extremities and the neck, MD patients are characterized by a significantly higher adipose tissue mass compared to the HC group. CONCLUSIONS: The results of this study confirm the hypothesis of a high stress level with a disturbed hypothalamic-pituitary-adrenal (HPA) axis leading to a Cushing-like habitus and high visceral fat levels. The increased fat levels at the arms, as well as the whole body fat may be well-founded by a lack of activity in depression. These effects should be evaluated in further longitudinal studies investigating patients with a depressive syndrome and after remission.

Insulin sensitivity and liver fat: role of iron load.

CONTEXT: Increased liver fat (LF) is associated with insulin resistance. However, a considerable individual variability between LF and insulin sensitivity (IS) is observed, and at equal levels of LF, insulin-resistant as well as insulin-sensitive individuals are found. OBJECTIVE: Our objective was to study whether hepatic iron load (HIL) explains some of the variation between IS and LF. DESIGN: HIL was measured using a quantitative T2* magnetic resonance gradient echo imaging technique, and LF was measured by (1)H-magnetic resonance spectroscopy. Low T2* values indicate high HIL. We studied the association of LF and HIL with anthropometric data and IS. A total of 113 healthy nondiabetic subjects [69 females, 44 males; age 47 ± 1 yr; body mass index (BMI) = 28.9 ± 0.5 kg/m(2)] at increased risk for type 2 diabetes were included in the study. RESULTS: T2* values adjusted for age negatively associated with serum ferritin levels (P < 0.0001) and positively associated with IS (P = 0.009). In addition, T2* values associated with LF (P = 0.008) but not with BMI (P = 0.6). In a multivariate model, IS adjusted for gender, age, and BMI was associated with T2* values (P = 0.015). IS adjusted for gender and age was independently associated with LF (P = 0.033) and T2* values (P = 0.004). In a stepwise regression analysis, LF explained 13.5% (P < 0.01) of the variation in IS, and HIL explained an additional 4.1% (P = 0.03). CONCLUSIONS: HIL explains part of the variation between LF and IS. The mechanism by which iron load induces insulin resistance is possibly independent of the pathways involved in insulin resistance induced by fatty liver disease.