Metformin Associated Lactic Acidosis in Clinical Practice - A Case Series.

AIMS: The aim of this case report is to specify the frequency and mortality of Metformin-Associated Lactic Acidosis (MALA) in emergency medicine, as the diagnosis seems to occur more often than estimated. METHODS: To identify the subjects, we developed screening criteria for MALA. We measured the serum metformin concentration to confirm the diagnosis in all patients fulfilling these criteria. Retrospectively the patients were grouped according to individual risk (according to a defined risk score) and the application of renal replacement therapy. RESULTS: From 2013 until 2018 we were able to identify 11 MALA patients revealing a frequency of 1:4,000 emergency patients. Six patients survived and five died in the follow-up. All three patients in the high-risk group died although all of them received renal replacement therapy. In the low-risk group (three patients, one with renal replacement therapy), all patients survived, while in the intermediate-risk group (five patients, one with renal replacement therapy) three patients survived and two died. Additional severe comorbidities also contributed to mortality. CONCLUSIONS: Every patient matching the screening criteria of acute renal failure, lactic acidosis and continued intake of metformin can be considered a potential MALA case. A risk score assessment which includes severe comorbidities may help to identify high-risk individuals and should be evaluated in larger studies.To prevent MALA, patients should be trained to immediately interrupt their own metformin use when showing signs of volume depletion. Physicians should be aware of the additional risk factors such as co-medication with diuretics, ACE (angiotensin converting enzyme) ACE inhibitors and NSAIDs (non steroidal anti inflammatory drugs).

Brain insulin sensitivity is linked to adiposity and body fat distribution.

Brain insulin action regulates eating behavior and energy fluxes throughout the body. However, numerous people are brain insulin resistant. How brain insulin responsiveness affects long-term weight and body fat composition in humans is still unknown. Here we show that high brain insulin sensitivity before lifestyle intervention associates with a more pronounced reduction in total and visceral fat during the program. High brain insulin sensitivity is also associated with less regain of fat mass during a nine year follow-up. Cross-sectionally, strong insulin responsiveness of the hypothalamus associates with less visceral fat, while subcutaneous fat is unrelated. Our results demonstrate that high brain insulin sensitivity is linked to weight loss during lifestyle intervention and associates with a favorable body fat distribution. Since visceral fat is strongly linked to diabetes, cardiovascular risk and cancer, these findings have implications beyond metabolic diseases and indicate the necessity of strategies to resolve brain insulin resistance.

Elimination of Contrast Agent Gadobutrol with Sustained Low Efficiency Daily Dialysis Compared to Intermittent Hemodialysis.

BACKGROUND: In patients with renal failure, gadolinium-based contrast agents (GBCA) can be removed by intermittent hemodialysis (iHD) to prevent possible toxic effects. There is no data on the efficacy of GBCA removal via sustained low efficiency daily dialysis (SLEDD) which is mainly used in intensive care unit (ICU) patients. METHODS: We compared the elimination of the GBCA gadobutrol in 6 ICU patients treated with SLEDD (6-12 h, 90 L dialysate) with 7 normal ward inpatients treated with iHD (4 h, dialysate flow 500 mL/min). Both groups received 3 dialysis sessions on 3 consecutive days starting after the application of gadobutrol. Blood samples were drawn before and after each session and total dialysate, as well as urine was collected. Gadolinium (Gd) concentrations were measured using mass spectrometry and eliminated Gd was calculated from dialysate and urine. RESULTS: The initial mean plasma Gd concentration was 385 ± 183 µM for the iHD and 270 ± 97 µM for the SLEDD group, respectively (p > 0.05). The Gd-reduction rate after the first dialysis session was 83 ± 9 and 67 ± 9% for the iHD and the SLEDD groups, respectively (p = 0.0083). The Gd-reduction rate after the second and third dialysis was 94-98 and 89-96% for the iHD and the SLEDD groups (p > 0.05). The total eliminated Gd was 89 ± 14 and 91 ± 4% of the dose in the iHD and the SLEDD groups, respectively (p > 0.05). Gd dialyzer clearance was 95 ± 22 mL/min and 79 ± 19 mL/min for iHD and SLEDD, respectively (p > 0.05). CONCLUSIONS: Gd-elimination with SLEDD is equally effective as iHD and can be safely used to remove GBCA in ICU patients.

Urinary Neutrophil Gelatinase-Associated Lipocalin (NGAL) and proteinuria predict severity of acute kidney injury in Puumala virus infection.

BACKGROUND: Nephropathia epidemica (NE) is a mild form of hemorrhagic fever with renal syndrome (HFRS) that is caused by the Puumala virus. Periodic outbreaks have been described in endemic areas, with a substantial number of previously healthy individuals developing acute kidney injury (AKI). There is a considerable diversity in the clinical course of the disease, and few patients require renal replacement therapy. METHODS: We tested whether urinary neutrophil gelatinase associated lipocalin (uNGAL), urine albumin/creatinine ratio (uACR), urine protein/creatinine ratio (uPCR), urine dipstick protein, C-reactive protein, procalcitonin, leukocyte and platelet count, determined on admission to the hospital, can predict the severity of AKI. Sixty-one patients were analyzed during admission in the emergency department. RESULTS: The variables most strongly associated with peak plasma creatinine concentration were uNGAL (ß = 0.70, p <0.0001), uPCR (ß = 0.64, p = 0.001), uACR (ß = 0.61, p = 0.002), and dipstick proteinuria (ß = 0.34, p = 0.008). The highest AUC-ROC to predict stage 3 AKI according to the acute kidney injury network's (AKIN) classification was seen for uNGAL (0.81, p = 0.001). CONCLUSION: uNGAL accurately predicts the severity of AKI in NE. This could help emergency room physicians predict disease severity and allow for initial risk stratification.

Polymorphism rs3123554 in CNR2 reveals gender-specific effects on body weight and affects loss of body weight and cerebral insulin action.

OBJECTIVE: The cannabinoid-receptor system is involved in the regulation of food intake. Here, we test whether single nucleotide polymorphisms (SNPs) in CNR2, encoding the cannabinoid-receptor 2, are associated with weight in a cross-sectional cohort. Furthermore, we wanted to investigate if the identified hits influence weight loss during lifestyle intervention; and study a potential involvement of cerebral insulin action. METHODS: 2006 subjects at increased risk for type 2 diabetes mellitus were genotyped for 5 tagging SNPs in the CNR2 locus. All subjects underwent a 75-g OGTT. 345 subjects participated in a lifestyle intervention (TUebingen Lifestyle Intervention Programme). Cerebrocortical insulin sensitivity was measured by magnetoencephalography after intranasal insulin application in 43 subjects. RESULTS: In the cross-sectional cohort, the minor allele of rs3123554 was associated with lower BMI (Padd = 0.01, Prec = 0.004), and this was attributable to its effect in women only. Interestingly, during lifestyle intervention, carriers of the same allele lost less body weight (Padd = 0.03, Prec = 0.008). Moreover, carriers of this minor allele showed lower cerebral insulin sensitivity (Prec = 0.0402). CONCLUSIONS: The minor allele of rs3123554 is associated cross-sectionally with lower body weight, whereas during intervention the same allele led to less reduction of body weight. Reduced cerebral insulin sensitivity in carriers of this allele might contribute to these disadvantageous effects during lifestyle intervention.

[Rapid progressive glomerulonephritis as a nephrological emergency--case 8/2013]. / Die rapid-progressive Glomerulonephritis als nephrologischer Notfall--Fall 8/2013.

HISTORY AND ADMISSION FINDINGS: We report on a 53-year-old female patient who was admitted to hospital with fever, dyspnoea and arthralgias that was followed by diarrhoea and anuria. Upon respiratory deterioration she was referred to our hospital. INVESTIGATIONS: Urine analysis revealed an active urine sediment and kidney ultrasound showed hyperechoic renal parenchyma. Chest x-ray revealed widespread bilateral opacifications that were further investigated by bronchoscopy. A renal biopsy was performed due to an active urine sediment. DIAGNOSIS, TREATMENT AND COURSE: The patient suffered from pneumonia induced by pulmonary congestion and a newly acquired influenza infection. Histological examination of the kidney biopsy revealed an extracapillary proliferative IgA glomerulonephritis. After stabilization of the pulmonary situation and commencing hemodialysis, immunosuppressive therapy was started including cyclophosphamid. CONCLUSIONS: A rapid-progressive glomerulonephritis represents a nephrological emergency leading to acute kidney injury and dysfunction of other organs.

Leptin affects insulin action in astrocytes and impairs insulin-mediated physical activity.

BACKGROUND/AIMS: Impaired insulin action is an early event in the pathogenesis of obesity and type 2-diabetes, and among the metabolic confounders in obese, hyperleptinaemia is constantly present; however its impact on insulin action in the brain and locomotor activity is unknown. METHODS: We examined insulin action by Western Blot analysis and glycogen synthesis in primary astrocytes and brain tissue and detected locomotion in C57BL/6 mice. The insulin-mediated desire to move was evaluated in healthy volunteers and correlated to leptin levels. RESULTS: Leptin treatment led to a significant decrease in insulin-mediated phosphorylation of the insulin receptor and Akt473 which was accompanied by a decline in glycogen synthesis in primary astrocytes and significantly decreased insulin-induced phosphorylation of the insulin receptor and insulin receptor substrate-2 in brain tissues of mice. Intracerebroventricular insulin failed to promote locomotion in the presence of elevated leptin levels. Lean human subjects reported an increase in the desire to move following insulin which failed in obese and there was an inverse correlation between the insulin-mediated desire to move and leptin levels. CONCLUSIONS: Our data suggest a crosstalk of leptin and insulin in the brain which leads to a decline in locomotor activity. This might represent a molecular mechanism in obese to inhibit physical activity.

Insulin sensitivity of the human brain.

The brain is an insulin sensitive organ and insulin signaling is important to regulate feeding behavior, body weight, and cognitive processes. Insulin resistance in peripheral tissues is a hallmark in the development of type 2 diabetes mellitus (T2DM), yet the finding of insulin resistance in the brain is relatively novel. Studies in humans revealed that environmental factors like obesity, age, and the genetic background have an impact on central insulin sensitivity. According to the physiological effects of insulin in the brain, disturbances of this signaling chain lead to an impairment of cognitive functions and a deterioration of eating behavior with a potential role in the pathogenesis of obesity and T2DM. First attempts to treat insulin resistance not only in peripheral tissues but also in the CNS have therefore come on its way: Cerebral insulin resistance can at least partially be overcome by intranasal treatment with insulin or by commercial insulins that exhibit specific effects in the brain due to their pharmacokinetic properties. Despite the advances towards a better understanding of insulin function in the human brain in the last years, achieving a more profound knowledge of mechanisms behind central insulin function and identifying further strategies to overcome insulin resistance must be a main goal of future research.

An Obesity Risk SNP (rs17782313) near the MC4R Gene Is Associated with Cerebrocortical Insulin Resistance in Humans.

Activation of melanocortin-4 receptor (MC4R) by insulin sensitive neurons is a central mechanism in body weight regulation, and genetic variants in the MC4R gene (e.g., rs17782313) are associated with obesity. By using magnetoencephalography, we addressed whether rs17782313 affects the cerebrocortical insulin response. We measured the cerebrocortical insulin response by using magnetoencephalography in a hyperinsulinemic euglycemic clamp (versus placebo) in 51 nondiabetic humans (26 f/25 m, age 35 ± 3 years, BMI 28 ± 1 kg/m(2)). The C-allele of rs17782313 was minor allele (frequency 23%), and the genotype distribution (TT 30, TC 19, CC 2) was in Hardy-Weinberg-Equilibrium. Insulin-stimulated cerebrocortical theta activity was decreased in the presence of the C-allele (TT 33 ± 16 fT; TC/CC -27 ± 20 fT; P = .023), and this effect remained significant after adjusting for BMI and peripheral insulin sensitivity (P = .047). Cerebrocortical theta activity was impaired in carriers of the obesity risk allele. Therefore, cerebral insulin resistance may contribute to the obesity effect of rs17782313.

The insulin-mediated modulation of visually evoked magnetic fields is reduced in obese subjects.

BACKGROUND: Insulin is an anorexigenic hormone that contributes to the termination of food intake in the postprandial state. An alteration in insulin action in the brain, named "cerebral insulin resistance", is responsible for overeating and the development of obesity. METHODOLOGY/PRINCIPAL FINDINGS: To analyze the direct effect of insulin on food-related neuronal activity we tested 10 lean and 10 obese subjects. We conducted a magnetencephalography study during a visual working memory task in both the basal state and after applying insulin or placebo spray intranasally to bypass the blood brain barrier. Food and non-food pictures were presented and subjects had to determine whether or not two consecutive pictures belonged to the same category. Intranasal insulin displayed no effect on blood glucose, insulin or C-peptide concentrations in the periphery; however, it led to an increase in the components of evoked fields related to identification and categorization of pictures (at around 170 ms post stimuli in the visual ventral stream) in lean subjects when food pictures were presented. In contrast, insulin did not modulate food-related brain activity in obese subjects. CONCLUSIONS/SIGNIFICANCE: We demonstrated that intranasal insulin increases the cerebral processing of food pictures in lean whereas this was absent in obese subjects. This study further substantiates the presence of a "cerebral insulin resistance" in obese subjects and might be relevant in the pathogenesis of obesity.

The temporal sequence of magnetic brain activity for food categorization and memorization--an exploratory study.

The importance of food stimuli for all living organisms is defined by their relevance for survival. Therefore, visual processing of food stimuli is influenced by many factors, such as cultural and societal background. In this magnetoencephalography (MEG) study, we examined the categorization and memorization of visual food and non-food stimuli in lean subjects, using a one-back working memory task. We found an increase in neural activity in several different regions of the brain elicited by food stimuli in comparison to non-food stimuli. The first observed significant difference was found in low-level visual areas as early as 120 ms after stimulus onset. The stimulus category of the previous picture did not influence this effect. However, preceding stimuli modulated behavioral measures (reaction time and accuracy of responses) and later components of the evoked responses around 350 ms. The evoked magnetic field of this late component showed a significant increase inactivity in the temporal cortex for food versus non-food objects. This late component exhibited a significant correlation with the reaction time. The difference of category-specific effects in the early components and the behavioral modulation of late components could be useful for further investigations of the cortical activity in response to food stimuli, e.g. in subjects with eating disorders or obesity.

Insulin modulates food-related activity in the central nervous system.

CONTEXT: Previous data suggest a key role of central nervous insulin action in regulating energy homeostasis. OBJECTIVE: We therefore investigated whether insulin modulates brain responses to food and nonfood pictures in a functional magnetic resonance imaging study. DESIGN AND PATIENTS: Nine healthy, normal-weight subjects underwent two functional magnetic resonance imaging measurements to compare the effects of insulin and placebo administration during a visual recognition task with food and nonfood pictures. Insulin was administered intranasally to raise insulin concentrations in the cerebrospinal fluid without altering systemic effects in the periphery. Metabolic parameters were continuously determined during the experiments. MAIN OUTCOME MEASURE: We measured the changes in brain activity after intranasal insulin administration. RESULTS: Food pictures were detected faster when compared to nonfood pictures in all conditions without any effect of placebo or insulin. After insulin application, functional magnetic resonance imaging measurements showed a significantly reduced activity in the presence of food pictures compared to placebo in the right and left fusiform gyrus, the right hippocampus, the right temporal superior cortex, and the right frontal middle cortex. The brain activation induced by nonfood pictures remained unaffected by insulin. CONCLUSION: We demonstrate that intranasal insulin led to a reduction of activity in brain areas related to object processing and memory and may have an effect on brain activation with regard to the processing of food pictures. This effect might be part of a mechanism that terminates food intake in the postprandial state.

The insulin effect on cerebrocortical theta activity is associated with serum concentrations of saturated nonesterified Fatty acids.

CONTEXT: Insulin action in the brain contributes to adequate regulation of body weight, neuronal survival, and suppression of endogenous glucose production. We previously demonstrated by magnetoencephalography in lean humans that insulin stimulates activity in beta and theta frequency bands, whereas this effect was abolished in obese individuals. OBJECTIVE: The present study aims to define metabolic signals associated with the suppression of the cerebrocortical response in obese humans. DESIGN AND SETTING: We determined insulin-mediated modulation of spontaneous cerebrocortical activity by magnetoencephalography during a hyperinsulinemic euglycemic clamp and related it to measures of ectopic fat deposition and mediators of peripheral insulin resistance. Visceral fat mass and intrahepatic lipid content were quantified by magnetic resonance imaging and spectroscopy. Multiple regression analysis was used to analyze associations of cerebrocortical insulin sensitivity and metabolic markers related to obesity. PARTICIPANTS: Forty-nine healthy, nondiabetic humans participated in the study. RESULTS: In a multiple regression, insulin-mediated stimulation of theta activity was negatively correlated to body mass index, visceral fat mass, and intrahepatic lipid content. Although fasting saturated nonesterified fatty acids mediated the correlations of theta activity with abdominal and intrahepatic lipid stores, adipocytokines displayed no independent correlation with insulin-mediated cortical activity in the theta frequency band. CONCLUSIONS: Thus, insulin action at the level of cerebrocortical activity in the brain is diminished in the presence of elevated levels of saturated nonesterified fatty acids.

Impact of variation near MC4R on whole-body fat distribution, liver fat, and weight loss.

Polymorphisms near the melanocortin-4 receptor (MC4R) gene locus are associated with body weight. Recent studies have shown that they influence insulin sensitivity and incidence of the metabolic syndrome. Thus, we hypothesized that the candidate single-nucleotide polymorphism (SNP) rs17782313 near MC4R additionally influences body fat distribution and its change during lifestyle intervention. To test this, 343 German subjects were genotyped for SNP rs17782313. Body composition was assessed using magnetic resonance technique. Subjects were characterized by an oral glucose tolerance test (OGTT). A subgroup of 242 subjects participated in a 9-month lifestyle intervention. In the overall cohort, the C allele was associated with a higher BMI (P=0.0013), but had no impact on glucose tolerance or insulin sensitivity (all P>or=0.10). There was an effect of the SNP on total body fat (P=0.022) and nonvisceral fat (P=0.017), but not on liver fat and visceral fat (all P>or=0.33). In the subgroup undergoing lifestyle intervention, SNP rs17782313 had no impact on changes in body weight or fat distribution. Despite an association with BMI and nonvisceral adipose tissue, the SNP rs17782313 did not influence visceral adipose tissue. Thus, this candidate SNP for human obesity may preferentially affect the accumulation of subcutaneous adipose tissue. Furthermore, the variation near MC4R has no effect on success of weight loss during lifestyle intervention.

Effect of genetic variation in Kv1.3 on olfactory function.

BACKGROUND: Olfactory function is reduced in aged humans and diabetes mellitus patients. However, little is known about the pathogenic mechanisms leading to olfactory dysfunction. Recently, it has been shown that the voltage-gated potassium channel Kv1.3 is regulated by insulin and is highly expressed in the olfactory bulb. Furthermore, the function of this channel is associated with olfaction in mice and with glucose metabolism in mice and men. We therefore hypothesized that a functionally relevant polymorphism in Kv1.3 might alter olfactory function. METHODS: We investigated a group of 94 healthy subjects (male: n = 58, female: n = 36) for olfactory function and genotyped them for rs2821557 in the human Kv1.3 gene. Olfactory function was tested using standardised sniffing sticks, and parameters of glucose metabolism were assessed. RESULTS: We found a significant olfactory impairment in male homozygous carriers of the Kv1.3 polymorphism rs2821557 (recessive model, p = 0.018, adjusted for age) that could not be determined in female subjects due to the very small number of homozygous minor allele carriers (n = 1). In addition, we found a significant correlation of olfactory dysfunction with higher HbA1c and fasting plasma glucose (p = 0.004 and p = 0.001, both adjusted for age). We also found a loss of olfactory function with age (p = 0.006). Gender, body mass index and insulin sensitivity did not alter smelling function. CONCLUSIONS: The presence of genetic variation in Kv1.3 is associated with decreased olfactory function in healthy subjects. As olfactory function, glucose metabolism and genetic variation in Kv1.3 seem to be associated, further studies are needed to clarify the underlying mechanisms.

SIRT1 genetic variants associate with the metabolic response of Caucasians to a controlled lifestyle intervention--the TULIP Study.

BACKGROUND: Sirtuin1 (SIRT1) regulates gene expression in distinct metabolic pathways and mediates beneficial effects of caloric restriction in animal models. In humans, SIRT1 genetic variants associate with fasting energy expenditure. To investigate the relevance of SIRT1 for human metabolism and caloric restriction, we analyzed SIRT1 genetic variants in respect to the outcome of a controlled lifestyle intervention in Caucasians at risk for type 2 diabetes. METHODS: A total of 1013 non-diabetic Caucasians from the Tuebingen Family Study (TUEF) were genotyped for four tagging SIRT1 SNPs (rs730821, rs12413112, rs7069102, rs2273773) for cross-sectional association analyses with prediabetic traits. SNPs that associated with basal energy expenditure in the TUEF cohort were additionally analyzed in 196 individuals who underwent a controlled lifestyle intervention (Tuebingen Lifestyle Intervention Program; TULIP). Multivariate regressions analyses with adjustment for relevant covariates were performed to detect associations of SIRT1 variants with the changes in anthropometrics, weight, body fat or metabolic characteristics (blood glucose, insulin sensitivity, insulin secretion and liver fat, measured by magnetic resonance techniques) after the 9-month follow-up test in the TULIP study. RESULTS: Minor allele (X/A) carriers of rs12413112 (G/A) had a significantly lower basal energy expenditure (p = 0.04) and an increased respiratory quotient (p = 0.02). This group (rs12413112: X/A) was resistant against lifestyle-induced improvement of fasting plasma glucose (GG: -2.01%, X/A: 0.53%; p = 0.04), had less increase in insulin sensitivity (GG: 17.3%, X/A: 9.6%; p = 0.05) and an attenuated decline in liver fat (GG: -38.4%, X/A: -7.5%; p = 0.01). CONCLUSION: SIRT1 plays a role for the individual lifestyle intervention response, possibly owing to decreased basal energy expenditure and a lower lipid-oxidation rate in rs12413112 X/A allele carriers. SIRT1 genetic variants may, therefore, represent a relevant determinant for the response rate of individuals undergoing caloric restriction and increased physical activity.

Impact of variation in the FTO gene on whole body fat distribution, ectopic fat, and weight loss.

Polymorphisms in the fat mass- and obesity-associated (FTO) gene have been identified to be associated with obesity and diabetes in large genome-wide association studies. We hypothesized that variation in the FTO gene has an impact on whole body fat distribution and insulin sensitivity, and influences weight change during lifestyle intervention. To test this hypothesis, we genotyped 1,466 German subjects, with increased risk for type 2 diabetes, for single-nucleotide polymorphism rs8050136 in the FTO gene and estimated glucose tolerance and insulin sensitivity from an oral glucose tolerance test (OGTT). Distribution of fat depots was quantified using whole body magnetic resonance (MR) imaging and spectroscopy in 298 subjects. Two-hundred and four subjects participated in a lifestyle intervention program and were examined after a follow-up of 9 months. In the cross-sectional analysis, the A allele of rs8050136 in FTO was associated with a higher BMI, body fat, and lean body mass (all P < 0.001). There was a significant effect of variation in the FTO gene on subcutaneous fat (P < or = 0.05) and a trend for liver fat content, nonvisceral adipose tissue, and visceral fat (all P < or = 0.1). However, the single-nucleotide polymorphism was not associated with insulin sensitivity or secretion independent of BMI (all P > 0.05). During lifestyle intervention, there was also no influence of the FTO polymorphism on changes in body weight or fat distribution. In conclusion, despite an association with BMI and whole body fat distribution, variation in the FTO locus has no effect on the success of a lifestyle intervention program.

The CCR2 promoter polymorphism T-960A, but not the serum MCP-1 level, is associated with endothelial function in prediabetic individuals.

Monocyte-chemoattractant-protein (MCP)-1 and its receptor CCR2 have been shown to play a pivotal role in vascular inflammation and atherosclerotic plaque formation. However, it is currently unclear whether MCP-1/CCR2 triggered inflammation affects nitric oxide (NO)-bioavailability, hence influencing vascular function, a sign of early atherosclerosis. Therefore, we sought to investigate the association between serum levels of MCP-1 and NO-bioavailability, expressed as flow mediated dilation (FMD) in vivo, and the impact of CCR2 gene variations on FMD. We studied a German population of 242 prediabetic individuals (144 women, 98 men; mean age 45+/-0.8 years) via FMD by high-resolution ultrasound (13MHz). In order to replicate our findings, a second, independent population (n=115; 44 women, 77 men; mean age 48+/-1.0 years) (total=357 individuals) from Italy was studied. Vascular function in the Italian population was studied via intra-arterial application of acetylcholine. MCP-1 serum-levels were assessed by ELISA and CCR2 polymorphisms were determined by sequencing. MCP-1 serum levels showed no association with FMD (p=0.90), whereas the CCR2 promoter polymorphism was associated with elevated FMD (T/T: 5.6+/-0.3%; T/A: 6.7+/-0.4%; A/A: 8.3+/-0.8%; p=0.01) after adjusting for possible confounders. These results were confirmed in the independent Italian population (A/A: 97.1+/-20.3 vs. T/T: 60.5+/-5.6% forearm blood-flow increase; p<0.05). When testing for the functional relevance of the T-960A (rs3918359) polymorphism, we found that the A/A-genotype was associated with moderately increased protein binding in EMSA, increased promoter activity in luciferase assays and reduced transendothelial monocyte migration. In conclusion, MCP-1 serum levels do not reflect endothelial function in vivo in prediabetic individuals. However, the functionally relevant CCR2 promoter polymorphism T-960A (rs3918359) is associated with elevated vascular function. This might be due to reduced subendothelial inflammation, mediated by reduced transendothelial monocyte-migration ability.

Cerebrocortical beta activity in overweight humans responds to insulin detemir.

BACKGROUND: Insulin stimulates cerebrocortical beta and theta activity in lean humans. This effect is reduced in obese individuals indicating cerebrocortical insulin resistance. In the present study we tested whether insulin detemir is a suitable tool to restore the cerebral insulin response in overweight humans. This approach is based on studies in mice where we could recently demonstrate increased brain tissue concentrations of insulin and increased insulin signaling in the hypothalamus and cerebral cortex following peripheral injection of insulin detemir. METHODOLOGY/PRINCIPAL FINDINGS: We studied activity of the cerebral cortex using magnetoencephalography in 12 lean and 34 overweight non-diabetic humans during a 2-step hyperinsulinemic euglycemic clamp (each step 90 min) with human insulin (HI) and saline infusion (S). In 10 overweight subjects we additionally performed the euglycemic clamp with insulin detemir (D). While human insulin administration did not change cerebrocortical activity relative to saline (p = 0.90) in overweight subjects, beta activity increased during D administration (basal 59+/-3 fT, 1(st) step 62+/-3 fT, 2(nd) step 66+/-5, p = 0.001, D vs. HI). As under this condition glucose infusion rates were lower with D than with HI (p = 0.003), it can be excluded that the cerebral effect is the consequence of a systemic effect. The total effect of insulin detemir on beta activity was not different from the human insulin effect in lean subjects (p = 0.78). CONCLUSIONS/SIGNIFICANCE: Despite cerebrocortical resistance to human insulin, insulin detemir increased beta activity in overweight human subjects similarly as human insulin in lean subjects. These data suggest that the decreased cerebral beta activity response in overweight subjects can be restored by insulin detemir.